Takayuki Matsumoto

Hoshi University, Edo, Tōkyō, Japan

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Publications (113)349.71 Total impact

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    ABSTRACT: Diabetes mellitus increases the risk of cardiovascular disease, which is accompanied by functional and structural changes in the vascular system. Microparticles (MPs) have been described as biological vectors of endothelial dysfunction in other pathologies. However, the molecular mechanisms underlying their formation and signaling are unclear. We investigated the role of MPs derived from streptozotocin (STZ)-induced diabetic rats in endothelial function. Male Wistar rats were injected with STZ to induce diabetes, and MPs isolated from control or STZ-induced diabetic rats were characterized by dot blotting (assessed by CD62P detections), flow cytometry (assessed by annexin V detections), and ELISA. Carotid arteries from rats were incubated with MPs, and expressions of enzymes and endothelium-dependent relaxation were analyzed. The circulating levels of MPs, particularly the levels of platelet-derived MPs, from diabetic rats were higher than those present in controls. Endothelium-dependent relaxation induced by acetylcholine (ACh) was attenuated in carotid arteries from STZ-induced diabetic rats. Following the incubation of control carotid arteries with MPs isolated from STZ rats, ACh-induced endothelium-dependent relaxation was impaired, but MPs isolated from control rats had no such effect. Furthermore, the effect of MPs was mediated by a decrease in expression of endothelial nitric oxide synthase (eNOS) and the overexpression of caveolin-1. Circulating MPs isolated from STZ-induced diabetic rats induce endothelial dysfunction in carotid arteries and regulate protein expressions of eNOS and caveolin-1. These data advance our understanding of the deleterious effects of circulating MPs observed in disorders with diabetic complications. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Acta Physiologica 08/2015; DOI:10.1111/apha.12561 · 4.25 Impact Factor
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    ABSTRACT: To study the time-course relationship between vascular functions and endoplasmic reticulum (ER) stress in type 2 diabetes, we investigated the vascular function and associated protein expressions, including cyclooxygenase (COX), ER stress, and apoptotic markers, in renal arteries (RA) from type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats at young adult (4 months old) and aged (18 months old) stages. In RA of aged OLETF (vs. young OLETF), we found: 1) increased contractions induced by uridine adenosine tetraphosphate (Up4A) and phenylephrine, 2) decreased relaxation and increased contraction induced by acetylcholine at lower and higher concentrations, respectively, and 3) increased expression of COX-1 and CHOP (a proapoptotic protein). In aged rats, the expressions of COX-1, COX-2, PDI (an ER protein disulfide isomerase), Bax (a proapoptotic marker), and CHOP were increased in RA from OLETF rats [vs. age-matched control Long-Evans Tokushima Otsuka (LETO) rats]. Upregulations of PDI and Bax were seen in RA from young OLETF (vs. young LETO). No age-related alterations were apparent in the above changes in RA from LETO rats, excluding acetylcholine-induced contraction. Short-term treatment with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 100 mg/kg/day, i.p., for 1 week) to OLETF rats at the chronic stage of the disease (12 months old) could suppress renal arterial contractions induced by Up4A and acetylcholine. These results suggest that a long-term duration of disease may be important for the development of vascular dysfunction rather than aging, per se. The early regulation of ER stress may be important against the development of diabetes-associated vascular dysfunction.
    Rejuvenation Research 08/2015; DOI:10.1089/rej.2015.1662 · 3.93 Impact Factor
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    ABSTRACT: Hyperglycemia-induced reactive oxygen species (ROS) production plays a major role in the pathogenesis of diabetic vascular dysfunction. However, the underlying mechanisms remain unclear. Toll-like receptor 4 (TLR4), a key component of innate immunity, is known to be activated during diabetes. Therefore, we hypothesize that hyperglycemia activates TLR4 signaling in vascular smooth muscle cells (VSMCs) that triggers ROS production and causes vascular dysfunction. Rat mesenteric VSMCs exposed to high glucose (25 mmol/l) increased TLR4 expression and activated TLR4 signaling via upregulation of myeloid differentiation factor 88 (MyD88). TLR4 inhibitor CLI-095 significantly attenuated elevated levels of ROS and nuclear factor-kappa B (NF-κB) activity in VSMCs exposed to high glucose. Mesenteric arteries from streptozotocin-induced diabetic rats treated with CLI-095 (2 mg/kg/day) intraperitoneally for 2 weeks exhibited reduced ROS generation and attenuated noradrenaline-induced contraction. These results suggest that hyperglycemia-induced ROS generation and NF-κB activation in VSMCs are at least, in part, mediated by TLR4 signaling. Therefore, strategies to block TLR4 signaling pathways pose a promising avenue to alleviate diabetic-induced vascular complications. High glucose-induced TLR4 activation in vascular smooth muscle cells. Inhibition of TLR4 attenuated high glucose-induced ROS production and NF-κB activity in VSMC. Suppression of TLR4 signaling attenuated mesenteric contraction in diabetic rat.
