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Polyphenol-containing azuki bean (Vigna angularis) extract attenuates blood pressure elevation and modulates nitric oxide synthase and caveolin-1 expressions in rats with hypertension
Abstract
Azuki beans (Vigna angularis) contain polyphenols such as proanthocyanidins that exhibit potential radical scavenging activities. We herein investigated the effects of polyphenol-containing azuki bean extract (ABE) on elevated blood pressure, nitric oxide (NO) production, and expressions of endothelial NO synthase (eNOS), inducible NOS (iNOS), and caveolin-1 proteins in the aorta and kidney of chronically hypertensive rats.
Spontaneously hypertensive rats (SHRs/Izm) with approximately 200 mm Hg systolic blood pressure (SBP) were randomly divided into 2 groups fed either 0% or 0.9% ABE-containing diet. Age-matched normotensive Wistar-Kyoto rats were used as the control. The content of 24-h urinary nitrate/nitrite (NOx) excretion was measured to evaluate NO production. After 8 weeks of treatment, the eNOS, iNOS, and caveolin-1 protein expressions in the aorta and kidney were analyzed by western blotting. The SBP of the ABE-treated SHR was significantly lower than that of the untreated SHR. The level of 24-h urinary NOx excretion was significantly higher in the ABE-treated SHR than in the untreated SHR. The eNOS and iNOS expressions in the aorta and kidney were remarkably upregulated in the untreated SHR but suppressed in the ABE-treated SHR. The vascular and renal caveolin-1 expressions were upregulated in the ABE-treated SHR.
ABE reduced the elevated blood pressure and increased NO production in long-term treatment. It may be associated with the modulation of eNOS and iNOS protein expressions in the aorta and kidney during the development of hypertension.
... In addition, adzuki bean ethanolic extracts attenuated angiogenesis, diabetes, osteoporosis, muscle atrophy, and allergic inflammation, as well as delay in the progression of Alzheimer's disease [19][20][21][22][23]. Having integrated that, black soybeans and adzuki beans have the potential to be applied as functional foods. A few studies conducted the antihypertensive activity of adzuki bean extracts in aspects of macrophage infiltration, vascular oxidative stress, inflammation, blood pressure elevation, and NO production [24][25][26]. However, none of the previous studies have elucidated the antihypertensive activities of black soybeans or adzuki beans regarding the renin-angiotensin system (RAS). ...
... There was no previous in vivo study evaluating the antihypertensive effect of black soybean extracts. In the previous studies to evaluate the antihypertensive effect of adzuki bean extracts, adzuki bean extracts were fed with feed rather than oral gavage [24,25]. Consequently, the experimental doses (250 and 500 mg/kg) of BE and AE were determined based on previous studies related to other physiological activities rather than antihypertensive activity [27,28]. ...
... In our study, BE and AE did not change either the weight or feed intake. According to the previous findings, black soybean pulse powder did not alter body weight and feed intake in SHR [32], and adzuki bean extracts using 80% ethanol also did not change body weight in SHR [24,25]. The liver weight was increased in SHR compared to WKY (p < 0.05), which was rescued in CAP, indicating orderly model induction. ...
Hypertension, causing cardiovascular disease, stroke, and heart failure, has been a rising health issue worldwide. Black soybeans and adzuki beans have been widely consumed throughout history due to various bioactive components. We evaluated the antihypertensive effects of black soybean and adzuki bean ethanol extracts on blood pressure, renin-angiotensin system (RAS), and aortic lesion in spontaneously hypertensive rats. A group of WKY (normal) and six groups of spontaneously hypertensive rats were administered with saline (SHR), 50 mg/kg of captopril (CAP), 250 and 500 mg/kg of black soybean extracts (BE250 and BE500), 250 and 500 mg/kg of adzuki bean extracts (AE250 and AE500) for eight weeks. BE250, BE500, AE250, and AE500 significantly (p < 0.05) reduced relative liver weight, AST, ALT, triglyceride, total cholesterol, systolic blood pressure, and angiotensin-converting-enzyme level compared to SHR. The angiotensin II level in AE500 and renin mRNA expression in BE500 and AE500 were significantly (p < 0.05) decreased compared to SHR. The lumen diameter was significantly (p < 0.05) reduced in only CAP. Furthermore, systolic and diastolic blood pressure and angiotensin II level in AE500 were lower than those of BE500. These results suggest that AE exhibit more antihypertensive potential than BE in spontaneously hypertensive rats.
... The chemical compositions in adzuki bean were 4.9% moisture, 6.7% protein, 17.2% fat, 5.8% ash, and 65.4% carbohydrate, 1.1% dietary fiber, 9.3% total polyphenols and 9% proanthocyanidins (Mukai and Sato, 2009). The compositions per 100 g of manufactured adzuki bean were 4.26 g moisture, 2.89 g protein, 9.50 g water-soluble dietary fiber. ...
... 40% ethanol fraction of hot water extract by Diaion HP-20 column was also reported to lower the levels of blood glucose, serum insulin levels, urinary glucose, urinary microalbumin/ creatinine ratio, liver triacylglycerol, and total cholesterol of spontaneously diabetic KK-A y mice, type 2 diabetes (Itoh et al., 2009a). Mukai and Sato (2009) reported that 80% ethanol extract of adzuki bean attenuated the elevation of blood pressure of spontaneously hypertensive rats. It is consistent with a previous article which reported that adzuki bean extract suppressed the elevation of blood pressure in hypertensive rats (Sato et al., 2008). ...
... It is consistent with a previous article which reported that adzuki bean extract suppressed the elevation of blood pressure in hypertensive rats (Sato et al., 2008). The mechanism of lowereing blood pressure might be due to the increase of nitric oxide production and the decrease of the expressions of endothelial nitric oxide synthase and inducible nitric oxide synthase in the aorta and kidney of hypertensive rats (Mukai and Sato, 2009). ...
Adzuki bean (Vigna angularis) has been not only used as traditional Chinese medicine, but also used as a snack food or confectionery products for thousands of years in China. Adzuki bean is a good source of functional foods in Asian counties. It has been recorded that adzuki bean contain sugars, starch, proteins, fiber, polyphenols, and saponins. Adzuki bean owns lot of biological activities recorded from "Shen Nong's herbal classic" to the articles written by contemporary scientists. This review summarized chemical compositions in adzuki bean and their pharmacological effects, such as antioxidative effects, hepato-protective effects, anti-diabetic effects, blood pressure adjusting effects, anti-obesity effects, and anti-cancer effects and so on. Due to the limited information and non industrial scale production of chemical compositions like saponins from adzuki bean, further studies are suggested to focus on their chemicals, and the relationship of structure-activity for the bioactive compositions.
... In this same animal model, the treatment with genistein restored the reduced plasma NOx concentrations [71]. Mukai and Sato (2009) [72] reported the level of 24-h urinary NOx was significantly higher in the polyphenol-containing azuki bean extract (ABE)-treated SHR than in the untreated SHR, indicating that ABE treatment upregulated NO production. All these results are in agreement with several studies reporting that treatments with flavonoids such as quercetin suppress the development of hypertension associated with a reduced oxidant status due to their antioxidant properties. ...
... In this same animal model, the treatment with genistein restored the reduced plasma NOx concentrations [71]. Mukai and Sato (2009) [72] reported the level of 24-h urinary NOx was significantly higher in the polyphenol-containing azuki bean extract (ABE)-treated SHR than in the untreated SHR, indicating that ABE treatment upregulated NO production. All these results are in agreement with several studies reporting that treatments with flavonoids such as quercetin suppress the development of hypertension associated with a reduced oxidant status due to their antioxidant properties. ...
The objective of this study was to investigate the effects of onion and apple functional ingredients in homozygous (fa/fa) obese Zucker rats. Rodents were fed three diets: standard diet [obese control (OC) group], standard diet containing 10% onion [obese onion 10% (OO) group] and standard diet containing 10% apple [obese apple 10% (OA) group] for 8 weeks. Food intake and body weight gain were higher in obese than in lean rats. Food efficiency was lower in OO and AO groups compared with OC group. Within the obese groups, total cholesterol, LDL-cholesterol, triacylglycerols, glucose, insulin and triglyceride-glucose index were lower in OO group than in OC group, and HDL-cholesterol was higher in OO group than in OC group. In general, antioxidant activity (ABTS•+ and FRAP), antioxidant enzyme activities (CAT, SOD, GPx), GSH/GSSG ratio, nitrate/nitrite and GLP-1 increased in OO and OA groups compared with OC. Oxidative stress biomarkers, namely protein carbonyls, 8-hydroxy-2’-deoxyguanosine, 8-epi-prostaglandin F2α, inflammatory and vascular injury biomarkers (PAI-1, TIMP-1, VEGF, sICAM-1, sE-Selectin, MCP-1) and leptin, were lower in OO and OA groups than in OC group. Endothelial impairment was partially reversed, and superoxide content and gene expression of NLRP3, NFKβ1 and COX2 decreased, in OO and OA groups with respect to OC group. The study demonstrates that high pressure-processed onion and apple functional ingredients administration to obese Zucker rats causes beneficial effects on metabolic health, in particular through improving food efficiency ratio; exerting pronounced lipid-lowering effects; reducing glycemia, insulinemia, and biomarkers of hepatic injury (ALT, AST); improving antioxidant, oxidative stress, inflammatory and vascular injury biomarkers, metabolic hormones, and endothelial function; and decreasing proinflammatory gene expression of NLRP3, NFKβ1 and COX2.
... Red bean extract increased the grip strength, exercise endurance, muscle weight, and muscle fiber area, which could significantly decrease the mRNA expression of proteolytic-related genes, such as muscle ring finger and muscle atrophy F-box, by the preventing the translocation of Forkhead box 3 [95]. Adzuki bean extract may reduce the elevation of blood pressure by regulating endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) protein expression in the aorta and kidney [96]. High-fat-diet-induced obesity has been associated with cognitive and memory dysfunction. ...
... Adzuki beans also could mitigate liver function damage and hepatic steatosis, while adzuki beans and their extracts have positive effects on the kidneys and diabetic kidney disease (Figure 2). aorta and kidney [96]. High-fat-diet-induced obesity has been associated with cognitive and memory dysfunction. ...
Adzuki beans are grown in several countries around the world and are widely popular in Asia, where they are often prepared in various food forms. Adzuki beans are rich in starch, and their proteins contain a balanced variety of amino acids with high lysine content, making up for the lack of protein content of cereals in the daily diet. Therefore, the research on adzuki beans and the development of their products have broad prospects for development. The starch, protein, fat, polysaccharide, and polyphenol contents and compositions of adzuki beans vary greatly among different varieties. The processing characteristic components of adzuki beans, such as starch, isolated protein, and heated flavor, are reported with a view to further promote the processing and development of adzuki bean foods. In addition to favorable edibility, the human health benefits of adzuki beans include antioxidant, antibacterial, and anti-inflammatory properties. Furtherly, adzuki beans and extracts have positive effects on the prevention and treatment of diseases, including diabetes, diabetes-induced kidney disease or kidney damage, obesity, and high-fat-induced cognitive decline. This also makes a case for the dual use of adzuki beans for food and medicine and contributes to the promotion of adzuki beans as a healthy, edible legume.
... The body weights of the FE250 and FE500 groups were not different from those of the SHR group, despite greater food intake. Similarly, there was no significant difference in the body weight of the SHR model classified by legumes or cereals [21,22]. Furthermore, Captopril, a positive control treatment for hypertension, did not alter the body weight or food intake. ...
... The TBARS concentration in the plasma of the SHR group was significantly increased compared with that of the WKY group. These results indicate that oxidative stress is higher in SHRs than in WKY rats, as previously reported [22,36]. Both FE groups showed a significantly decreased TBARS concentration in the plasma compared with the SHR group. ...
Finger millet (Eleusine coracana) contains high levels of calcium and polyphenols, which have a variety of beneficial functions. We tested the hypothesis that finger millet ethanol extracts (FEs) have an antihypertensive effect in spontaneously hypertensive rats (SHRs). The study groups were assigned as follows: (1) Wistar Kyoto rats (normal); (2) SHRs treated with saline (negative control); (3) SHRs treated with captopril 50 mg/kg bw (positive control); (4) SHRs treated with FE 250 mg/kg bw (FE250); and (5) SHRs treated with FE 500 mg/kg bw (FE500). FE supplementation improved the lipid profiles, including the triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels, without deterioration in liver function. The thiobarbituric acid reactive substance concentration and superoxide dismutase activity significantly improved after the application of FE250 and FE500. Interestingly, FE250 and FE500 application dramatically reduced the systolic blood pressure. FE supplementation exhibited powerful control over the renin-angiotensin system by reducing the angiotensin-converting enzyme levels and renin mRNA expression in the kidney. Additionally, FE500 application ameliorated vascular remodeling, reversed the thickening media, and decreased the media thickness/lumen diameter ratio of the aorta. These results imply that FEs are a potent antihypertensive nutraceutical for regulating the renin–angiotensin system and simultaneously inhibiting oxidative stress.
... Several biological mechanisms have been proposed to elucidate the protective effects of F&V on the cardiovascular system (Table 9). In vivo models show inhibition of lipid oxidation, an increase in antioxidant capacity of the serum and plasma (Harasym and Oledzki 2014) reduction of oxidative stress (Thompson 2010) an antiinflammatory effect (Loke et al. 2008), prevention of platelet aggregation, reduction in vascular tone (Wang et al. 2014c), and induction of glutathione endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) (Mukai and Sato 2009) to be potential mechanisms of action. ...
