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Cardiovascular research 10/2011; 92(1):180. · 5.80 Impact Factor
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Cardiovascular research 10/2011; 92(1):181. · 5.80 Impact Factor
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Cardiovascular research 10/2011; 92(1):180. · 5.80 Impact Factor
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Metabolism: clinical and experimental 09/2011; 60(9):1355. · 2.59 Impact Factor
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Metabolism: clinical and experimental 09/2011; 60(9):1355. · 2.59 Impact Factor
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ABSTRACT: The Fenofibrate Intervention and Event Lowering in Diabetes study demonstrated that treatment with fenofibrate in individuals with type 2 diabetes mellitus not only reduced nonfatal coronary events but also diminished the need for laser treatment of diabetic retinopathy and delayed the progression of diabetic nephropathy. However, the mechanism by which fenofibrate may have altered the microvasculature remains unclear. We thus investigated the effect of fenofibrate on human glomerular microvascular endothelial cells (HGMEC). Treatment of HGMEC with fenofibrate resulted in transient activation of adenosine monophosphate-activated protein kinase (AMPK), thereby inducing the phosphorylation of Akt and endothelial nitric oxide synthase, leading to nitric oxide production. We compared AMPK activation induced by bezafibrate and WY14643 with that induced by fenofibrate in HGMEC as well as HepG2 cells. Only fenofibrate activated AMPK in HGMEC. Fenofibrate also inhibited nuclear factor-κB activation by advanced glycation end-products, thereby suppressing the expression of various adhesion molecule genes in HGMEC. Suppression of fenofibrate-induced inhibition of nuclear factor-κB activation was observed in cells treated with AMPK small interfering RNA or compound C. Furthermore, fenofibrate was observed to significantly suppress apoptosis of HGMEC in hyperglycemic culture medium. Treatment with compound C or Nw-nitro-L-arginine methyl ester (L-NAME) abolished the suppressive effect of fenofibrate on HGMEC apoptosis. Our findings suggest that fenofibrate might exert a protective effect on the microvasculature by suppressing inflammation and apoptosis through AMPK activation beyond its lipid-lowering actions.
Metabolism: clinical and experimental 04/2011; 60(4):513-22. · 2.59 Impact Factor
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Yoshiaki Kawagoe, Yoshiyuki Hattori,
Ayuko Nakano,
Chie Aoki,
Seiichi Tanaka,
Satoshi Ohta,
Toshie Iijima,
Atsuko Tomizawa,
Teruo Jojima,
Hiroyuki Kase,
Kikuo Kasai
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ABSTRACT: It is well established that statins improve the prognosis of patients with coronary artery disease. However, it is still unclear whether the protective effects of statins relate to lipid lowering alone or whether other pleiotropic effects may contribute. Thus, we compared the endothelial function among two groups of diabetic patients treated with fluvastatin 60 mg (F60) or fluvastatin 20 mg combined with ezetimibe 10 mg (F20/E10). The endothelial function was evaluated by measuring flow-mediated vasodilatation (FMD) at baseline and follow-up at 10 weeks. Similar improvements in FMD were observed in the two groups. The reduction in low-density lipoprotein cholesterol (LDL-C) was less pronounced in the F60 group, compared with the F20/E10 group. A significant reduction in remnant-like lipoprotein particles cholesterol (RLP-C) was observed in the F20/E10 group, but not in the F60 group. A correlation between the observed reduction in LDL-C or RLP-C and the improvement in FMD was observed in F20/E10 group. These results suggest that high-dose fluvastatin might have pleiotropic effects of potential clinical benefit, and that the combination of ezetimibe with a reduced dose of fluvastatin may also significantly improve endothelial function with reduction of LDL-C and RLP-C.