    Journal of Molecular Medicine 07/2015; DOI:10.1007/s00109-015-1318-7 · 4.74 Impact Factor
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    ABSTRACT: Vascular dysfunction plays a pivotal role in the development of systemic complications associated with arterial hypertension and diabetes. The endothelium, or more specifically, various factors derived from endothelial cells tightly regulate vascular function, including vascular tone. In physiological conditions, there is a balance between endothelium-derived factors, i.e. relaxing factors (EDRFs) and contracting factors (EDCFs), which properly mediate vascular homeostasis. However, in disease states, such as diabetes and arterial hypertension, there is an imbalance between EDRF and EDCF, with a reduction of EDRF signalling and an increase of EDCF signalling. Among EDCFs, cyclooxygenase-derived vasoconstrictor prostanoids play an important role in the development of vascular dysfunction associated with hypertension and diabetes. Moreover, uridine adenosine tetraphosphate (Up4 A), identified as an EDCF in 2005, also modulates vascular function. However, the role of Up4 A in hypertension- and diabetes-associated vascular dysfunction is unclear. In the present review we focused on experimental and clinical evidence that implicate these two EDCFs (vasoconstrictor prostanoids and Up4 A) in vascular dysfunction associated with hypertension and diabetes. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13205 · 4.99 Impact Factor
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    ABSTRACT: Impaired nitric oxide (NO), soluble guanylyl cyclase (sGC) and cyclic guanosine monophosphate (cGMP) signaling (NO-sGC-cGMP) has been implicated in the pathogenesis of diabetic vascular dysfunction. Efforts to directly target this signaling have led to the development of sGC agonists that activate the heme group of sGC (stimulators) or preferentially activate sGC when the heme is oxidized (activators). In this study, we hypothesized that resistance arteries from female rats with spontaneous type 2 diabetes (Goto-Kakizaki rats) would have reduced vasodilatory responses to heme-dependent sGC activation and increased responses to heme-independent sGC activation as compared to control rats (Wistar). Endothelium-dependent and -independent relaxation was assessed in isolated segments from mesenteric resistance arteries (MA) mounted in a wire myograph. GK MA had reduced responses to acetylcholine (ACh; pEC50: 7.96 ± 0.06 vs. 7.66 ± 0.05, p<0.05) and sodium nitroprusside (SNP; pEC50: 8.34 ± 0.05 vs. 7.77 ± 0.04, p<0.05). There were no group differences in 8-Br-cGMP-induced relaxation and protein kinase G-1 (PKG-1) expression (p>0.05). GK MA had attenuated responses to BAY 41-2272 (heme-dependent sGC stimulator; pEC50: 7.56 ± 0.05 vs. 6.93 ± 0.06, p<0.05) and BAY 58-2667 (heme-independent sGC activator; pEC50: 10.82 ± 0.07 vs. 10.27 ± 0.08, p<0.05) and increased sensitivity to sildenafil [phosphodiestarase 5 (PDE5) inhibitor; pEC50: 7.89 ± 0.14 vs. 8.25 ± 0.13, p<0.05]. Isolated resistance arteries from female rats of reproductive age that spontaneously develop type 2 diabetes have increased sensitivity to PDE5 inhibition and reduced responsiveness to sGC activators and stimulators. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 05/2015; DOI:10.1152/ajpheart.00079.2015 · 4.01 Impact Factor
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    ABSTRACT: Immune system activation is a common feature of hypertension pathogenesis. However, the mechanisms that initiate this activation are not well understood. Innate immune system recognition and response to danger is becoming apparent in many cardiovascular diseases. Danger signals can arise from not only pathogens, but also damage-associated molecular patterns (DAMPs). Our first hypothesis was that the DAMP, mitochondrial DNA (mtDNA), which is recognized by Toll-like receptor 9 (TLR9), is elevated in the circulation of spontaneously hypertensive rats (SHR), and that the deoxyribonuclease enzymes responsible for its degradation, have decreased activity in SHR. Based on these novel SHR phenotypes, we further hypothesized that (1) treatment of SHR with an inhibitory oligodinucleotide for TLR9 (ODN2088) would lower blood pressure and that (2) treatment of normotensive rats with a TLR9-specific CpG oligonucleotide (ODN2395) would cause endothelial dysfunction and increase blood pressure. We observed that SHR have elevated circulating mtDNA and diminished deoxyribonuclease I and II activity. Additionally, treatment of SHR with ODN2088 lowered systolic blood pressure. On the other hand, treatment of normotensive rats with ODN2395 increased systolic blood pressure and rendered their arteries less sensitive to acetylcholine-induced relaxation and more sensitive to norepinephrine-induced contraction. This dysfunctional vasoreactivity was due to increased cyclooxygenase and p38 mitogen-activated protein kinase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability. Circulating mtDNA and impaired deoxyribonuclease activity may lead to the activation of the innate immune system, via TLR9, and contribute to elevated arterial pressure and vascular dysfunction in SHR. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    Cardiovascular Research 04/2015; 107(1). DOI:10.1093/cvr/cvv137 · 5.81 Impact Factor