... Proposed Mechanism(s) Harasym and Oledzki (2014) Inhibition of lipid oxidation John et al. (2002), Harasym and Oledzki (2014) Increase in antioxidant capacity of the serum and plasma da Silva Pereira et al. (2014) Protection against oxidation of cholesterol and other lipids in the arteries Mayne (2003), Wallace (2011), Harasym and Oledzki (2014) Reduction in overall oxidative stress Loke et al. (2008) Anti-inflammatory effect Lefer (1990), Wang et al. (2014c) Increase formation of endothelial prostacyclin that inhibits platelet aggregation and reduces vascular tone Mukai and Sato (2009) Induction of glutathione, eNOS, and iNOS the lungs. Increased F&V intake may be protective against COPD development due to their high vitamin, mineral, and polyphenol content. ...
Fruit and vegetables (F&V) have been a cornerstone of healthy dietary recommendations; the 2015–2020 U.S. Dietary Guidelines for Americans recommend that F&V constitute one-half of the plate at each meal. F&V include a diverse collection of plant foods that vary in their energy, nutrient, and dietary bioactive contents. F&V have potential health-promoting effects beyond providing basic nutrition needs in humans, including their role in reducing inflammation and their potential preventive effects on various chronic disease states leading to decreases in years lost due to premature mortality and years lived with disability/morbidity. Current global intakes of F&V are well below recommendations. Given the importance of F&V for health, public policies that promote dietary interventions to help increase F&V intake are warranted. This externally commissioned expert comprehensive narrative, umbrella review summarizes up-to-date clinical and observational evidence on current intakes of F&V, discusses the available evidence on the potential health benefits of F&V, and offers implementation strategies to help ensure that public health messaging is reflective of current science. This review demonstrates that F&V provide benefits beyond helping to achieve basic nutrient requirements in humans. The scientific evidence for providing public health recommendations to increase F&V consumption for prevention of disease is strong. Current evidence suggests that F&V have the strongest effects in relation to prevention of CVDs, noting a nonlinear threshold effect of 800 g per day (i.e., about 5 servings a day). A growing body of clinical evidence (mostly small RCTs) demonstrates effects of specific F&V on certain chronic disease states; however, more research on the role of individual F&V for specific disease prevention strategies is still needed in many areas. Data from the systematic reviews and mostly observational studies cited in this report also support intake of certain types of F&V, particularly cruciferous vegetables, dark-green leafy vegetables, citrus fruits, and dark-colored berries, which have superior effects on biomarkers, surrogate endpoints, and outcomes of chronic disease.
... Adzuki beans contain dietary fiber, saponins, and polyphenols. Moreover, adzuki bean is reported to possess anti-oxidant [9], anti-inflammatory [10], anti-hypertensive [11], and anti-diabetic properties [9,12]. Despite the many reported properties of adzuki bean, no study has evaluated its potential to treat Alzheimer's disease. ...
... It is thought that these extracts suppress Aβ42 and alpha-synuclein aggregation and therefore protect neurons by preventing the destruction of neuronal membranes triggered by aggregation. Multiple reports have indicated that the adzuki bean contains polyphenols [11,24,25], which are reported to inhibit the aggregation of various amyloid proteins [26,27]. Although further studies are needed, it is possible that an adzuki bean extract can directly contact Aβ and suppress Aβ42 aggregation. ...
BACKGROUND/OBJECTIVES
Alzheimer's disease is a neurodegenerative disease that induces symptoms such as a decrease in motor function and cognitive impairment. Increases in the aggregation and deposition of amyloid beta protein (Aβ) in the brain may be closely correlated with the development of Alzheimer's disease. In this study, the effects of an adzuki bean extract on the aggregation of Aβ were examined; moreover, the anti-Alzheimer's activity of the adzuki extract was examined.
MATERIALS/METHODS
First, we undertook thioflavin T (ThT) fluorescence analysis and transmission electron microscopy (TEM) to evaluate the effect of an adzuki bean extract on Aβ42 aggregation. To evaluate the effects of the adzuki extract on the symptoms of Alzheimer's disease in vivo, Aβ42-overexpressing Drosophila were used. In these flies, overexpression of Aβ42 induced the formation of Aβ42 aggregates in the brain, decreased motor function, and resulted in cognitive impairment.
RESULTS
Based on the results obtained by ThT fluorescence assays and TEM, the adzuki bean extract inhibited the formation of Aβ42 aggregates in a concentration-dependent manner. When Aβ42-overexpressing flies were fed regular medium containing adzuki extract, the Aβ42 level in the brain was significantly lower than that in the group fed regular medium only. Furthermore, suppression of the decrease in motor function, suppression of cognitive impairment, and improvement in lifespan were observed in Aβ42-overexpressing flies fed regular medium with adzuki extract.
CONCLUSIONS
The results reveal the delaying effects of an adzuki bean extract on the progression of Alzheimer's disease and provide useful information for identifying novel prevention treatments for Alzheimer's disease.
... Recently, many studies have reported that adzuki bean extracts exert a variety of physiological functions, including antioxidant, anti-inflammatory, antiatherosclerosis, anticancer, and procardiovascular activities [5,6]. An adzuki bean extract suppressed obesity [7], reduced blood pressure [8], reduced the serum cholesterol level [9], suppressed hyperglycemia [10], and reduced the numbers of infiltrating macrophages and attenuated glomerular expansion in mouse and rat models of streptozoicin-induced diabetic nephropathy [11]. Flavonoids in the adzuki bean may mediate such beneficial effects [8,9,11]. ...
... An adzuki bean extract suppressed obesity [7], reduced blood pressure [8], reduced the serum cholesterol level [9], suppressed hyperglycemia [10], and reduced the numbers of infiltrating macrophages and attenuated glomerular expansion in mouse and rat models of streptozoicin-induced diabetic nephropathy [11]. Flavonoids in the adzuki bean may mediate such beneficial effects [8,9,11]. ...
This study explored the optimal preparation and the antioxidant levels of rice/adzuki bean mixtures. We compared the quality and physicochemical characteristics of cooked mixtures of rice and adzuki beans prepared using normal and high-pressure rice cookers, with and without the addition of alcohol (15%, v/v). The water-binding capacity and swelling power decreased upon addition of adzuki beans, but water solubility increased. The peak, trough, final, and setback viscosities decreased, but the breakdown viscosity increased. The total polyphenol and flavonoid contents increased after addition of adzuki beans. Total polyphenol contents in cooked rice/20% (w/w) Arari and Geomguseul bean mixtures in a normal cooker with addition of alcohol were 3.00 and 3.09 times higher than plain rice. The flavonoid contents were 10.33 and 8.90 times higher than plain rice. The predominant phenolic acids in cooked rice/Arari bean mixtures were p -coumaric acid and trans -3-hydroxycinnamic acid, and in cooked rice/Geomguseul bean mixtures, they were syringic acid and trans -3-hydroxycinnamic acid. Overall, phenolic acid levels were higher in mixtures cooked in plain water. The DPPH- and ABTS-radical-scavenging activities increased upon addition of adzuki beans. DPPH radical-scavenging activities in cooked rice/20% (w/w) Arari and Geomguseul bean mixtures in a normal cooker with addition of alcohol were 9.09 and 9.22 times higher than plain rice. ABTS radical-scavenging activities were 8.74 and 9.01 times higher than plain rice. Moreover, rice/adzuki bean mixtures prepared in a normal cooker, with addition of alcohol, exhibited higher antioxidant levels than other samples. We present the antioxidative properties of rice/adzuki bean mixtures prepared in different ways; these data will aid manufacturers.
... Vigna angularis that has been usually used as dietary azuki bean was known to have antioxidative [31], hepatoprotective [32], antimicrobial [33], osteogenic [34], anti-inflammatory [9,35], hypotensive [36,37], antimetastatic [38], and immunomodulatory [39] activities. Until now, there is no evidence on the antiangiogenic activity of Vigna angularis. ...
... Tube formation (% of control) indicating that inhibitory effect of EVA on angiogenesis in HUVECs could be by inhibition of Akt. In addition, azuki bean was reported to contain four furanylmethyl glycosides, angularides A-D, one ent-kaurane diterpene glycoside, angularin A, and four triterpenoid saponins, angulasaponins A-D, cyanidin and (+)-catechin, proanthocyanidins, digalactosyl ononitol, and gibberellin 2-oxidases [36,44,[58][59][60]. Among them, anthocyanidin was well known to exert antiangiogenic activity in endothelial cells [61,62]. ...
Though dietary azuki bean (
Vigna angularis
) seed containing antioxidant proanthocyanidins was known to have multibiological activities including antioxidant, hypotensive, anti-inflammatory, and immunomodulatory activities, the antiangiogenic activity of ethanol extract of
Vigna angularis
(EVA) was never reported so far. In the present study, the antiangiogenic mechanism of EVA was examined in human umbilical vein endothelial cells (HUVECs). EVA showed weak cytotoxicity in HUVECs, while it significantly suppressed the VEGF induced proliferation of HUVECs. Consistently, wound healing assay revealed that EVA inhibited the VEGF induced migration of HUVECs. Also, EVA abrogated the VEGF induced tube formation of HUVECs in a concentration dependent fashion. Furthermore, Matrigel plug assay showed that EVA significantly reduced the hemoglobin level of Matrigel plug in mice compared to untreated control. Of note, EVA effectively attenuated the phosphorylation of VEGFR2, Erk, and Akt in VEGF-treated HUVECs. Overall, our findings suggest that EVA inhibits angiogenesis in VEGF-treated HUVECs via inhibition of phosphorylation of VEGFR2, ERK, and Akt.
... The diet is also an important factor in the up-regulation of eNOS. It is known that flavonoid consumption potentiates NO endothelium-dependent relaxation (Duffy et al., 2001;Fisher, Hughes, Gerhard-Herman, & Hollenberg, 2003;Mukai & Sato, 2009;Schroeter et al., 2006;Stein, Keevil, Wiebe, Aeschlimann, & Folts, 1999;Yamamoto, Suzuki, & Hase, 2008). Prostaglandin I2 (PGI 2 ), which is known as prostacyclin, is also an important vasodilator endothelial factor. ...
Grape seed procyanidin extract Nitric oxide Polyphenols Prostacyclin Spontaneously hypertensive rats A B S T R A C T The aim of this study was to evaluate the involvement of endothelial-relaxing factors as possible antihypertensive mechanism of low-molecular-weight procyanidin rich grape seed extract (LM-GSPE). Thirty 17-20-week-old male spontaneously hypertensive rats (SHR) were administered water or 375 mg/kg LM-GSPE by intragastric gavage. One millilitre of saline, 30 mg/kg NG-Nitro-L-arginine methyl ester (L-NAME) or 5 mg/kg indomethacin was administrated intraperitoneally. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded before and 6 h after oral administration. Plasma concentration of 6-keto-prostaglandin F1a (PGF1a) was quantified. In addition, we evaluated the relaxation caused by LM-GSPE in different aorta preparations. The antihypertensive effect of LM-GSPE was completely and partially abolished by L-NAME and indomethacin, respectively. In addition , plasma PGF1a was increased in LM-GSPE-administered rats. Finally, LM-GSPE relaxed the intact aorta preparations but did not relax the endothelium-denuded aorta rings. L-NAME inhibited the relaxation caused by LM-GSPE in the SHR aorta rings, but indometha-cin did not. Therefore, the antihypertensive effect of LM-GSPE in SHR is endothelium dependent, and it could be mediated by changes in endothelium-derived nitric oxide bio-availability. Nevertheless, prostacyclin could also contribute additionally to this effect.
... Adzuki beans are rich in proteins, vitamins, flavonoids, minerals, but have low calories and fat [6,7]. In addition, adzuki beans as a kind of medicinal food have antioxidant, anti-hypertensive, anti-inflammatory, anti-diabetic, and other effects [7][8][9]. ...
Adzuki beans are an important food legume crop in East Asia. A large number of adzuki bean accessions are maintained in the Chinese national seed genebank. A collection of 59 elite cultivars, 389 landraces, and 27 wild adzuki beans were selected and phenotyped extensively for yield and yield-related traits at two different locations (Nanning and Nanyang, China). Ten agronomic and yield-related traits were scored, and the data were subjected to analysis of variance (ANOVA), principal component analysis (PCA), correlation, and cluster analysis. Significant variation was observed for genotypes, locations, and genotype x environment interaction for most traits. Also, there were significant differences in the phenotypes among accessions of different germplasm types. The broad-sense heritability of traits studied ranged from 4.4% to 77.8%. The number of seeds per pod (77.8%), 100-seed weight (68.0%), and number of plant branches (63.9%) had a high heritability. A total of 10 traits were transformed into 3 comprehensive factors by principal component analysis, and the first three principal component factors contributed 72.31% of the total variability. Cluster analysis categorized the 475 adzuki bean accessions into five distinct groups. The results described in this study will be useful for adzuki bean breeders for the development of varieties with high end-use quality.
... Dimeric eNOS produces NO instead of ROS, thus contributing to vasodilatation. Similarly, Mukai et al. 148 reported an increase in eNOS and inducible NO synthase (iNOS) expression levels in both the aorta and kidney in a hypertensive rat model supplemented with an azuki bean extract. ...