Endocrine Journal 02/2011; 58(3):171-5. · 2.03 Impact Factor
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ABSTRACT: We investigated the effects of endoplasmic reticulum (ER) stress inducers thapsigargin (TG) and tunicamycin (Tm) on immunostimulant lipopolysaccharide/interferon (LPS/IFN)-induced expression of isoform of nitric oxide synthase (iNOS) and nitric oxide (NO) production in vascular smooth muscle cells. LPS/IFN-induced iNOS mRNA expression was markedly enhanced by TG, whereas iNOS mRNA expression was strongly attenuated by Tm. Similarly, production of iNOS protein was markedly upregulated by TG but virtually eliminated by Tm. LPS/IFN-induced guanosine triphosphate cyclohydrolase I mRNA expression was slightly reduced by TG and markedly inhibited by Tm. Similarly, LPS/IFN-mediated induction of cellular biopterin was modestly reduced by TG and markedly inhibited by Tm. TG modestly enhanced LPS/IFN-induced activation of NF-κB, whereas Tm had no effect on it. Cellular respiration was reduced by TG and Tm in a concentration-dependent manner, which was confirmed by apoptosis assay. Thus, TG and Tm-induced ER stress and differently modulated NO production through alterations in iNOS expression and activity independently of NF-κB activation and caused a similar degree of ER stress-induced apoptosis.
Journal of cardiovascular pharmacology 01/2011; 57(4):434-8. · 2.83 Impact Factor
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Nippon rinsho. Japanese journal of clinical medicine 11/2010; 68 Suppl 9:186-9.
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ABSTRACT: An HMG-CoA reductase inhibitor, fluvastatin, appears to act directly on the blood vessel wall to stabilize plaques in situ, agents that share this property have been termed vascular statins.
We investigated the effects of fluvastatin on endothelial nitric oxide synthase (eNOS) phosphorylation and expression, as well as terahydrobiopterin (BH4) metabolism, in human umbilical vein endothelial cells (HUVEC).
Fluvastatin was observed to enhance eNOS phosphorylation at Ser-1177 and Ser-633 through the PI3-kinase/Akt and PKA pathways, respectively. Inhibition of eNOS phosphorylation using inhibitors of these pathways attenuated acute NO release in response to fluvastatin. The mRNA of GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme of the first step of de novo BH4 synthesis, as well as eNOS, was upregulated in HUVEC treated with fluvastatin. In parallel with this observation, fluvastatin increased intracellular BH4. Pre-treatment of HUVEC with the selective GTPCH inhibitor, 2,4-diamino-6-hydroxypyrimidine, reduced intracellular BH4 and decreased citrulline formation following stimulation with ionomycin. Furthermore, the potentiating effect of fluvastatin was reduced by limiting the cellular availability of BH4.
Our data demonstrate that fluvastatin phosphorylates and activates eNOS, and increases eNOS expression in vascular endothelial cells. In addition to modulating eNOS, fluvastatin potentiates GTPCH gene expression and BH4 synthesis, thereby increasing NO production and preventing relative shortages of BH4.
International journal of cardiology 11/2010; 156(1):55-61. · 7.08 Impact Factor
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ABSTRACT: Ghrelin contains an octanoic acid at the third residue serine, and the presence of octanoic acid on ghrelin is critical to its physiological functions. The precise mechanism for the deacylation of ghrelin in circulation remains to be clarified, although the level of deacylated ghrelin (des-acyl ghrelin) is higher than that of acylated ghrelin in serum. In this study, rapid identification of ghrelin deacylation activity was achieved by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and a ghrelin deacylation enzyme was purified 1515-fold from fetal bovine serum. Chromatographic separation showed a 24-kDa band on SDS-PAGE corresponding to ghrelin deacylation activity, and the protein band was identified as acyl-protein thioesterase 1 (APT1)/lysophospholipase I. A ghrelin deacylation enzyme in medium from HepG2 cells was also purified and identified as APT1. Although it lacks a secretion signal sequence, APT1 may be released by cells expressing APT1, mainly from liver in vivo. APT1 was originally purified as a cytosolic lysophospholipid hydrolyzing enzyme (lysophospholipase I), and recombinant APT1 exhibited deacylation activity as well as lysophospholipase activity in vitro. APT1 is released at high levels from RAW264.7 macrophage-like cells into the culture medium after stimulation with lipopolysaccharide (LPS), and LPS suppresses APT1 mRNA and protein expressions in these cells. More potent ghrelin deacylase activities were detected in sera from LPS-treated rats than in control sera. These results suggested that the serum activity of APT1 may play an important role in determination of the concentration of des-acyl ghrelin in circulation, especially under septic inflammation.