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    ABSTRACT: Aldosterone promotes non-genomic effects in endothelial and vascular smooth muscle cells via activation of mineralocorticoid receptors (MR) and G protein-coupled estrogen receptors (GPER). GPER activation is associated with beneficial/protective effects in the vasculature. Considering that vascular dysfunction plays a major role in diabetes-associated complications, we hypothesized that the beneficial effects mediated by vascular GPER activation, in response to aldosterone, are decreased in diabetes. Mesenteric resistance arteries from female, 14-16 weeks-old, control and diabetic (db/db) mice were used. Phenylephrine (PhE)-induced contractions were greater in arteries from db/db vs. control mice. Aldosterone (10 nM) increased maximal contractile responses to PhE in arteries from control mice, an effect elicited via activation of GPER. Although aldosterone did not increase PhE responses in arteries from db/db mice, blockade of GPER and MR decreased PhE-induced contractile responses in db/db mesenteric arteries. Aldosterone also reduced the potency of acetylcholine (ACh)-induced relaxation in arteries from both control and db/db mice via MR-dependent mechanisms. GPER antagonism further decreased ACh-induced relaxation in the control group, but did not affect ACh responses in the diabetic group. Aldosterone increased extracellular signal-regulated kinase (ERK)1/2 phosphorylation in arteries from control and db/db mice by a GPER-dependent mechanism. GPER, but not MR, gene and protein expression, determined by RT-PCR and immunoblotting/immunofluorescence assays respectively, were increased in arteries from db/db mice vs. control arteries. These findings indicate that aldosterone activates both vascular MR and GPER and that the beneficial effects of GPER activation are decreased in arteries from diabetic animals. Our results further elucidate the mechanisms by which aldosterone influences vascular function and contributes to vascular dysfunction in diabetes.
    Frontiers in Pharmacology 03/2015; 6:34. DOI:10.3389/fphar.2015.00034 · 3.80 Impact Factor
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    ABSTRACT: Activation of Toll-like receptor 3 (TLR3), a pattern recognition receptor of the innate immune system, is associated with vascular complications. However, whether activation of TLR3 alters vascular contractility is unknown. We, therefore, hypothesized that TLR3 activation augments vascular contractility and activates vascular smooth muscle cell (VSMC) contractile apparatus proteins. Male mice were treated with polyinosinic-polycytidylic acid (Poly I:C group, 14 days), a TLR3 agonist; control mice received saline (vehicle, 14 days). At the end of protocol, blood pressure was measured by tail cuff method. Aortas were isolated and assessed for contractility experiments using a wire myograph. Aortic protein content was used to determine phosphorylated/total interferon regulatory factor 3 (IRF3), a downstream target of TLR3 signaling, and ERK1/2 using Western blot. We investigated the TLR3/IRF3/ERK1/2 signaling pathway and contractile-related proteins such as phosphorylated/total myosin light chain (MLC) and caldesmon (CaD) in aortic VSMC primary cultures. Poly I:C-treated mice exhibited (vs. vehicle-treated mice) (1) elevated systolic blood pressure. Moreover, Poly I:C treatment (2) enhanced aortic phenylephrine-induced maximum contraction, which was suppressed by PD98059 (ERK1/2 inhibitor), and (3) increased aortic levels of phosphorylated IRF3 and ERK1/2. Stimulation of mouse aortic VSMCs with Poly I:C resulted in increased phosphorylation of IRF3, ERK1/2, MLC, and CaD. Inhibition of ERK1/2 abolished Poly I:C-mediated phosphorylation of MLC and CaD. Our data provide functional evidence for the role of TLR3 in vascular contractile events, suggesting TLR3 as a potential new therapeutic target in vascular dysfunction and regulation of blood pressure.