In recent times, a great number of plants have been studied in order to identify new components with nutraceutical properties, among which are polyphenols. Dietary polyphenols represent a large group of bioactive molecules widely found in food of plant origin and they have been found able to prevent onset and progression of degenerative diseases, as well as reducing and controlling their symptoms. These health protective effects have been mainly related to their antioxidant and anti-inflammatory properties. However, it must be considered that application of isolated polyphenols as nutraceuticals is quite limited due to their poor systemic distribution and relative bioavailability. The present review highlights the potential effect of dietary intervention with polyphenol-rich food and plant extracts in patients with cancer, diabetes and neurodegenerative, autoimmune, cardiovascular and ophthalmic diseases, as well as the possible molecular mechanisms of action suggested in numerous studies with animal models.
... Additionally, polyphenols in adzuki beans are known to inhibit the aggregation of various amyloid proteins [57,58]. Deposition of Aβ42 aggregates in the brain and oxidative stress are AD symptoms. ...
Polyphenols are secondary metabolites of plants, fruits, and vegetables. They act as antioxidants against free radicals from UV light, pathogens, parasites, and oxidative stress. In Drosophila models, feeding with various polyphenols results in increased antioxidant capacity and prolonged lifespan. Therefore, dietary polyphenols have several health advantages for preventing many human diseases, including cardiovascular diseases, cancer, and neurodegenerative diseases. However, the exact role of polyphenols in neurodegenerative diseases is still yet to be completely defined. This review focuses on the most recent studies related to the therapeutic effect of polyphenols in neurodegenerative disease management and provides an overview of novel drug discovery from various polyphenols using the Drosophila model.
... Studies evaluating the antihypertensive potential of natural products have indicated that the intake of red wine or red wine polyphenols reduced systolic blood pressure in the spontaneously hypertensive rats [77][78][79]. Similarly, an antihypertensive effect has also been observed in response to the consumption of a grape seed extract [80], green and black tea extracts [81], blueberry [82], and an azuki bean extract [83] in the spontaneously hypertensive rat. Of interest, intake of a polyphenol-rich cocoa powder up to 300 mg/kg body weight was able to reduce blood pressure to a similar level as 50 mg/kg of Captopril, an angiotensin-converting enzyme inhibitor, in the spontaneously hypertensive rat [84]. ...
Since last few decades, considerable data have been suggested that the protective effect of anthocyanin on cardiovascular system is likely to involve an improvement of endothelial function by increase nitric oxide (NO) formation. However, comprehensive studies on the subsequent mechanisms of protective effect by anthocyanin intracellular transportation in vascular endothelial cell is poorly understood. The aim of this thesis is to evaluate the possibility that SGLT1 and 2, the two major sodium-glucose cotransporters (SGLT), contribute to blackcurrant anthocyanins and its major glucoside- and rutinoside-conjugated anthocyanins uptake into endothelial cells that promoting the subsequent activation of endothelial nitric oxide synthase (eNOS) pathway using isolated blood vessels and cultured endothelial cells. An anthocyanin rich blackcurrant extract (BCE) induced NO-mediated endothelium dependent relaxation in porcine coronary artery rings and activated Akt-eNOS signaling pathway in cultured endothelial cell. Furthermore, additional experiments suggested that such a protective effect of anthocyanin is based on the type of glucoside in anthocyanin structure and contribution of SGLTs for the intracellular transportation of anthocyanins. An ability of anthocyanin against endothelial dysfunction is highly potentiated in the endothelial cell replicative senescence model by the increase anthocyanin efflux according to the high expression of SGLTs. Altogether, the present findings indicate that blackcurrant anthocyanins are potent activator of the endothelial NO pathway in native and cultured endothelial cells. Among blackcurrant anthocyanins, glucose derivatives such as cyanidin and delphinidin -3-O-glucoside are the most potent anthocyanins for activation of NO pathway. In conclusion, anthocyanin can be more prominent by preferentially targeting an early stage of atherosclerotic site by their increase expression of SGLT1 and 2.
... Endothelial NOS is one of four isoforms of NOS, which also include iNOS, nNOS, and bNOS [42,43]. NO synthesis, which is regulated by eNOS in endothelial cells, is closely connected to vasodilation related to blood pressure [44]. It has been reported that NO released by HUVECs activates sGC, which is a NO receptor in SMC, thereby converting GTP to cGMP, and this activation can lead to vascular relaxation [24,45]. ...
Background
Many studies on the effect of saponin-rich Codonopsis lanceolata as a bioactive source for improving physical health have been performed. C. lanceolata contains triterpenoid saponins, including lancemasides. These saponins are known to be particularly involved in the regulation of blood pressure or hypertension. This study investigated whether lancemaside A (LA), a major triterpenoid saponin from C. lanceolata, regulates nitric oxide (NO) production via the activation of endothelial NO synthase (eNOS) in human umbilical vein endothelial cells.
Methods
Upon separation with petroleum ether, ethyl acetate, and n-butanol, LA was found to be abundant in the n-butanol-soluble portion. For further purification of LA, HPLC was performed to collect fraction, and LA was identified using analysis of LC/MSMS and ¹³C-NMR values. In in vitro, the effects of LA on NO release mechanism in HUVECs were investigated by Griess assay, quantitative real-time reverse-transcription PCR, and Western blotting.
Results
Our results showed that NO production was efficiently improved by treatment with LA in a dose-dependent manner. In addition, the LA treatment resulted in extensive recovery of the NO production suppressed by the eNOS inhibitor, L-NAME, compared with that in the control group. Additionally, the level of eNOS mRNA was increased by this treatment in a dose-dependent manner. These results suggested that LA is an inducer of NO synthesis via eNOS mRNA expression. Also, the study indicated that LA is involved in activating the PI3K/Akt/eNOS signaling pathway.
Conclusion
These results suggested that LA is an inducer of NO synthesis via eNOS mRNA expression. Also, the study indicated that LA is involved in activating the PI3K/Akt/eNOS signaling pathway. These findings suggest the value of using LA as a component of functional foods and natural pharmaceuticals.
... In Taiwan, V. luteola is grown in the open seaside at elevation below 100 m and spread over the island [17]. The Vigna genus has been reported to show antioxidant [18,19], antifungal [20], antitumor [21,22], deworming [23,24], hypoglycemic [25,26], hepatoprotective [27,28], kidney protection [29,30], antibacterial [31,32], hypotensive [33,34], and hypolipidemic [35,36] bioactivities. In our previous research, the constituents and anti-inflammatory bioactivity of V. vexillata were investigated and the results exhibited potent inhibitory activity of superoxide generation and elastase release [37]. ...
Seventy-three compounds were identified from the methanol extract of V. luteola, and among these, three new (1–3) were characterized by spectroscopic and mass spectrometric analyses. The isolated constituents were assessed for anti-inflammatory potential evaluation, and several purified principles exhibited significant superoxide anion and elastase inhibitory effects.
... Other health benefits from underutilised beans such as the potential presence of antidiabetic activity from adzuki bean and mung bean (Luo et al., 2016;Itoh et al., 2004), anti-proliferation of different types of cancer cells namely-human mammary hormone dependent cancer cell, colorectal adenocarcinoma cells, hepatocellular carcinoma cells, and gastric adenocarcinoma cells by black eyed pea (Xu & Chang, 2012;Gutiérrez-Uribe et al., 2011), inhibition of pancreatic lipase activity from mung bean, red bean and moth bean (Sreerama et al., 2012), antimicrobial activity from list of legumes such as pigeon pea (Devi et al., 2016;Kanatt et al., 2011), inhibition of tyrosinase activity, anti LDL-lipid peroxidation (Bazzano et al., 2011) and antihypertension from adzuki bean (Mukai & Sato, 2009;Xu et al., 2007). These are believed to be related to antioxidant potential. ...
Beans are seeds of leguminous plants and are rich in macronutrients and micronutrients such as polyphenols predominantly phenolic acids and flavonoids that may have health benefits arising from their antioxidant and other properties. Beans, especially from underutilised legumes, may play an important role in future world food supply. However, there has been limited investigation into the nutritional composition of underutilised beans compared with commercial beans such as soya bean. Therefore, this study aimed to improve the extraction, identification and quantification methodologies for characterizing soluble free, conjugated and insoluble bound phenolics from underutilised beans using high performance liquid chromatography (HPLC) and liquid chromatography – mass spectrophotometry (LC-MS). Six underutilised beans (adzuki bean, black eyed pea, bambara groundnut, lablab bean, mung bean, pigeon pea) were found to possess a comparable amount of antioxidant activity to commercial beans and this showed positive correlation with their phenolic compounds. Optimisation revealed that 80% methanol was most suitable for extracting soluble phenolics compared with 80% acetone and acetate buffer, although subsequent HPLC profiling showed strong similarities among all three solvents. Alkaline hydrolysis for 5 mins followed by SPE partitioning on soluble extracts and alkaline hydrolysis for 1 h followed by acetonitrile salting out liquid-liquid partitioning on residue were the optimum procedures for estimating the conjugated phenolics and releasing the bound phenolics. The methods showed better recovery, were more solvent friendly and had shorter drying times than ethylacetate liquid-liquid partitioning. Using 20 phenolic standards, more phenolics were detected by LC-MS than HPLC. Black eyed pea had the most diverse soluble phenolics profile (n=13), followed by adzuki bean and bambara groundnut (n=11) whilst soya bean exhibited the most diverse bound phenolics profile (n=7), followed by pigeon pea and adzuki bean (n=5). Five phenolics were found at the highest concentration in bound extracts from adzuki bean (consist of gallic acid at least 5-fold higher than in soya bean), bambara groundnut (consist of protocatechuic acid at least 160-fold higher than in soya bean), lablab bean (consist of p-coumaric acid at least 3-fold higher than in soya bean), black eyed pea (consist of ferulic acid at least 0.5-fold higher than in soya bean), soya bean (sinapic acid) and others were found at highest concentrations in soluble extracts from different beans. In conclusion, this study has achieved its objectives by developing the comprehensive profiling of phenolics for underutilised beans with optimised extraction methodologies and analysis techniques. The outcome was that underutilised beans are potential alternative resources to commercial beans since they possess higher concentrations of, and more diversified, phenolics than soya bean. This is the first report of optimised extraction methodologies and analysis techniques for the comprehensive analysis of phenolics in underutilised beans. It has generated phenolic profiles from the application of the optimised methodologies and produced useful reference databases for future studies and serves to create an awareness of the potential of underutilised beans as alternative food resources.
... Studies evaluating the antihypertensive potential of natural products have indicated that the intake of red wine or red wine polyphenols reduced systolic blood pressure in the spontaneously hypertensive rats [77][78][79]. Similarly, an antihypertensive effect has also been observed in response to the consumption of a grape seed extract [80], green and black tea extracts [81], blueberry [82], and an azuki bean extract [83] in the spontaneously hypertensive rat. ...
Epidemiological studies have indicated that regular intake of polyphenol-rich diets such as red wine and tea, are associated with a reduced risk of cardiovascular diseases. The beneficial effect of polyphenol-rich products has been attributable, at least in part, to their direct action on the endothelial function. Indeed, polyphenols from tea, grapes, cacao, berries, and plants have been shown to activate endothelial cells to increase the formation of potent vasoprotective factors including nitric oxide (NO) and to delay endothelial ageing. Moreover, intake of such polyphenol-rich products has been associated with the prevention and/or the improvement of an established endothelial dysfunction in several experimental models of cardiovascular diseases and in Humans with cardiovascular diseases. This review will discuss both experimental and clinical evidences indicating that polyphenols are able to promote endothelial and vascular health, as well as the underlying mechanisms.
... In addition to SOD activity, the expression levels and activity of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) in the kidney are involved in the onset of hypertension [26]. Azuki bean polyphenol inhibits hypertension via modulation of eNOS and iNOS expression levels in the kidney [31]. Although the expression levels of eNOS and iNOS were not analyzed in this study, the novel mechanisms of the anti-hypertensive effects of AP may potentially be elucidated by focusing on eNOS and iNOS in future studies. ...
We have previously demonstrated that acacia polyphenol (AP) exerts strong anti-obesity, anti-diabetic, and anti-atopic dermatitis effects. In the present study, we investigated the anti-hypertensive effects of AP. Spontaneously hypertensive rats (SHR) with hypertension and control Wistar Kyoto rats (WKY) were used. WKY and SHR were fed AP-containing food or AP-free food (control group) ad libitum for 4 weeks, and their blood pressures were measured. After AP administration, both systolic and diastolic blood pressures were significantly lower in the SHR group than in the control group. There were no differences in the systolic or diastolic blood pressure of WKY between the AP group and the control group. Angiotensin-converting enzyme (ACE) activity,nicotinamide adenine dinucleotide phosphate(NADPH)oxidaseexpression, and superoxide dismutase (SOD) activity in SHR kidneys were not altered by AP administration. Blood SOD activity in SHR was significantly higher in the AP group than in the control group. AP exerts anti-hypertensive effects on hypertension but has almost no effect on normal blood pressure. The anti-hypertensive effects of AP may be related to the anti-oxidative effects of increased blood SOD activity.
... Hypertension is a predominant factor in the development of various cardiovascular diseases including atherosclerosis, heart attack and coronary disease. With spontaneously hypertensive rats (SHRs), other researchers also have proven that phenolic extracts from legume could reduce blood pressure and suppress inflammatory responses, such as intracellular ROS level, overexpression of proinflammatory enzymes including iROS, COX-1, generation of O 2 − , as well as NADPH oxidase (Mukai & Sato, 2009, 2011. Lentil (Lens culinaris), black soybean (Glycine max), and black turtle bean (Phaseolus vulgaris) are dry legumes, and belong to three different scientific genera, which are widely cultivated in the world, and preferred by different groups of consumers in different parts of the world. ...