Endocrinology 10/2010; 151(10):4765-75. · 4.46 Impact Factor
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ABSTRACT: Patients with dyslipidemia and advanced renal failure are at markedly increased risk of cardiovascular morbidity and mortality. We evaluated the efficacy and safety of ezetimibe administration to patients with endstage renal failure (ESRF) who are undergoing hemodialysis. Ezetimibe at 10 mg/day was given to 20 patients for 12 weeks. Efficacy was determined by monitoring lipids, and safety was determined by monitoring clinical and laboratory parameters. We also evaluated the effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis. Compared to baseline values, LDL-cholesterol (LDL-C) was reduced by 24.9% (p<0.005) after 12 weeks of ezetimibe administration. Treatment with ezetimibe did not change HDL-cholesterol, triglyceride and HbA1c values but caused a significant reduction in remnant like particles-cholesterol (RLP-C, p<0.05) and high-sensitive C-reactive protein (hsCRP, p<0.05). Ezetimibe therapy decreased cholesterol absorption markers (campesterol and sitosterol) and increased a marker of cholesterol synthesis (lathosterol). A highly significant correlation was observed between alterations in LDL-C and campesterol levels in response to ezetimibe therapy. No patients reported musculoskeletal symptoms. None of the patients experienced elevations in their creatine kinase or liver transaminase levels. Ezetimibe not only reduced serum LDL-C, but also RLP-C and hsCRP, in ESRF patients. Inhibition of cholesterol absorption by ezetimibe is an important therapeutic option in these patients due to its efficacy and safety.
Endocrine Journal 09/2010; 57(11):1001-5. · 2.03 Impact Factor
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ABSTRACT: Cilostazol is a selective inhibitor of phosphodiesterase 3, by which it increases intracellular cAMP and activates protein kinase A, thereby inhibiting platelet aggregation and inducing peripheral vasodilation. We investigated whether cilostazol might prevent nuclear factor (NF)-kappaB activation by activating AMP-activated protein kinase (AMPK) in vascular smooth muscle cells (VSMC).
Cilostazol was observed to activate AMPK, as well as its downstream target, acetyl-CoA carboxylase, in rat VSMC. Phosphorylation of AMPK with cilostazol was not affected by co-treatment with an adenylate cyclase inhibitor, SQ 22536. Furthermore, a cell-permeable cyclic AMP analog, pCTP-cAMP, did not influence cilostazol-induced AMPK phosphorylation. These findings suggest that cilostazol-induced AMPK activation occurs through a signalling pathway independent of cyclic AMP. Cilostazol dose-dependently inhibited LPS-induced NF-kappaB activation in the present study. It was also observed to inhibit LPS-induced iNOS gene promoter activity and iNOS gene expression, resulting in markedly reduced NO production. An AMPK inhibitor compound C or siRNA for AMPK attenuated the observed cilostazol-induced inhibition of NF-kappaB activation by LPS. Ingestion of cilostazol inhibited NF-kappaB activation, as well as the induction of iNOS mRNA and protein expression, within the aortas of LPS-treated rats.
In light of these findings, we suggest that cilostazol might attenuate cytokine-induced expression of the iNOS gene by inhibiting NF-kappaB following AMPK activation in VSMC.
Journal of atherosclerosis and thrombosis 02/2010; 17(5):503-9. · 2.69 Impact Factor
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ABSTRACT: A 68-year-old woman developed Cushingoid features three months prior to admission. She was found to have a markedly elevated plasma ACTH-cortisol level. Magnetic resonance imaging (MRI) revealed a mass in the left sphenoidal sinus, which had become enlarged to a point where it could not be removed by transsphenoidal surgery. We decided to proceed with radiation therapy to shrink the tumor. However, it was ineffective. Despite a reduction in serum cortisol levels using metyrapone, she died of septic shock. We describe a rare case of an ACTH-secreting pituitary adenoma within the sphenoid sinus.
Internal Medicine 01/2010; 49(8):763-6. · 0.94 Impact Factor
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ABSTRACT: Adiponectin is an adipocyte-specific protein that plays an important regulatory role in the development or prevention of diabetes and atherosclerosis.
In the present study, we examined the effect of a proteolytic cleavage product of adiponectin, known as globular adiponectin (gAd), on induction of gene expression and activation of various signaling pathways in vascular endothelial cells.