    Pflügers Archiv - European Journal of Physiology 03/2015; DOI:10.1007/s00424-015-1697-1 · 3.07 Impact Factor
  • Maria Alicia Carrillo-Sepulveda · Takayuki Matsumoto
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    ABSTRACT: Aims: Diabetes-induced vascular complications are associated with vascular smooth muscle cell (VSMC) phenotypic modulation, switching from a contractile to a synthetic-proliferative phenotype. Loss of caveolin-1 is involved with proliferation of VSMCs. We tested the hypothesis that mesenteric VSMCs from type 2 diabetic Goto-Kakizaki (GK) rat undergo phenotypic modulation and it is linked to decreased caveolin-1 expression. Methods: VSMCs were isolated from mesenteric arteries from GK rats and age-matched control Wistar rats. Western blotting was used to determine expression of target proteins such as caveolin-1, calponin (marker of differentiation), and proliferating cell nuclear antigen (PCNA, marker of proliferation). In addition, we measured intracellular reactive oxygen species (ROS) production using H2DCF-DA and activation of extracellular signal-regulated kinase (ERK1/2) by western blotting in VSMCs from GK stimulated with lipopolysaccharide (LPS), an endotoxin upregulated in diabetes. Results: Mesenteric VSMCs from diabetic GK rats exhibited decreased caveolin-1 and calponin expression and increased PCNA expression compared to control. Increased levels of ROS and phospho-ERK1/2 expression were also found in GK VSMCs. LPS augmented ROS and phosphorylated ERK1/2 levels to a greater extent in GK VSMCs than in control. Likewise, high glucose decreased caveolin-1 and calponin expression, increased PCNA expression and augmented ROS production in control mesenteric VSMCs. Conclusion: These results suggest that mesenteric VSMCs from diabetic GK rats undergo phenotypic modulation and it is associated with decreased caveolin-1 expression. These alterations may be due to enhanced inflammatory stimuli and glucose levels present in diabetic milieu. © 2014 S. Karger AG, Basel.
    Cellular Physiology and Biochemistry 10/2014; 34(5):1497-1506. DOI:10.1159/000366354 · 3.55 Impact Factor
  • Takayuki Matsumoto · Shun Watanabe · Kumiko Taguchi · Tsuneo Kobayashi
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    ABSTRACT: Serotonin (5-hydroxytryptamine: 5-HT) plays important roles in the cardiovascular system; however, the relationship between 5-HT-induced vasocontraction and the arterial 5-HT system including metabolism and signal transduction, in the presence of chronic type 2 diabetes (T2D) remains unclear. Therefore, we investigated 5-HT-induced contraction and associated mechanisms in carotid arteries from chronic T2D Goto-Kakizaki (GK) rats. Contractions in response to 5-HT were examined in carotid arteries from GK rats (42-46 weeks old). To investigate the response mechanisms of arterial smooth muscle, we constructed concentration-response curves for TCB2 (5-HT2A-receptor agonist), BW723C86 (5-HT2B-receptor agonist), and 5-HT in the presence of various inhibitors using endothelium-denuded preparations. Carotid arterial expressions of monoamine oxidase-A (MAO-A), serotonin transporter (SERT), and 5-HT2A were detected by immunoblotting. 5-HT-induced contraction was increased in carotid arteries from GK compared to control Wistar rats in both endothelium-intact and -denuded preparations. In denuded preparations, we found that: 1) TCB2-induced contraction was increased in GK rat arteries (vs. Wistar); 2) MAO-A inhibitor did not affect 5-HT-induced contraction, whereas SERT inhibitor augmented such contractions in both groups; and 3) differences in 5-HT-induced contractions were abolished by p38 MAPK, PI3K, and Rho kinase inhibitors. Carotid arterial expressions of MAO-A, SERT, and 5-HT2A remained unchanged in the groups. The results suggest that 5-HT-induced contraction is augmented in T2D GK rat carotid arteries. This augmentation is due to smooth muscle activation partly mediated by p38 MAPK, PI3K, and Rho kinases, and may also be partly due to arterial SERT activity.