Lentil, black soybean and black turtle bean are commonly consumed legumes of different genera, containing high phenolic contents, which are effective antioxidants and angiotensin-I converting enzyme (ACE) inhibitors. However, these legumes’ phenolic compositions and ACE inhibition ability have not been compared. Crude water extract (CE) was semi-purified (SPE) and fractionated using column chromatography. Results showed that purification and fractionation could substantially increase phenolic contents and antioxidant capacities. Heating and variety had great effect on phenolic substances, antioxidant potential and mass yield of extracts and fractions. Only crude extracts showed potent ACE inhibitory activity. Black turtle bean's ACE inhibition potential was largely reduced by cooking. The order from low to high in terms of ACE inhibitory activity was black turtle bean < lentil < black soybean. Identification and quantification of individual phenolic compounds by UV spectroscopy and LC-MSⁿ analysis confirmed 18, 22, and 14 compounds, respectively, for the three legumes.
... Some biological mechanisms have been proposed to explain these protective effects by using in vivo models, such as inhibition of lipid oxidation, an increase in the antioxidant capacity of serum or plasma (Harasym and Oledzki, 2014), protection against the oxidation of cho lesterol and other lipids in cell membranes (da Silva Pereira et al., 2014), reduction in oxidative stress (Thomp son, 2010), an anti-inflammatory effect (Loke et al., 2008), prevention of platelet aggregation, reduction in vascular tone , and induction of glutathione, endothelial NO synthase (eNOS), and inducible NOS (iNOS) (Mukai and Sato, 2009). Using rat cardiomyoblast H9c2 cells (Park et al., 2009;Angeloni et al., 2007), human umbilical vein endothelial cells (HUVECs) (Gong et al., 2010), J774A.1 macrophages (Hwang et al., 2003), and monocyte-derived macrophages (La et al., 2009), cell lines treated with methanolic onion extract (0.05 and 0.1 g/mL), quercetin (30 μM), rutin (200 μM), resveratrol (20 μM), and cranberry proanthocyanidins (25 and 50 μg/mL) induced anti-apoptotic effects, evidenced by inhibition of cytochrome C release to cytoplasm and inactivation of H 2 O 2 -induced caspases-3, increase in bioavailability of nitric oxide (NO), and reduction in matrix metalloprotei nases 9, 7, 8, and 13 production. ...
... A recent meta-analysis [6] has shown that consumption of pulses benefits cardiovascular health in humans by affecting biological processes linked to control of BP. It has been proposed that components of dietary pulses such as peptides, isoflavones and arginine-related compounds affect BP control through the renin-angiotensin system and nitric oxide (NO) production [7]. ...
PurposeUrine samples were obtained from a previously completed study that showed lentil consumption attenuates the increase in blood pressure that occurs over time in spontaneously hypertensive rats (SHRs). The objective of the present study was to compare the metabolite profile of the urine samples from control and lentil-fed SHR in relation to the compounds present in lentils but not in other pulses. Methods
The urine samples were from 17-week-old, male SHR fed semi-purified diet prepared with powder (30 %, w/w) from cooked whole pulses or a pulse-free control diet (n = 8/group) for 4 weeks. Pulse powders, control diet and urine samples were extracted using acetonitrile and analyzed by a high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). ResultsTwenty-seven metabolites were significantly different in urine samples from lentil-fed SHR compared to SHR fed control diet, but only 7 were not present in the urine of SHR fed other pulses. Of these metabolites, only citrulline is linked to blood pressure regulation via production of the vasodilator nitric oxide (NO). Several arginine-related compounds that are NO synthase substrates or inhibitors were detected in lentils but not the control diet or other pulse powders. Conclusions
Consumption of lentils increases the availability of arginine and several related compounds that could potentially elevate production of NO and contribute to the blood pressure-lowering effects of lentil-rich diets.
... It was also the strongest shrink blood vessels material [17] which had been discovered until now. NO was produced from L-arginine in vascular endothelial cell under the catalytic through Carbon monoxide synthase (NOS) [18,19]. NO is a vital inflammatory mediator in our body. ...
... The antihypertensive properties of flavanols are associated with different biological activities, such as nitric oxide (NO)mediated vasodilation (Mukai & Sato, 2009;Yamamoto, Suzuki, & Hase, 2008), reduced oxidative status caused by the antioxidant capacity of these compounds (Duarte et al., 2001;Negishi et al., 2004;Peng et al., 2005;Pons et al., 2014) and an inhibition of angiotensin converting enzyme (ACE) (Persson, Persson, Hägg, & Andersson, 2011;Persson, Josefsson, Persson, & Andersson, 2006), which is a key enzyme in the control of BP. The involvement of NO in the antihypertensive effect of grape seed flavanols has been recently described by our group in SHR (Quiñones et al., 2014) and CHR (Pons et al., 2016). ...
... Protein eNOS and AT 1 R expression levels were determined in aortic tissue homogenates following a previously described Western blot method [27] with some modifications. Homogenates were electrophoresed on a sodium dodecyl sulfate polyacrylamide gel electrophoresis system. ...
This study examined the effect of Carthamus tinctorius (CT) extract plus captopril treatment on blood pressure, vascular function, nitric oxide (NO) bioavailability, oxidative stress and renin-angiotensin system (RAS) in N ω-Nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Rats were treated with L-NAME (40 mg/kg/day) for five weeks and given CT extract (75 or 150 or 300 or 500 mg/kg/day): captopril (5 mg/kg/day) or CT extract (300 mg/kg/day) plus captopril (5 mg/kg/day) for two consecutive weeks. CT extract reduced blood pressure dose-dependently, and the most effective dose was 300 mg/kg/day. L-NAME-induced hypertensive rats showed abnormalities including high blood pressure, high vascular resistance, impairment of acetylcholine-induced vasorelaxation in isolated aortic rings and mesenteric vascular beds, increased vascular superoxide production and plasma malondialdehyde levels, downregulation of eNOS, low level of plasma nitric oxide metabolites, upregulation of angiotensin II type 1 receptor and increased plasma angiotensin II. These abnormalities were alleviated by treatment with either CT extract or captopril. Combination treatment of CT extract and captopril normalized all the abnormalities found in hypertensive rats except endothelial dysfunction. These data indicate that there are synergistic antihypertensive effects of CT extract and captopril. These effects are likely mediated by their anti-oxidative properties and their inhibition of RAS.
... Previous phytochemical reports on this plant dealt with the several phenolic compounds, saponins and furanylmethyl glycosides (Ariga and Asao, 1981;Kitagawa et al., 1983;Jiang et al., 2014). Earlier pharmacological studies on this plan showed that it has various bioactivities such as anti-inflammatory, antioxidant, anti-hypotensive, hypoglycemic and hepatoprotective effects (Han et al., 2004;Itoh et al., 2009;Mukai and Sato, 2009;Yumiko et al., 2009;Jiang et al., 2014). Subsequent activity-guided chromatography of the methanolic extract of V. angularis led to the isolation of compound 1, vitexin (Fig. 1). ...
Several theories emphasize that aging is closely related to oxidative stress and disease. The formation of excess ROS can lead to DNA damage and the acceleration of aging. Vigna angularis is one of the important medicinal plants in Korea. We isolated vitexin from V. angularis and elucidated the lifespan-extending effect of vitexin using the Caenorhabditis elegans model system. Vitexin showed potent lifespan extensive activity and it elevated the survival rates of nematodes against the stressful environments including heat and oxidative conditions. In addition, our results showed that vitexin was able to elevate antioxidant enzyme activities of worms and reduce intracellular ROS accumulation in a dose-dependent manner. These studies demonstrated that the increased stress tolerance of vitexin-mediated nematode could be attributed to increased expressions of stress resistance proteins such as superoxide dismutase (SOD-3) and heat shock protein (HSP-16.2). In this work, we also studied whether vitexin-mediated longevity activity was associated with aging-related factors such as progeny, food intake, growth and movement. The data revealed that these factors were not affected by vitexin treatment except movement. Vitexin treatment improved the body movement of aged nematode, suggesting vitexin affects healthspan as well as lifespan of nematode. These results suggest that vitexin might be a probable candidate which could extend the human lifespan.
... Expressions of the p47 phox NADPH oxidase subunit and eNOS proteins in aortic homogenates were determined following a previously described method with some modifications [17,40]. The aortic homogenates (15 µg) were electrophoresed on an SDS polyacrylamide gel and electrotransferred onto a polyvinylidenedifluoride membrane. ...
The effect of ellagic acid on oxidative stress and hypertension induced by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) was investigated. Male Sprague-Dawley rats were administrated with L-NAME (40 mg/kg/day) for five weeks. L-NAME induced high systolic blood pressure (SBP) and increased heart rate (HR), hindlimb vascular resistance (HVR) and oxidative stress. Concurrent treatment with ellagic acid (7.5 or 15 mg/kg) prevented these alterations. Co-treatment with ellagic acid was associated with up-regulation of endothelial nitric oxide synthase (eNOS) protein production and alleviation of oxidative stress as indicated by decreased superoxide production in the vascular tissue, reduced plasma malondialdehyde levels, reduced NADPH oxidase subunit p47phox expression and increased plasma nitrate/nitrite levels. Our results indicate that ellagic acid attenuates hypertension by reducing NADPH oxidase subunit p47phox expression, which prevents oxidative stress and restores NO bioavailability.
... The seed of this plant has been used as a food or a traditional medicine for the treatment of several diseases such as edema, beriberi, constipation, and diabetes (Yao et al., 2011). Previous pharmacological studies on the seed of V. angularis (aka: adzuki beans) revealed that it has various therapeutic properties on the aging-related diseases such as arthritis, osteoporosis, type 2 diabetes, and hypertension (Mukai and Sato, 2009;Itoh et al., 2014;Oh et al., 2014;Yao et al., 2011). ...
The seed of Vigna angularis has long been cultivated as a food or a folk medicine in East Asia. Genistein (4',5,7-trihydroxyisoflavone), a dietary phytoestrogen present in this plant, has been known to possess various biological properties. In this study, we investigated the possible lifespan-extending effects of genistein using Caenorhabditis elegans model system. We found that the lifespan of nematode was significantly prolonged in the presence of genistein under normal culture condition. In addition, genistein elevated the survival rate of nematode against stressful environment including heat and oxidative conditions. Further studies demonstrated that genistein-mediated increased stress tolerance of nematode could be attributed to enhanced expressions of stress resistance proteins such as superoxide dismutase (SOD-3) and heat shock protein (HSP-16.2). Moreover, we failed to find genistein-induced significant change in aging-related factors including reproduction, food intake, and growth, indicating genistein exerts longevity activity independent of affecting these factors. Genistein treatment also led to an up-regulation of locomotory ability of aged nematode, suggesting genistein affects healthspan as well as lifespan of nematode. Our results represent that genistein has beneficial effects on the lifespan of C. elegans under both of normal and stress condition via elevating expressions of stress resistance proteins.
... 28 The azuki bean (VA) is a common plant used in food and oriental medicine in East Asia. There are many reports on the components and clinical applications of VA. 19,[29][30][31] In particular, the antioxidant activity of VA has been established. 22 UVB is the main external factor that leads to oxidative stress, which is initiated by ROS and eventually results in premature skin aging. ...
Abstract Exposure to ultraviolet (UV) radiation induces various pathological changes, such as thickened skin and wrinkle formation. In particular, UVB irradiation increases MMP-1 production and collagen degradation, leading to premature aging, termed photoaging. The azuki bean (Vigna angularis; VA) has been widely used as a food product as well as a traditional medicine. However, its activity needs additional study to confirm its functional application in foods and cosmetics for protecting skin. In this study, hot-water extract from VA (VAE) and its active component, rutin, were investigated to determine their antiphotoaging effects. VAE was found to have antioxidant activity. In UVB-exposed NHDF cells with VAE and rutin treatments, MMP-1 production was significantly suppressed (90% and 47%, respectively). The effects of both topical and oral administration of VAE were tested in UVB-irradiated hairless mice. VAE suppressed wrinkle formation and skin thickness by promoting elastin, procollagen type I, and TGF-β1 expression (118%, 156%, and 136%, respectively) and by diminishing MMP-1 production. These results suggest that VAE may be effective for preventing skin photoaging accelerated by UVB radiation.
Pulses (beans, peas, and lentils) have been consumed for at least 10,000 years and are among the most extensively used foods in the world. Legumes (including alfalfa, clover, lupins, green beans and peas, peanuts, soybeans, dry beans, broad beans, dry peas, chickpeas, and lentils) represent an important component of the human diet in several areas of the world, especially in the developing countries, where they complement the lack of proteins from cereals, roots, and tubers. In some regions of the world, legume seeds are the only protein supply in the diet.
In this research, the Biblical verses concerning beans are described. Therefore, this research deals with various aspects of the beans.
The Bible gives a description of the consumption of beans. Over the years, humans have recognized the many positive health benefits of beans. However, some toxic and adverse side effects may be experienced. Nevertheless, beans should be included in the modern menu of human nutrition, as in ancient times.