We showed that gAd induces the expression of a number of genes using PCR arrays, including MCP-1, VCAM-1, E-selectin, IL-6, and IL-8, all of which have been previously shown to be associated with adiponectin, as well as SOD2, PAI-1, and CSF2, which is a new finding. We also demonstrated that gAd activates AMPK, Akt, and NF-kB, as well as various MAPKs, including ERK1/2, JNK, and p38MAPK.
Upstream regulation of gene expression might involve two or more activated pathways which interact with one another.
Life sciences 08/2009; 85(11-12):457-61. · 2.56 Impact Factor
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ABSTRACT: Telmisartan is an angiotensin-II type 1 receptor (AT1R) blocker, currently used to treat patients with hypertension. Telmisartan, in addition to its effect on AT1R, is thought to activate the nuclear transcription factor, peroxisome proliferator-activated receptor-gamma (PPAR gamma), thereby acting as a partial PPAR gamma agonist. This study was conducted to examine whether telmisartan might suppress cytokine-induced inflammatory signaling in vascular endothelial cells, thereby attenuating cellular inflammation possibly by PPAR gamma activation. Telmisartan caused a dose-dependent suppression of the tumor necrosis factor-alpha (TNFalpha)-induced activation of nuclear factor (NF)-kappaB in vascular endothelial cells in this study. The PPAR gamma antagonist, GW9662, did not influence the inhibitory effect of telmisartan on NF-kappaB activation. The thiazolidinediones neither influenced TNFalpha-induced NF-kappaB activation nor influenced the inhibitory effect of telmisartan in this process. Telmisartan dose dependently diminished the TNFalpha-induced gene expression of VCAM-1, and GW9662 did not attenuate this effect. Thus, telmisartan inhibits the cytokine-induced expression of the VCAM-1 gene by blocking NF-kappaB activation independently of PPAR gamma activation. Although the mechanism by which this occurs remains unclear, our findings suggest that telmisartan-induced anti-inflammatory effects might have favorable effects on vasculature in hypertensive patients.
Hypertension Research 08/2009; 32(9):765-9. · 2.58 Impact Factor
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Toshio Nishikimi,
Chikako Inaba-Iemura,
Kimihiko Ishimura,
Kazuyoshi Tadokoro,
Shogo Koshikawa,
Keiko Ishikawa,
Kazumi Akimoto, Yoshiyuki Hattori,
Kikuo Kasai,
Naoto Minamino,
Nobuyo Maeda,
Hiroaki Matsuoka
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ABSTRACT: This study was designed to examine whether natriuretic peptide/natriuretic peptide receptor-A (NPR-A) system attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanism involved.
Three groups were studied: untreated UUO in wild-type mice; untreated UUO in NPR-A KO mice; and ANP treated (0.05 microg/kg/min) UUO in wild-type mice. We measured histological and immunohistochemical findings (alpha-SMA and F4/80), tissue cGMP levels, various mRNA expression levels by real-time PCR analysis, and transcription factor levels (AP-1 and NF-kappaB) in renal tissue.
Compared with wild-type UUO mice, NPRA-KO UUO mice had abnormal morphological findings (fibrous area: +26%, alpha-SMA expression: +30%) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF-beta, collagen I, collagen III, PAI-1, renin and angiotensinogen, whereas there were no differences in F4/80 positive cells or the mRNA expression levels of ICAM-1, osteopontin, or MCP-1 between the two groups. In contrast, ANP pre-treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF-beta, collagen I, collagen III, PAI-1, ICAM-1, osteopontin, MCP-1, renin, and angiotensinogen. NPRA-KO UUO mice had higher AP-1 levels than wild-type UUO mice and ANP pre-treatment reduced AP-1 and NF-kappaB activity.
The endogenous natriuretic peptide/NPR-A system may inhibit renal fibrosis partly via inhibition of the angiotensin/AP-1/TGF-beta/collagen pathway and exogenous ANP pre-treatment may inhibit it partly via both the angiotensin/AP-1/TGF-beta/collagen and NF-kappaB/inflammatory pathways.