    Pharmacological Research 09/2014; 87. DOI:10.1016/j.phrs.2014.07.001 · 3.98 Impact Factor
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    Keiko Ishida · Kumiko Taguchi · Takayuki Matsumoto · Tsuneo Kobayashi
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    ABSTRACT: Diabetes is associated with endothelial dysfunction and platelet activation, both of which may contribute to increased cardiovascular risk. The purpose of this study was to characterize circulating platelets in diabetes and clarify their effects on endothelial function. Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Each experiment was performed by incubating carotid arterial rings with platelets (1.65×107 cells/mL; 30 min) isolated from STZ or control rats. Thereafter, the vascular function was characterized in isolated carotid arterial rings in organ bath chambers, and each expression and activation of enzymes involved in nitric oxide and oxidative stress levels were analyzed. Endothelium-dependent relaxation induced by acetylcholine was significantly attenuated in carotid arteries treated with platelets isolated from STZ rats. Similarly, treatment with platelets isolated from STZ rats significantly reduced ACh-induced Akt/endothelial NO synthase signaling/NO production and enhanced TXB2 (metabolite of TXA2), while CD61 (platelet marker) and CD62P (activated platelet marker) were increased in carotid arteries treated with platelets isolated from STZ rats. Furthermore, the platelets isolated from STZ rats decreased total eNOS protein and eNOS dimerization, and increased oxidative stress. These data provide direct evidence that circulating platelets isolated from diabetic rats cause dysfunction of the endothelium by decreasing NO production (via Akt/endothelial NO synthase signaling pathway) and increasing TXA2. Moreover, activated platelets disrupt the carotid artery by increasing oxidative stress.
    PLoS ONE 07/2014; 9(7):e102310. DOI:10.1371/journal.pone.0102310 · 3.23 Impact Factor
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    ABSTRACT: Diabetes is characterized by the development of endothelial dysfunction, which affects both nitric oxide (NO)-mediated relaxation and endothelium-derived contracting factors, associated with vascular oxidative stress. There is a growing body of evidence suggesting that polyphenols have several beneficial effects, such as antioxidant and anti-inflammatory activities. This study investigated whether short-term treatment with polyphenols (chlorogenic acid (CA), morin (MO), resveratrol (RV)) can improve endothelial dysfunction related to diabetes. Aorta reactivity was determined in organ chambers, and we measured NO production and thromboxane B2 (TXB2; a metabolite of TXA2) from aortas in response to acetylcholine (ACh). Streptozotocin (STZ)-induced diabetic mice (16 weeks) were injected with solvent (ethanol, 10% v/v; intraperitoneally (i.p.)), CA (0.03 mmol/kg/d), MO (0.03 mmol/kg/d), and RV (0.03 mmol/kg/d) for 5 d. The ACh-induced endothelium-dependent relaxation was markedly reduced in rings of STZ-induced diabetic mice compared to controls. The treatment with polyphenols (significantly: MO, tendency: CA and RV) for only 5 d improved the NO components of relaxation, but did not normalize ACh-stimulated NO production. However, polyphenol treatment suppressed the ACh-stimulated level of TXB2 in aortas from STZ-induced diabetic mice. Thus, treatment with polyphenols caused basal NO production and a prompt improvement of the endothelial function in diabetic mice, and this may involve the normalization of TXA2 levels, not NO production, under ACh stimulation.
    Biological & Pharmaceutical Bulletin 06/2014; 37(6):1056-61. DOI:10.1248/bpb.b14-00157 · 1.78 Impact Factor
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    ABSTRACT: The dramatic worldwide increase in the prevalence of diabetes has generated an attempt by the scientific community to identify strategies for its treatment and prevention. Vascular dysfunction is a hallmark of diabetes and frequently leads to the development of atherosclerosis, coronary disease-derived myocardial infarction, stroke, peripheral arterial disease and diabetic “triopathy” (retinopathy, nephropathy and neuropathy). These vascular complications, developing in an increasingly younger cohort of diabetic patients, contribute to morbidity and mortality. Despite the development of new anti-diabetic or anti-hyperglycemic drugs; however, vascular complications remain to be a problem. This warrants a need for new therapeutic strategies to tackle diabetic vasculopathy. There is a growing body of evidence showing that peptide-binding G protein-coupled receptors (peptide-biding GPCRs) play an important role in the pathophysiology of vascular dysfunction during diabetes. Thus, in this review, we discuss some of the peptide-binding GPCRs involved in the regulation of vascular function that have potential to be a therapeutic target in the treatment of diabetic vasculopathy.This article is protected by copyright. All rights reserved.