Background and objectives
Diabetes is a serious metabolic disease. The present study investigated the ability of diets supplemented with raw and cooked adzuki bean to mitigate the effects of diabetes and related metabolic disorders in type 2 diabetic mice induced by a high-fat diet combined with streptozotocin (STZ).
Findings
Compared with untreated diabetic mice, raw adzuki bean (RAB) supplementation significantly reduced food intake, glycated serum protein (GSP), and fasting blood glucose (FBG), and improved glucose tolerance. Cooked adzuki bean (CAB) supplementation cannot effectively improve FBG, but significantly reduce weight loss and GSP. In addition, adzuki bean supplementation significantly reduced low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels. Histological observations confirmed the ability of adzuki bean supplementation to prevent pancreatic and liver damage. The content of total flavonoids and catechins in adzuki bean decreased significantly after processing.
Conclusions
Although RAB and CAB supplementation showed many beneficial impacts on type 2 diabetic mice, the lower efficacy of CAB is likely caused by a loss of bioactive substances from processing.
Significance and novelty
These findings may contribute to a better understanding of the benefits of adzuki bean as a dietary supplement to prevent type 2 diabetes mellitus (T2DM) and related metabolic disorders.
Litchi chinensis seed is a valuable byproduct of the subtropical fruit litchi (L. chinensis Sonn.), whose extract (LSE) has been confirmed to ameliorate dyslipidemia, hyperglycemia, and oxidative stress caused by type 2 diabetes. However, if LSE exerts an effect on anti-hypertension and hypertensive renal damage remains unknown. In this study, 13 polyphenols and one fatty acid were identified by UPLC-Q/TOF-MS. Network pharmacological analysis revealed that the therapeutic effects of LSE may be involved in multitargets and multipathways, such as the TNF signaling pathway, interleukin (IL)-6-mediated signaling pathway, NF-kappa B signaling pathway, removal of superoxide radicals, negative regulation of blood pressure, and so forth. Moreover, spontaneously hypertensive rats (SHRs) were daily gavaged with LSE (60 mg/kg) for 10 weeks. LSE remarkably reduced systolic blood pressure (SBP). The hypertension-induced renal damage was improved by suppressing inflammation and oxidative stress, which was consistent with the prediction of network pharmacology. In addition, LSE treatment remarkably increased the relative abundances of Lactobacillus and the production of short-chain fatty acids in the intestine. Our study indicated that a byproduct of litchi, namely, litchi seed, may be effective in reducing SBP and alleviating hypertensive renal damage.
The aim of the present research was to investigate the antioxidant properties and anthocyanin profiles in the black seed coated adzuki bean (Vigna angularis, Geomguseul cultivar). The acidic 60% methanol extract (40 μg/mL) contains the highest total phenolic and flavonoid contents (486 ± 3 mg GAE/100 g; 314 ± 10 mg CE/100 g) with potent antioxidant properties (trolox equivalent 1272 ± 26 and 662 ± 24 mg TE/100 g) against ABTS and DPPH radicals compared to other methanol–water ratios (20, 40, 80, and 100%). Ten anthocyanin components were identified in this extract including delphinidin-3,5-O-digalactoside (1), delphinidin-3,5-O-diglucoside (2), delphinidin-3-O-galactoside (3), delphinidin-3-O-glucoside (4), delphinidin-3-O-rutinoside (5), delphinidin-3-O-(p-coumaroyl)glucoside (6), cyanidin-3-O-glucoside (7), petunidin-3-O-galactoside (8), petunidin-3-O-glucoside (9) and petunidin-3-O-(p-coumaroyl)glucoside (10) via NMR spectroscopy and UPLC-Q-Orbitrap-MS/MS analysis. The key anthocyanins 3 and 4 of delphinidin type were isolated by reversed phase C-18 MPLC. Our results indicate that the anthocyanin profiles as well as the high phenolic and flavonoid contents are important factors determining the antioxidant effects of black adzuki bean.
High-fat diet (HFD)-induced obesity is related to cognitive and memory dysfunction. Much attention was focused on functional foods as a therapeutic strategy to treat cognitive decline by obesity. In the present study, we confirmed the protective effect of Vigna angularis (VA) on cognitive and memory impairment in an obese mouse model. For 16 weeks, mice were fed HFD and VA extract was administered during 4 weeks at 100 and 200 mg/kg. The cognitive abilities of HFD-induced mice were evaluated using behavioral tests. Compared with the control group, VA groups were improved spatial and recognition ability. In T-maze and novel object recognition tests, VA 100 and VA 200 groups showed increased ratios of exploration of a novel object/route compared to a familiar object/route. Moreover, VA 100 and VA 200 groups reached the platform faster than the control group in a Morris water maze test. Therefore, VA extract may protect against HFD-induced cognitive impairment and memory dysfunction. (PNU-IACUC; approval no. PNU-2019-2166).
Pulses possess excellent nutritional profile with low glycemic index, low cholesterol and fats, considerable amounts of carbohydrates, and appreciable levels of vitamins and minerals. In addition to being an explicit source of nutrients, grain legumes also provide many bioactive compounds having beneficial metabolic and/or physiological effects on the body. These bioactive compounds are also known as nutraceutical compounds (Siddhuraju and Becker 2007). The term “nutraceutical” was coined by Stephen DeFelice in the year 1989 and can be defined as “a food (or part of a food) that provides medical or health benefits, including the prevention and/or treatment of diseases”. Simply the nutraceuticals are bioactive compounds in foods that provide health benefits including prevention, protection, and treatment of diseases (Belem 1999). In view of their synergistic medicinal value, economical status, and no side effects, the nutraceuticals compounds have catch the eye of food nutritionist around the world during the last few decades as a potential substitute of present-day medicines (Raskin et al. 2002). The potential health benefits of nutraceuticals compounds are likely due to complex biochemical and cellular interactions which together promote overall health of an individual (Dillard and German 2000). The beneficial health promotion effects and increasing health consciousness of the people have been resulted in the rapid growth of nutraceutical industry.
Twenty-two health functional legumes and industrial crops contain several phytochemicals and extracts which have potential use as medicinal plants or functional foods in the United States and other countries worldwide. The objective of this study was to present a review of several legume species in the United States Department of Agriculture (USDA), Agricultural Research Service (ARS), Plant Genetic Resources Conservation Unit's (PGRCU) collection for potential use as non-traditional human and veterinary medicinal plants. Specific phytochemicals and extracts from various plant organs will be identified and discussed from these legumes and industrial crops. Potential phyto-pharmaceuticals including flavonoids, glycosides, phenolics, cliotides, steroids, and saponin from butterfly pea (Clitoria ternatea L.) flowers, seed coats, and roots; saponin, steroids, anthro-quinones, terpinoids, flavonoids, and phlabotanin from Indigofera cassioides Rottler ex DC. leaves; dequelin, dehydrodeguelin, rotenol, rotenone, tephrosin, and sumatrol from hyacinth bean [Lablab purpureus (L.) Sweet] seeds and roots; L-dopa from velvetbean (Mucuna pruriens (L.) DC. and Sesbania bispinosa (Jacq.) W. Wight seeds; pachyerosin from jicama (Pachyrhizus erosus (L.) Urb. seeds; vitexin from blue wiss [Teramnus labialis (L.f.) Spreng] aerial parts and flavonol glycoside from stems; caffeic, ferulic, cinnamic acids, and kaempferol from mothbean (Vigna aconitifolia (Jacq.) Marechal sprouts; 7S globulins from mungbean (V. radiata (L.) R. Wilczek seeds; defensin, unguilin, trypsin/chymotrypsin inhibitor, 7S globulins from cowpea (V. unguiculata (L.) Walp seeds, and plant extracts. These phytochemicals and extracts have been shown to have multiple potential uses including antifungal, antibacterial, anti-asthmatic, anti-tuberculosis, anti-malaria, Parkinson's disease management, anti-cancer, antioxidant, oxidative stress reduction, cholesterol reduction, anti-Leishmania amazonensi, anti-breast cancer, anti-inflammatory, skin disease inhibition, reducing blood pressure, immunostimulation, myocardial ischemia protection, anthelmintic, improve eye surface protection from dry eye symptoms, and preventing oral bacteria and kidney damage. These species could provide the human and veterinary medicinal and functional food industries with valuable health products and can be used by other scientist's and breeders for the development of unique germplasm and/or advanced cultivars with one or more of these traits. Furthermore, many more plant species in the Plant Genetic Resources Conservation Unit (PGRCU) collection need to be evaluated for the identification, quantification, and variability of potentially and very valuable health traits which are currently unknown.
Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertension and cardiovascular remodeling are associated with oxidative stress and inflammation. Garcinia mangostana Linn., has been reported to have antioxidant and anti-inflammatory properties. This study investigated whether Garcinia mangostana pericarp extract (GME) could prevent L-NAME-induced hemodynamic alterations, cardiovascular remodeling, oxidative stress and inflammation in rats. Male Sprague-Dawley rats were given 40 mg/kg/day of L-NAME in drinking water to induce hypertension, and were simultaneously treated with GME at a dose of 200 mg/kg/day. Rats that received L-NAME for five weeks had high blood pressure, left ventricular hypertrophy and thickening of aortic wall. Vascular superoxide production, plasma malondialdehyde (MDA), and plasma tumor necrosis factor alpha (TNF-α) were significantly increased in L-NAME-hypertensive rats (p < 0.05). This was consistent with up-regulation of the p47phox NADPH oxidase subunit and iNOS protein expression in aortic tissues (p < 0.05). Low levels of plasma nitric oxide metabolites were observed in L-NAME hypertension. GME prevented the development of hypertension and cardiovascular remodeling induced by L-NAME with reduced oxidative stress and inflammation. These data suggest that GME had a protective effect against L-NAME-induced hypertension and cardiovascular remodeling via suppressing p47phox NADPH oxidase subunit and iNOS protein expression resulting in enhancing NO bioavailability.
Pulses supply many bioactive substances, such as enzyme inhibitors, lectins, phytates and phenolic compounds. Phenolic compounds are found in minor amounts in food but have significant metabolic and/or physiological effects. Enzyme inhibitors can diminish protein digestibility, and lectins can reduce nutrient absorption, but both have little effect after cooking. Because bioactive compounds can be beneficial or adverse, depending on the processing conditions, an assessment of their various physiological effects is necessary to determine whether they should be preserved or eliminated. Pulses are normally consumed after processing, which not only improves the palatability of foods but also increases the bioavailability of nutrients and bioactive compounds. Recent findings from the literature published within the last 10 years about the effect of cooking and germination is compiled and summarized.
A large body of evidence has demonstrated beneficial effects of polyphenol-rich diets and herbal medicines on the vascular system. However, polyphenols encompass diverse compounds, and conclusions are limited by poor extract compositional data and lack of bioassay-guided fractionation aimed at identifying the active constituents. Research on the vasorelaxant potential of chemically defined proanthocyanidins is hitherto confined. A few studies focused only on purified fractions or well-characterized compounds, supporting unambiguously the beneficial effects of proanthocyanidins on endothelial dysfunction. The proanthocyanidin-containing samples evoked endothelium-dependent relaxation in arteries through multiple mechanisms, including the NO-cGMP pathway and, to a lesser extent, activation of the endothelium-derived hyperpolarizing factors (EDHF)-signaling cascade in a redox-sensitive manner. EDHF events are primarily associated with the modulation of Ca2+-dependent and -independent K+ channel functions. In addition, the vascular tone appears to be regulated to various extents by the intracellular Ca2+ concentration. This chapter presents a brief overview of the signaling events in relaxation, summarizes the literature on the vasorelaxant effects of proanthocyanidins in isolated arteries, and provides a critical assessment of plant-based test materials.
Non-glutinous rice boiled with adzuki bean (adzuki-meshi) is often prepared in Japan, and the colour of rice in adzuki-meshi is purplish red, suggesting the transfer of adzuki bean components to rice. In fact, red-coloured rice of adzuki-meshi contained adzuki bean flavonoids such as (+)-catechin, (−)-epicatechin, taxifolin, quercetin 7-O-glucoside, rutin, quercetin, and cyanidin-catechin conjugates (vignacyanidins). A salivary component nitrite reacted with the above flavonoids in adzuki-meshi under the conditions simulating the stomach. The reaction resulted in the decrease in the antioxidative components of adzuki-meshi, and the decrease was accompanied by the production of functional compounds like nitric oxide (•NO), 6,8-dinitrosocatechin, 6,8-dinitrosoepicatechin, and 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone from nitrous acid, (+)-catechin, (−)-epicatechin, and quercetin, respectively. In this manuscript, functions of adzuki-meshi are discussed considering the reactions of the flavonoids with nitrite in the stomach.
Azuki is regarded to have been domesticated in China, Manchuria, Korea or Japan from its wild ancestral form, Vigna angularis var. nipponensis (Ohwi) Ohwi & Ohashi. Recently, the natural distribution of Vigna angularis var. nipponensis was reported to be wider than recognized before, ranging from Japan, Korea, China to Himalaya (Tibet, Bhutan, Nepal). Almost all global production of azuki occurs in four countries: Japan, China, Taiwan, and South Korea.
As a kind of small grain, with high protein, low fat, rich nutrition and delicious taste, rice bean is one of the main edible beans in China. Because of its rosy seed coat and rich starch in seeds, it is also named as ‘Red bean’ or ‘Adzuki bean’. The cultivation procedure and application techniques of rice bean are extensively documented in the ancient Chinese agricultural book Qimin Yaoshu (533–544 AD), in which it indicates that rice bean plantation has at least 1500 years of history in China.