Regulatory Peptides 03/2009; 154(1-3):44-53. · 2.11 Impact Factor
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ABSTRACT: Statins appear to play a role in preventing atherosclerosis. Here, we compared the effects of two statins, fluvastatin, a lipid-soluble "vascular statin", and rosuvastatin, a water-soluble "superstatin" with potent LDL-lowering potency, on endothelial function, as evaluated by flow-mediated vasodilatation (FMD) of the brachial artery following forearm ischemia in ultrasound studies of patients with type 2 diabetes. For this, we treated 30 hypercholesterolemic diabetic patients with 30 mg fluvastatin or 2.5 mg rosuvastain for 3 months, and measured FMD, LDL-cholesterol, HDL-cholesterol, high-sensitive C-reactive protein, oxidized LDL, and urine isoprostane. We found that fluvastatin improved FMD (%) from 3.85+/-1.43 to 5.61+/-2.48, while rosuvastatin improved FMD from 3.63+/-1.76 to 4.97+/-2.70 (change in FMD: fluvastatin 1.76+/-1.59 vs. rosuvastatin 1.34+/-1.56). On the other hand, fluvastatin lowered LDL-cholesterol (mg/dl) from 152+/-62.9 to 120+/-43.9, while rosuvastatin lowered LDL-cholesterol from 153+/-29.4 to 91.9+/-18.8, which was a more potent change. Thus, we conclude that fluvastatin exerts a protective action on vascular endothelial cells despite being a less potent cholesterol-lowering agent, while rosuvastatin exerts similar effects and has a potent cholesterol-lowering effect, in diabetic patients.
International journal of cardiology 02/2009; 144(1):108-9. · 7.08 Impact Factor
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ABSTRACT: Cilostazol is a selective inhibitor of phosphodiesterase 3 that increases intracellular cyclic AMP (cAMP) levels and activates protein kinase A, thereby inhibiting platelet aggregation and inducing peripheral vasodilation. We hypothesized that cilostazol may prevent inflammatory cytokine induced-nuclear factor (NF)-kappaB activation by activating AMP-activated protein kinase (AMPK) in vascular endothelial cells.
Cilostazol was observed to activate AMPK and its downstream target, acetyl-CoA carboxylase, in human umbilical vein endothelial cells (HUVEC). Phosphorylation of AMPK with cilostazol was not affected by co-treatment with an adenylate cyclase inhibitor, SQ 22536, and a cell-permeable cAMP analogue, pCTP-cAMP, did not induce AMPK phosphorylation and had no effect on cilostazol-induced AMPK phosphorylation, suggesting that cilostazol-induced AMPK activation occurs through a signalling pathway independent of cyclic AMP. Cilostazol also dose-dependently inhibited tumour necrosis factor alpha (TNFalpha)-induced NF-kappaB activation and TNFalpha-induced I kappa B kinase activity. Furthermore, cilostazol attenuated the TNFalpha-induced gene expression of various pro-inflammatory and cell adhesion molecules, such as vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, monocyte chemoattractant protein-1 (MCP-1), and PECAM-1 in HUVEC. RNA interference of AMPK alpha 1 or the AMPK inhibitor compound C attenuated cilostazol-induced inhibition of NF-kappaB activation by TNFalpha.
In the light of these findings, we suggest that cilostazol might attenuate the cytokine-induced expression of adhesion molecule genes by inhibiting NF-kappaB following AMPK activation.
Cardiovascular research 10/2008; 81(1):133-9. · 5.80 Impact Factor
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ABSTRACT: Adiponectin circulates in plasma as various isoforms. However, the biological activity of each isoform has not been firmly established. High molecular weight (HMW) adiponectin may be the active form of adiponectin, while a proteolytic cleavage product of adiponectin, known as globular adiponectin (gAd), has recently been shown to activate vascular endothelial cells. We compared HMW adiponectin with gAd to investigate whether they could activate nuclear factor kappa B (NF-kappaB) and suppress cytokine-induced NF-kappaB activation in vascular endothelial cells. HMW adiponectin was found to activate NF-kB modestly compared to the activation observed with gAd. HMW adiponectin requires a shorter incubation period to demonstrate inhibition against tumour necrosis factor alpha (TNFalpha)-induced NF-kappaB activation, compared with gAd. gAd strongly activates NF-kappaB, thereby inducing the expression of various pro-inflammatory and adhesion molecule genes, and requires a longer incubation period to show inhibition against cytokine-induced NF-kappaB activation. Thus, HMW adiponectin might function to protect against inflammatory stimuli, while cleavage of adiponectin at inflammatory sites might enhance the inflammatory process.
Diabetes & Vascular Disease Research 07/2008; 5(2):123-7. · 2.12 Impact Factor