In a previous study we demonstrated the antihypertensive effect of asiatic acid. The current study investigated the effect of asiatic acid on cardiovascular remodeling and possible mechanisms involved in Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats were treated with L-NAME (40 mg/kg/day) for three weeks in order to induce hypertension. Hypertensive rats were administered asiatic acid (20 mg/kg/day) or vehicle for a further two weeks. We found that hypertensive rats showed high systolic blood pressure, left ventricular (LV) hypertrophy, increases in LV fibrosis, aortic wall thickness and aortic collagen deposition (P < 0.05). Moreover, decreased plasma nitrate and nitrite (NOx) and increased plasma tumor necrosis factor alpha (TNF-α) were observed in hypertensive rats (P < 0.05). This was consistent with downregulation of endothelial nitric oxide synthase (eNOS) expression and upregulation of inducible nitric oxide synthase (iNOS) expression in heart and aortic tissues (P < 0.05). Levels of malondialdehyde (MDA) in plasma, aortic and heart tissues were significantly increased in hypertensive rats (P < 0.05). Asiatic acid markedly reduced blood pressure, alleviated cardiovascular remodeling, and restored plasma NOx and TNF-α as well as eNOS/iNOS expression in heart and aortic tissues (P < 0.05). Additionally, there was a significant reduction of MDA levels in the tissues of treated hypertensive rats. In conclusion, this study demonstrates the therapeutic effects of asiatic acid on blood pressure and cardiovascular remodeling, which is possibly related to the restoration of eNOS/iNOS expression, and the resulting anti-inflammatory and antioxidant activities. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Abstract Vigna species are important food resources and are traditionally used for the treatment of various diseases. In this study, we examined the inhibitory effects of Vigna nakashimae (VN) extract on high-fat diet (HFD)-induced hepatic steatosis and elucidated the molecular mechanisms. C57BL/6J mice were fed an HFD with or without VN extract for 16 weeks. VN extract decreased HFD-induced body weight, liver weight, hepatic lipid accumulation, and plasma alanine aminotransferase, and suppressed oxidative stress and inflammation associated with hepatitis. VN extract decreased plasma lipid levels and the expression of lipogenic genes in the livers of HFD-fed mice. VN extract significantly increased phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and acetyl-CoA carboxylase, and expression of fatty acid oxidation genes in the liver of VN-treated HFD mice and HepG2 cells. Further, VN extract inhibited insulin or glucose-stimulated lipogenesis in HepG2 cells. In conclusion, VN extract prevents HFD-induced hepatic steatosis and lipotoxicity through AMPK activation.
Endothelial nitric oxide synthase (eNOS) is a dually acylated peripheral membrane protein that targets to the Golgi region
and caveolae of endothelial cells. Recent evidence has shown that eNOS can co-precipitate with caveolin-1, the resident coat
protein of caveolae, suggesting a direct interaction between these two proteins. To test this idea, we examined the interactions
of eNOS with caveolin-1 in vitro and in vivo. Incubation of endothelial cell lysates or purified eNOS with glutathioneS-transferase (GST)-caveolin-1 resulted in the direct interaction of the two proteins. Utilizing a series of GST-caveolin-1
deletion mutants, we identified two cytoplasmic domains of caveolin-1 that interact with eNOS, the scaffolding domain (amino
acids 61–101) and to a lesser extent the C-terminal tail (amino acids 135–178). Incubation of pure eNOS with peptides derived
from the scaffolding domains of caveolin-1 and -3, but not the analogous regions from caveolin-2, resulted in inhibition of
eNOS, inducible NOS (iNOS), and neuronal NOS (nNOS) activities. These results suggest a common mechanism and site of inhibition.
Utilizing GST-eNOS fusions, the site of caveolin binding was localized between amino acids 310 and 570. Site-directed mutagenesis
of the predicted caveolin binding motif within eNOS blocked the ability of caveolin-1 to suppress NO release in co-transfection
experiments. Thus, our data demonstrate a novel functional role for caveolin-1 in mammalian cells as a potential molecular
chaperone that directly inactivates NOS. This suggests that the direct binding of eNOS to caveolin-1, per se, and the functional consequences of eNOS targeting to caveolae are likely temporally and spatially distinct events that regulate
NO production in endothelial cells. Additionally, the inactivation of eNOS and nNOS by the scaffolding domain of caveolin-3
suggests that eNOS in cardiac myocytes and nNOS in skeletal muscle are likely subject to negative regulation by this muscle-specific
caveolin isoform.
Grape seed proanthocyanidins have been reported to possess a broad spectrum of pharmacological and medicinal properties against oxidative stress. We have demonstrated that IH636 proanthocyanidin extract (GSPE) provides excellent protection against free radicals in both in vitro and in vivo models. GSPE had significantly better free radical scavenging ability than vitamins C, E and β-carotene and demonstrated significant cytotoxicity towards human breast, lung and gastric adenocarcinoma cells, while enhancing the growth and viability of normal cells. GSPE protected against tobacco-induced apoptotic cell death in human oral keratinocytes and provided protection against cancer chemotherapeutic drug-induced cytotoxicity in human liver cells by modulating cell cycle/apoptosis regulatory genes such as bcl2, p53 and c-myc. Recently, the bioavailability and mechanistic pathways of cytoprotection by GSPE were examined on acetaminophen-induced hepatotoxicity and nephrotoxicity, amiodarone-induced pulmonary toxicity, doxorubicin-induced cardiotoxicity, DMN-induced immunotoxicity and MOCAP-induced neurotoxicity in mice. Serum chemistry changes, integrity of genomic DNA and histopathology were assessed. GSPE pre-exposure provided near complete protection in terms of serum chemistry changes and DNA damage, as well as abolished apoptotic and necrotic cell death in all tissues. Histopathological examination reconfirmed these findings. GSPE demonstrated concentration-/dose-dependent inhibitory effects on the drug metabolizing enzyme cytochrome P450 2E1, and this may be a major pathway for the anti-toxic potential exerted by GSPE. Furthermore, GSPE treatment significantly decreased TNF-induced adherence of T-cells to HUVEC by inhibiting VCAM-1 expression. These results demonstrate that GSPE is highly bioavailable and may serve as a potential therapeutic tool in protecting multiple target organs from structurally diverse drug- and chemical-induced toxicity.
Endothelial nitric oxide synthase (eNOS) is a dually acylated peripheral membrane protein that targets to the Golgi region and caveolae of endothelial cells. Recent evidence has shown that eNOS can co-precipitate with caveolin-1, the resident coat protein of caveolae, suggesting a direct interaction between these two proteins. To test this idea, we examined the interactions of eNOS with caveolin-1 in vitro and in vivo. Incubation of endothelial cell lysates or purified eNOS with glutathione S-transferase (GST)-caveolin-1 resulted in the direct interaction of the two proteins. Utilizing a series of GST-caveolin-1 deletion mutants, we identified two cytoplasmic domains of caveolin-1 that interact with eNOS, the scaffolding domain (amino acids 61-101) and to a lesser extent the C-terminal tail (amino acids 135-178). Incubation of pure eNOS with peptides derived from the scaffolding domains of caveolin-1 and -3, but not the analogous regions from caveolin-2, resulted in inhibition of eNOS, inducible NOS (iNOS), and neuronal NOS (nNOS) activities. These results suggest a common mechanism and site of inhibition. Utilizing GST-eNOS fusions, the site of caveolin binding was localized between amino acids 310 and 570. Site-directed mutagenesis of the predicted caveolin binding motif within eNOS blocked the ability of caveolin-1 to suppress NO release in co-transfection experiments. Thus, our data demonstrate a novel functional role for caveolin-1 in mammalian cells as a potential molecular chaperone that directly inactivates NOS. This suggests that the direct binding of eNOS to caveolin-1, per se, and the functional consequences of eNOS targeting to caveolae are likely temporally and spatially distinct events that regulate NO production in endothelial cells. Additionally, the inactivation of eNOS and nNOS by the scaffolding domain of caveolin-3 suggests that eNOS in cardiac myocytes and nNOS in skeletal muscle are likely subject to negative regulation by this muscle-specific caveolin isoform.
Increasing evidence shows that red wine consumption has cardioprotective effects. These effects have been attributed to the polyphenolic compounds in grapes.
We studied the effects of red grape seed proanthocyanidins on the recovery of postischemic function in isolated rat hearts.
Two groups of rats were fed different doses of proanthocyanidin-rich extract for 3 wk and another group was untreated and served as controls. The animals were then anesthetized and the hearts were isolated and subjected to 30 min of ischemia followed by 2 h of reperfusion. Coronary effluents were collected during the third minute of reperfusion for measurement of oxygen free radicals by using electron spin resonance spectroscopy.
In rats treated with 50 and 100 mg grape seed proanthocyanidins/kg, the incidence of reperfusion-induced ventricular fibrillation was reduced from its control value of 92% to 42% and 25%, respectively (P < 0.05 for both). The incidence of ventricular tachycardia showed the same pattern. In rats treated with 100 mg proanthocyanidins/kg, the recovery of coronary flow, aortic flow, and developed pressure after 60 min of reperfusion was improved by 32% +/- 8%, 98% +/- 8%, and 37% +/- 3%, respectively (P < 0.05 for all) compared with untreated control rats. Electron spin resonance studies indicated that proanthocyanidins significantly inhibited the formation of oxygen free radicals. In rats treated with 100 mg proanthocyanidins/kg, free radical intensity was reduced by 75% +/- 7% (P < 0.05) compared with the control rats.
Grape seed proanthocyanidins have cardioprotective effects against reperfusion-induced injury via their ability to reduce or remove, directly or indirectly, free radicals in myocardium that is reperfused after ischemia.
Gene therapy refers to the transfer of specific genes to the host tissue to intervene in a disease process, with resultant alleviation of the symptoms of a particular disease. Cardiovascular gene transfer is not only a powerful technique for studying the function of specific genes in cardiovascular biology and pathobiology, but also a novel and promising strategy for treating cardiovascular diseases. Since the mid-1990s, nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide (NO) from L-arginine, has received considerable attention as a potential candidate for cardiovascular gene therapy, because NO exerts critical and diverse functions in the cardiovascular system, and abnormalities in NO biology are apparent in a number of cardiovascular disease processes including cerebral vasospasm, atherosclerosis, postangioplasty restenosis, transplant vasculopathy, hypertension, diabetes mellitus, impotence and delayed wound healing. There are three NOS isoforms, i.e., endothelial (eNOS), neuronal (nNOS) and inducible (iNOS). All three NOS isoforms have been used in cardiovascular gene transfer studies with encouraging results. This review will discuss the rationale of NOS gene therapy in different cardiovascular disease settings and summarize the results of experimental NOS gene therapy from various animal models of cardiovascular disease to date.
Caveolae are the sites in the cell membrane responsible for concentrating an array of signaling molecules critical for cell function. Recent studies have begun to identify the functions of caveolin-1, the 22-kDa caveolar protein that oligomerizes and inserts into the cytoplasmic face of the plasma membrane. Caveolin-1 appears to regulate caveolar internalization by stabilizing caveolae at the plasma membrane rather than controlling the shape of the membrane invagination. Because caveolin-1 is a scaffolding protein, it has also been hypothesized to function as a "master regulator" of signaling molecules in caveolae. Deletion of the caveolin-1 gene in mice resulted in cardiac hypertrophy and lung fibrosis, indicating its importance in cardiac and lung development. In the endothelium, caveolin-1 regulates nitric oxide signaling by binding to and inhibiting endothelial nitric oxide synthase (eNOS). Increased cytosolic Ca2+ or activation of the kinase Akt leads to eNOS activation and its dissociation from caveolin-1. Caveolae have also been proposed as the vesicle carriers responsible for transcellular transport (transcytosis) in endothelial cells. Transcytosis, the primary means of albumin transport across continuous endothelia, occurs by fission of caveolae from the membrane. This event is regulated by tyrosine phosphorylation of caveolin-1 and dynamin. As Ca2+ influx channels and pumps are localized in caveolae, caveolin-1 is also an important determinant of Ca2+ signaling in endothelial cells. Many of these findings were presented in San Diego, CA, at the 2003 Experimental Biology symposium "Caveolin Regulation of Endothelial Function" and are reviewed in this summary.
Superoxide is increased in the vessel wall of spontaneously hypertensive rats (SHR) where, if "blocked," potentiates endothelium-dependent vasodilation. The purpose of this study was to determine the role of superoxide anion in hypertension and its interaction with nitric oxide (NO). For this purpose we used a low molecular weight synthetic superoxide dismutase mimetic (M40403), known to remove selectively superoxide anion. Baseline mean arterial pressure (MAP) was significantly elevated in the SHR compared with its normal counterpart, Wistar Kyoto (WKY). M40403 at a dose (2 mg x kg(-1) x h(-1)), which had no effect in the WKY, significantly decreased MAP in SHR rats. To determine whether superoxide anion increases MAP by inactivating NO, NO synthesis was blocked with N(G) nitro-arginine methyl ester (L-NAME, 3 mg/kg i.v.), a nonselective nitric oxide synthase inhibitor. L-NAME (3 mg/kg, i.v) blocked the anti-hypertensive effect of M40403 (2 mg/kg over 30 min). When used at a dose that yielded similar increases in MAP, norepinephrine (2.1 microg/kg) failed to alter the anti-hypertensive effects of M40403 in the SHR. To investigate whether the anti-hypertensive effect of M40403 was associated with an improvement of the alterations in vascular reactivity, a separate group of experiments was carried out ex vivo. Endothelium-dependent vasorelaxation to acetylcholine (10 nM-10 microM), an index of endothelial function, was reduced in aortic rings taken from SHR rats when compared with WKY rats. In vivo treatment with M40403 caused an improvement of the degree of the endothelial dysfunction in SHR rats. Furthermore, immunohistochemical analysis for nitrotyrosine (the product formed from the interaction of nitric oxide with superoxide) revealed a positive staining in aorta from SHR rats. The degree of staining for nitrotyrosine was markedly reduced in tissue sections obtained from SHR rats treated with M40403. Our data suggest that overt production of superoxide in SHR couples with nitric oxide, reducing its function and leading to a loss of blood vessel tone and hypertension. Another important effect appears to be at the level of endothelial cellular integrity, where by interacting with nitric oxide, superoxide anion forms peroxynitrite and subsequent endothelial cell dysfunction. By removing superoxide, M40403 restores blood pressure to near-to-normal values.
Procyanidins B-l and B-3 from azuki beans showed remarkable scavenging activities, especially to hydrophilic radicals. The inhibition rate constants for the scavenging of hydrophilic peroxyl radicals generated from 2, 2′-azobis(2-amidinopropane)hydrochloride in aqueous media were calculated at 37°C to be kinh = 6.0×10⁴M⁻¹s⁻¹, 5.9×10⁴M⁻¹s⁻¹, 2.7×10⁴M⁻¹s⁻¹, 5.0×10⁴M⁻¹s⁻¹ and 1.1 × 10⁵M⁻¹s⁻¹, and the stoichiometric factors as n=8.4, 8.0, 3.7, 1.2 and 1.7 for procyanidin B-1, procyanidin B-3, (+)-catechin, ascorbic acid and α-tocopherol, respectively. Thus, the dimeric procyanidin molecule could trap eight radicals. The production and structures of procyanidin B-3 radicals are discussed on the basis of the ESR spectra observed by autoxidation of procyanidin B-3 in an aqueous alkaline methanol solution. © 1990, Japan Society for Bioscience, Biotechnology, and Agrochemistry. All rights reserved.
Procyanidins B-1 and B-3 from azuki beans showed remarkable scavenging activities, especially to hydrophilic radicals. The inhibition rate constants for the scavenging of hydrophilic peroxyl radicals generated from 2,2′-azobis(2-amidinopropane)hydrochloride in aqueous media were calculated at 37°C to be kinh = 6.0 × 104 m−1s−1, 5.9 × 104 m−1 s−1, 2.7 × 104 m −1 s−1, 5.0 × 104 m−1 s−1 and 1.1 × 105 m−1 s−1, and the stoichiometric factors as n = 8.4, 8.0, 3.7, 1.2 and 1.7 for procyanidin B-1, procyanidin B-3, (+)-catechin, ascorbic acid and α-tocopherol, respectively. Thus, the dimeric procyanidin molecule could trap eight radicals. The production and structures of procyanidin B-3 radicals are discussed on the basis of the ESR spectra observed by autoxidation of procyanidin B-3 in an aqueous alkaline methanol solution.
The effects of an oral daily dose (10 mg kg−1) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed.
Quercetin induced a significant reduction in systolic (−18%), diastolic (−23%) and mean (−21%) arterial blood pressure and heart rate (−12%) in SHR but not in WKY rats.
The left ventricular weight index and the kidney weight index in vehicle-treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin-treated SHR in parallel with the reduction in systolic blood pressure.
Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium-dependent relaxation to acetylcholine (Emax=58±5%vs 78±5%, P<0.01) in isolated aortae.
The 24 h urinary isoprostane F2α excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin-treated SHR rats both parameters were similar to those of vehicle-treated WKY.
These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug.
British Journal of Pharmacology (2001) 133, 117–124; doi:10.1038/sj.bjp.0704064
The reaction of lipid peroxides in animal tissues with thiobarbituric acid was dependent on pH of the reaction mixture as was the case for linoleic acid hydroperoxide. The optimum pH was found to be 3.5. Taking this fact into consideration, a standard procedure for the assay of lipid peroxide level in animal tissues by their reaction with thiobarbituric acid was developed as follows. Ten percent ( tissue homogenate was mixed with sodium dodecyl sulfate, acetate buffer (pH 3.5), and aqueous solution of thiobarbituric acid. After heating at 95°C for 60 min, the red pigment produced was extracted with n-butanol-pyridine mixture and estimated by the absorbance at 532nm. As an external standard, tetramethoxy-propane was used, and lipid peroxide level was expressed in terms of nmol malondialdehyde. Using this method, the liped peroxide level in the liver of rats suffering from carbon tetrachloride intoxication was investigated. The results were in good agreement with previously reported data obtained by measuring diene content.
The available data on the role of the L-arginine/nitric oxide (NO) pathway in the genesis of hypertension in spontaneously hypertensive rats (SHR) are limited and contradictory. In an attempt to address this issue, male SHR were studied during the early phase of evolution of hypertension (age 8 to 12 weeks) to distinguish the primary changes of NO metabolism from those caused by advanced hypertension, vasculopathy, and aging late in the course of the disease. A group of age-matched male Wistar-Kyoto rats (WKY) served as controls. The SHR exhibited a marked rise in arterial blood pressure and a significant increase in urinary excretion and plasma concentration of NO metabolites (nitrite/nitrate [NOx]). Likewise, the SHR showed a significant elevation of thoracic aorta NO synthase (NOS) activity coupled with significant increases of kidney, aorta, inducible NOS (iNOS), and endothelial NOS (eNOS) proteins. In an attempt to determine whether the enhanced L-arginine/NO pathway is a consequence of hypertension, studies were repeated using 3-week-old animals before the onset of hypertension. The study revealed significant increases in urinary NOx excretion as well as vascular eNOS and renal iNOS proteins. In conclusion, the L-arginine/NO pathway is upregulated in young SHR both before and after the onset of hypertension. Thus, development of hypertension is not due to a primary impairment of NO production in SHR. On the contrary, NO production is increased in young SHR both before and after the onset of hypertension.
The hypothesis that the decreased nitric oxide (NO) availability observed in spontaneously hypertensive stroke-prone rats (SHRSP) is due to excess superoxide (O2-) was examined. O2- generation, measured by lucigenin chemiluminescence, was studied in 12- to 16-week male and female Wistar-Kyoto rats (WKY) and SHRSP. In addition, expression of the gene encoding endothelial NO synthase, the enzyme involved in NO generation, was investigated. O2- generation was increased in male and female SHRSP (4.11+/-0.24 and 3. 84+/-0.28 nmol O2-. min-1. mg-1 respectively) compared with their WKY counterparts and was significantly higher in male than female WKY (1.22+/-0.08 in males and 0.8+/-0.08 nmol O2-. min-1. mg-1 respectively) (SHRSP versus WKY P<0.0001, 95% CI -3.39, -2.51; male versus female WKY P=0.0029, 95% CI -0.67, -0.17). Removal of the endothelium by rubbing or addition of NO synthase inhibitors attenuated O2- generation in SHRSP but not WKY. In males, removal of the endothelium reduced O2- generation from 3.86+/-0.12 to 1.35+/-0. 08 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.29, 2.81), whereas addition of L-NAME caused a reduction from 4.13+/-0.17 to 1.32+/-0.16 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.36, 2.83). Similar reductions were observed in females. L-arginine had no significant effect, but tetrahydrobiopterin significantly decreased O2- generation in SHRSP from 4.04+/-0.11 to 2.36+/-0.40 nmol. min-1. mg-1 (P=0.0026, 95% CI 0.89, 2.44). Endothelial NO synthase mRNA expression was significantly greater in SHRSP than in WKY and in WKY males than in WKY females. These results show that O2- generation is increased in SHRSP and that the tissue and enzymatic sources of this excess O2- appear to be the endothelium and eNOS, respectively. The increase in O2- generation could explain the decreased availability of basal NO observed in this model of genetic hypertension.
We recently showed elevated reactive oxygen species (ROS), reduced urinary excretion of NO metabolites (NOx), and increased NO sequestration as nitrotyrosine in various tissues in rats with lead-induced hypertension. This study was designed to discern whether the reduction in urinary NOx in lead-induced hypertension is, in part, due to depressed NO synthase (NOS) expression. Male Sprague-Dawley rats were randomly assigned to a lead-treated group (given lead acetate, 100 ppm, in drinking water and regular rat chow), a group given lead and vitamin E-fortified chow, or a normal control group given either regular food and water or vitamin E-fortified food for 12 weeks. Tail blood pressure, urinary NOx excretion, plasma malondialdehyde (MDA), and endothelial and inducible NOS (eNOS and iNOS) isotypes in the aorta and kidney were measured. The lead-treated group exhibited a rise in blood pressure and plasma MDA concentration, a fall in urinary NOx excretion, and a paradoxical rise in vascular and renal tissue eNOS and iNOS expression. Vitamin E supplementation ameliorated hypertension, lowered plasma MDA concentration, and raised urinary NOx excretion while significantly lowering vascular, but not renal, tissue eNOS and iNOS expression. Vitamin E supplementation had no effect on either blood pressure, plasma MDA, or NOS expression in the control group. The study also revealed significant inhibition of NOS enzymatic activity by lead in cell-free preparations. In conclusion, lead-induced hypertension in this model was associated with a compensatory upregulation of renal and vascular eNOS and iNOS expression. This is, in part, due to ROS-mediated NO inactivation, lead-associated inhibition of NOS activity, and perhaps stimulatory actions of increased shear stress associated with hypertension.
Much attention has been focused on the role of nitric oxide in hypertension and cardiovascular disease. More recently, the role of superoxide anion and its interaction with nitric oxide has been investigated in this context. This review will concentrate on the role of superoxide in human and experimental hypertension, paying particular attention to the potential sources of superoxide within the vasculature and discussing some of the molecular mechanisms surrounding its production and dismutation. We discuss what is known about the human superoxide dismutase enzymes. We conclude that the balance between nitric oxide and superoxide is more important than the absolute levels of either alone.
Earlier studies have demonstrated evidence for increased reactive oxygen species, enhanced NO synthase (NOS) expression, and elevated NO production in spontaneously hypertensive rats (SHR). Given the negative-feedback regulation of NOS by NO, we hypothesized that enhanced NO inactivation by ROS may contribute to compensatory upregulation of NOS in SHR. The present study was designed to test this hypothesis. Eight-week-old male SHR and Wistar-Kyoto rats were treated for 3 weeks with either a placebo or the potent antioxidant, lazaroid (desmethyltirilazad, 10 mg. kg(-1). d(-1), by gastric gavage). Tail arterial blood pressure, urinary excretion of NO metabolites (ie, nitrate and nitrite), and immunodetectable NOS isotype proteins in the vascular, renal, cardiac, and cerebral tissues were measured. The placebo-treated SHR group showed a marked elevation of blood pressure and a significant upregulation of aorta, kidney, and cardiac tissue endothelial and inducible NOS (eNOS and iNOS, respectively) proteins and of brain and renal tissue neuronal NOS. Lazaroid therapy ameliorated hypertension and mitigated the upregulation of eNOS and iNOS in vascular, renal, and cardiac tissues but had limited effect on the expression of renal and brain neuronal NOS. In contrast, lazaroid therapy had no effect on blood pressure, urinary nitrate and nitrite excretion, or tissue NOS isotype expressions in the Wistar-Kyoto group. These findings support the role of oxidative stress in the genesis and/or maintenance of hypertension and compensatory upregulation of the expression of eNOS and iNOS in SHR.
Severe aortic stenosis above the renal arteries leads to a reduction in renal perfusion, increased renin secretion, and elevation of arterial blood pressure above the stenotic site. Nitric oxide (NO) plays an important role in regulation of renal and systemic vascular resistance, renal blood flow, and Na(+) handling. Abdominal aortic banding provides an excellent model for simultaneous testing of the effects of increased and decreased pressure, flow, and shear stress in the same animal.
We studied protein expressions of endothelial NO synthase (eNOS), inducible NOS (iNOS), and neuroneal NOS (nNOS) isotypes in the renal cortex, renal medulla, heart, brain, and aorta segments above and below the stenosis site three weeks after abdominal aortic banding above the renal arteries. The results were compared with those obtained in the sham-operated controls. NOS isotype proteins were measured by Western blot.
Compared with the control group, the banded group showed significant up-regulations of eNOS, iNOS, and nNOS in renal cortex and medulla. Likewise, heart eNOS, brain nNOS, and thoracic aorta eNOS proteins were significantly increased in the banded group. However, eNOS and iNOS expressions were unchanged in the aorta segment below the stenotic site. Likewise, iNOS expression in the heart and thoracic aorta remained unchanged in the banded animals. No significant difference was found in creatinine clearance or urinary protein excretion between the two groups.
These findings clearly demonstrate the up-regulatory action of increased pressure on eNOS expression in the thoracic aorta and heart and of nNOS expression in the brain. These data further show up-regulation of all NOS isotypes in the kidney, which must have helped to mitigate the associated hypoperfusion.
1. The effects of an oral daily dose (10 mg kg(-1)) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. 2. Quercetin induced a significant reduction in systolic (-18%), diastolic (-23%) and mean (-21%) arterial blood pressure and heart rate (-12%) in SHR but not in WKY rats. 3. The left ventricular weight index and the kidney weight index in vehicle-treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin-treated SHR in parallel with the reduction in systolic blood pressure. 4. Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium-dependent relaxation to acetylcholine (E(max)=58+/-5% vs 78+/-5%, P<0.01) in isolated aortae. 5. The 24 h urinary isoprostane F(2 alpha) excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin-treated SHR rats both parameters were similar to those of vehicle-treated WKY. 6. These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug.
Chronic exposure to low levels of lead causes hypertension (HTN) that is, in part, due to increased inactivation of nitric oxide (NO) by reactive oxygen species (ROS). The latter results in functional NO deficiency and compensatory up-regulation of NO synthase (NOS). We have previously shown evidence for increased hydroxyl radical (*OH) activity in rats with lead-induced HTN. Since in the biological systems *OH is primarily derived from superoxide (O2*) we hypothesize that lead-induced oxidative stress and HTN must be due to increased O2* production and as such could be ameliorated by administration of a cell-permeable O2* scavenger. We, therefore, studied the effects of the superoxide dismutase (SOD)-mimetic drug tempol (15 mmol/kg/day i.p. x 2 weeks) and placebo in lead-exposed (given lead acetate, 100 ppm in the drinking water for 12 weeks) and normal control rats. Lead exposure resulted in a marked elevation of blood pressure, a significant reduction in urinary NO metabolites (NO(chi)) excretion, and up-regulations of endothelial and inducible NOS abundance in the kidney, aorta, and heart and of neuronal NOS in the cerebral cortex and brain stem. Administration of tempol ameliorated HTN, increased urinary NO(chi) excretion, and reversed the compensatory up-regulation of NOS isoforms in rats with lead-induced HTN. These abnormalities recurred within 2 wk after discontinuation of tempol. In contrast to the lead-exposed rats, the normal control rats showed no change in either blood pressure, urinary NO(chi) excretion, or tissue NOS expression in response to either administration or discontinuation of tempol. Thus, the study supports the presence of increased O2* activity and its role in the pathogenesis of HTN and altered NO metabolism in lead-exposed animals.
Endothelial nitric oxide synthase (eNOS) is important for cardiovascular homeostasis, vessel remodeling, and angiogenesis. Given the impact of endothelium- derived nitric oxide (NO) in vascular biology, much work in the past several years has focused on the control of NO synthesis by regulatory proteins that influence its function. Indeed calcium-activated calmodulin is important for regulation of NOS activity. Herein we discuss why other proteins, in addition to calmodulin, are necessary for eNOS regulation and summarize the biology of negative and positive regulators of eNOS function in vitro, in cells, and in blood vessels.
Diabetic nephropathy has become the leading cause of uremia. Several lines of evidence suggest dietary factors other than protein intake have a substantial role in the progression of diabetic nephropathy to end-stage renal disease. The present investigation was initiated to evaluate whether a carbohydrate-restricted, low-iron-available, polyphenol-enriched (CR-LIPE) diet may delay and improve the outcome of diabetic nephropathy to a greater extent than standard protein restriction. To this aim, 191 diabetic patients, all with type 2 diabetes, were randomized to either CR-LIPE or standard protein restriction and the following outcomes monitored: doubling of serum creatinine, cumulative incidence of end-stage renal disease, and all cause mortality. Over a mean follow-up interval of 3.9 +/- 1.8 years, serum creatinine concentration doubled in 19 patients on CR-LIPE (21%) and in 31 control subjects (39%) (P < 0.01). Renal replacement therapy or death occurred in 18 patients on CR-LIPE (20%) and in 31 control subjects (39%) (P < 0.01). These differences were independent from follow-up interval, sex, mean arterial blood pressure, HbA(1c), initial renal dysfunction, and angiotensin system inhibitor use. In conclusion, CR-LIPE was 40-50% more effective than standard protein restriction in improving renal and overall survival rates.
Accumulating evidence indicates that reactive oxygen species (ROS) play major roles in the initiation and progression of cardiovascular dysfunction associated with diseases such as hyperlipidemia, diabetes mellitus, hypertension, ischemic heart disease, and chronic heart failure. ROS produced by migrating inflammatory cells as well as vascular cells (endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts) have distinct functional effects on each cell type. These include cell growth, apoptosis, migration, inflammatory gene expression, and matrix regulation. ROS, by regulating vascular cell function, can play a central role in normal vascular physiology, and can contribute substantially to the development of vascular disease.
Flavonoids are known to possess cardioprotective properties. Vascular endothelial function is a surrogate marker for cardiovascular diseases, including hypertension. We have studied the effects of chronic flavonoid treatment on vascular endothelial functions in spontaneously hypertensive rats (SHR). Starting from 6-7 weeks old, SHR were given flavonoids (baicalein, flavone, or quercetin) orally (10 mg/kg, once daily) to the SHRs for 4 weeks. Aortas from all the flavonoid-treated animals showed remarkably higher endothelium-dependent relaxations to acetylcholine, to a similar extent as those pretreated with the angiotensin-converting enzyme inhibitor, captopril. However, in contrast to other experimental groups, flavone pretreatment also enhanced the endothelium-independent relaxations to sodium nitroprusside. In addition, treatment with either flavone or quercetin induced a significant attenuation in systolic blood pressure of the hypertensive animals. The present results suggest that chronic treatment with the flavonoids (baicalein, flavone, and quercetin) preserves vascular endothelial functions in hypertensive animals through several possible actions, including increasing endothelial nitric oxide production and bioavailability and reduction in blood pressure.
Several studies have found that chronic treatment with the dietary flavonoid quercetin lowers blood pressure and restores endothelial dysfunction in hypertensive animal models. We hypothesized that increased endothelial nitric oxide synthase (eNOS) and/or decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein expression and activity, and reduced reactive oxygen species might be involved in the improvement of endothelial function induced by quercetin in spontaneously hypertensive rats (SHR).
Male SHR and Wistar-Kyoto (WKY) rats (5 weeks old) were treated with quercetin (10 mg/kg) or vehicle for 13 weeks. Changes in vascular expression of eNOS, caveolin-1 and p47 were analysed by Western blot, eNOS activity by conversion of [H]arginine to L-[H]citrulline, and NADPH oxidase activity by NADPH-enhanced chemoluminescence of lucigenin.
In SHR, quercetin reduced the increase in blood pressure and heart rate and enhanced the endothelium-dependent aortic vasodilation induced by acetylcholine, but had no effect on the endothelium-independent response induced by nitroprusside. However, quercetin had no effect on endothelium-dependent vasoconstriction and aortic thromboxane B2 production. Compared to WKY, SHR showed upregulated eNOS and p47 protein expression, downregulated caveolin-1 expression, increased NADPH-induced superoxide production but, paradoxically, eNOS activity was reduced. Chronic quercetin treatment prevented all these changes in SHR. In WKY, quercetin had no effect on blood pressure, endothelial function or the expression or activity of the proteins analysed.
Enhanced eNOS activity and decreased NADPH oxidase-mediated superoxide anion (O2) generation associated with reduced p47 expression appear to be essential mechanisms for the improvement of endothelial function and the antihypertensive effects of chronic quercetin.
In the kidney nitric oxide (NO) has numerous important functions including the regulation of renal haemodynamics, maintenance of medullary perfusion, mediation of pressure-natriuresis, blunting of tubuloglomerular feedback, inhibition of tubular sodium reabsorption and modulation of renal sympathetic neural activity. The net effect of NO in the kidney is to promote natriuresis and diuresis. Significantly, deficient renal NO synthesis has been implicated in the pathogenesis of hypertension. All three isoforms of nitric oxide synthase (NOS), namely neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2) and endothelial NOS (eNOS or NOS3) are reported to contribute to NO synthesis in the kidney. The regulation of NO synthesis in the kidney by NOSs is complex and incompletely understood. Historically, many studies of NOS regulation in the kidney have emphasized the role of variations in gene transcription and translation. It is increasingly appreciated, however, that the constitutive NOS isoforms (nNOS and eNOS) are also subject to rapid regulation by post-translational mechanisms such as Ca(2+) flux, serine/threonine phosphorylation and protein-protein interactions. Recent studies have emphasized the role of post-translational regulation of nNOS and eNOS in the regulation of NO synthesis in the kidney. In particular, a role for phosphorylation of nNOS and eNOS at both activating and inhibitory sites is emerging in the regulation of NO synthesis in the kidney. This review summarizes the roles of NO in renal physiology and discusses recent advances in the regulation of eNOS and nNOS in the kidney by post-translational mechanisms such as serine/threonine phosphorylation.
Endothelial dysfunction is an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular diseases. Epidemiological studies report an inverse association between dietary flavonoid consumption and mortality from cardiovascular diseases. In the present paper, we review the effects of flavonoids, especially quercetin and wine polyphenols, on endothelial function and dysfunction and its potential protective role in hypertension, ischemic heart disease and stroke. In vitro studies show that flavonoids may exert multiple actions on the NO-guanylyl cyclase pathway, endothelium-derived hyperpolarizing factor(s) and endothelin-1 and protect endothelial cells against apoptosis. In vivo, flavonoids prevent endothelial dysfunction and reduce blood pressure, oxidative stress and end-organ damage in hypertensive animals. Moreover, some clinical studies have shown that flavonoid-rich foods can improve endothelial function in patients with hypertension and ischemic heart disease. Altogether, the available evidence indicates that quercetin and wine polyphenols might be of therapeutic benefit in cardiovascular diseases even though prospective controlled clinical studies are still lacking.
To analyse the influence of hypertension in the modulation induced by inducible NOS (iNOS)-derived NO and superoxide anion (O(2) (*-)) of vasoconstrictor responses and the sources of O(2) (*-) implicated.
Vascular reactivity experiments were performed in segments of aorta from normotensive, Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR); protein and mRNA expressions were respectively measured by western blot and quantitative reverse transcription-polymerase chain reaction and O(2) (*-) production was evaluated by ethidium fluorescence.
The contractile responses to phenylephrine (1 nM-30 microM) and 5-hydroxytryptamine (0.1-100 microM) were greater in aortic segments from SHR than WKY. The selective iNOS inhibitor, 1400W (10 microM), increased the phenylephrine contraction only in WKY segments; however, iNOS protein and mRNA expressions were greater in aorta from SHR than WKY. Superoxide dismutase (SOD, 150 U ml(-1)) reduced phenylephrine and 5-hydroxytryptamine responses only in aorta from SHR; the NAD(P)H oxidase inhibitor apocynin (0.3 mM) decreased phenylephrine and 5-hydroxytryptamine responses more in vessels from SHR than WKY. Co-incubation with SOD plus 1400W potentiated the phenylephrine and 5-hydroxytryptamine responses more in segments from SHR than WKY. O(2) (*-) production was greater in aorta from SHR than WKY; apocynin abolished this difference.
Increased O(2) (*-) formation from NADP(H) oxidase in vessels from hypertensive rats contributes to the vasoconstrictor responses and counteract the increase of NO from iNOS and the consequent modulation of these responses.
1. Hypertension is a major risk factor for myocardial infarction and renal damage, and it has also been shown to have pro-inflammatory actions that increase the formation of reactive oxygen species. Macrophage infiltration has been suggested to play a role in the pathogenesis of hypertension. Azuki beans are known to contain pro-anthocyanidins, a group of polyphenolic bioflavonoids with remarkable radical-scavenging activities in vitro. Therefore, the aim of the present study was to investigate the effect of polyphenol-containing azuki bean extract (ABE) on systolic blood pressure (SBP) and macrophage infiltration in the heart and kidney of spontaneously hypertensive rats (SHR). 2. Spontaneously hypertensive rats and control normotensive Wistar-Kyoto (WKY) rats were divided into two groups fed either 0 or 0.8% ABE in their diets. Tail SBP and macrophage kinetics in the heart and kidney were examined. 3. The SBP of the SHR group was higher than that of age-matched WKY rats throughout the treatment period. After 8 weeks of treatment, the increased SBP in ABE-treated SHR was significantly less than that in untreated SHR. 4. Nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH)-stimulated superoxide (O2-) production was enhanced in the kidney and heart in SHR and WKY rats compared with levels in the absence of NADH or NADPH. The NADPH-stimulated superoxide (O2-) levels in the kidney in untreated SHR was significantly higher than that in untreated WKY rats. The (O2-) levels in ABE-treated SHR were significantly decreased compared with the untreated SHR group. 5. In immunohistochemical analyses, the number of macrophages in the heart and in the glomeruli and tubulointerstitium of the kidney was significantly higher in ABE-untreated SHR than in ABE-untreated WKY rats. Conversely, there was a significant decrease in the number of macrophages in ABE-treated SHR compared with the untreated SHR. There were significant positive correlations between SBP and the number of ED1-positive macrophages in the heart and tubulointerstitial and glomerular areas of the kidney in WKY rats and SHR. 6. In conclusion, the results of the present study suggest that ABE attenuates the elevation of SBP and macrophage infiltration in the heart, as well as in the glomeruli and tubulointerstitium of the kidney, in our SHR model.
Role of NADPH oxidase and iNOS in vasoconstrictor
- Briones Z Am Alvarez
- R Hernanz
- Perez-Giron
- Alonso Mj Jv
- Salaices
Alvarez Z, Briones AM, Hernanz R, Perez-Giron JV, Alonso MJ, Salaices M. Role of NADPH oxidase and iNOS in vasoconstrictor Br J Pharmacol 2008;153:926e35.