    Acta Physiologica 03/2014; 211(1). DOI:10.1111/apha.12281 · 4.25 Impact Factor
  • Shingo Nemoto · Takayuki Matsumoto · Kumiko Taguchi · Tsuneo Kobayashi
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    ABSTRACT: Objective We investigated the relationships among protein tyrosine phosphatase 1B (PTP1B), angiotensin II (Ang II), and insulin signaling in the presence of endothelial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rat aortas. Methods and results Aortas isolated from GK or control Wistar rats were examined in the presence or absence of Ang II with or without a selective antagonist of the Ang II type 1 (AT1) receptor or a PTP1B inhibitor to evaluate vascular functional and molecular mechanisms, such as insulin-induced relaxation, nitric oxide (NO) production, phosphorylation of insulin receptor substrate (IRS)-1, endothelial NO synthase (eNOS), and phosphorylation, and the subcellular localization of PTP1B. GK aortas exhibited reductions of: 1) insulin-induced relaxation, 2) NO production, 3) Ser1177-p-eNOS, and 4) Tyr612-p-IRS-1. Pre-incubation with a PTP1B inhibitor normalized these reductions. In Wistar aortas, the four above-mentioned parameters were reduced by Ang II, but were completely inhibited by co-treatment with the PTP1B inhibitor. The membrane expression of PTP1B was greater in GK than in Wistar aortas, and it was increased by Ang II in Wistar rats. The membrane PTP1B expression in the presence of insulin + Ang II was reduced by the PTP1B inhibitor or AT1-receptor antagonist. Conclusions These results suggest that the membrane PTP1B suppressed insulin-mediated aortic relaxation, and this was due to the Ang II-AT1-receptor signaling pathway. The inhibition of PTP1B warrants further investigation as a potential therapeutic target for endothelial dysfunction in type 2 diabetes.
    Atherosclerosis 03/2014; 233(1). DOI:10.1016/j.atherosclerosis.2013.12.032 · 3.97 Impact Factor
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    ABSTRACT: The rising epidemic of diabetes worldwide is of significant concern. Although the ultimate objective is to prevent the development and find a cure for the disease, prevention and treatment of diabetic complications is very important. Vascular complications in diabetes, or diabetic vasculopathy, include macro- and microvascular dysfunction and represent the principal cause of morbidity and mortality in diabetic patients. Endothelial dysfunction plays a pivotal role in the development and progression of diabetic vasculopathy. Endothelin-1 (ET-1), an endothelial cell-derived peptide, is a potent vasoconstrictor with mitogenic, pro-oxidative and pro-inflammatory properties that are particularly relevant to the pathophysiology of diabetic vasculopathy. Overproduction of ET-1 is reported in patients and animal models of diabetes and the functional effects of ET-1 and its receptors are also greatly altered in diabetic conditions. The current therapeutic approaches in diabetes include glucose lowering, sensitization to insulin, reduction of fatty acids and vasculoprotective therapies. However, whether and how these therapeutic approaches affect the ET-1 system remain poorly understood. Accordingly, in the present review, we will focus on experimental and clinical evidence that indicates a role for ET-1 in diabetic vasculopathy and on the effects of current therapeutic approaches in diabetes on the vascular ET-1 system.
    Life sciences 01/2014; 118(2). DOI:10.1016/j.lfs.2013.12.216 · 2.30 Impact Factor
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    Takayuki Matsumoto · Shun Watanabe · Ryusuke Kawamura · Tsuneo Kobayashi
    Life Sciences 12/2013; 93(25-26). DOI:10.1016/j.lfs.2014.01.052 · 2.30 Impact Factor
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    ABSTRACT: Pre-existing diabetes increases the risk of maternal and fetal complications during pregnancy and this may be due to underlying maternal vascular dysfunction and impaired blood supply to the uteroplacental unit. Endothelial dysfunction and reduced vascular smooth muscle responsiveness to nitric oxide (NO) are common vascular impairments in type 2 diabetes (T2D). We hypothesized that uterine arteries from diabetic rats would have reduced vascular smooth muscle sensitivity to NO as compared to non-diabetic rats due to impairment in the NO/soluble guanylate cyclase (sGC)/guanosine 3':5' cyclic monophosphate (cGMP) signaling pathway. Uterine arteries from pregnant Goto-Kakizaki (GK, model of T2D) and Wistar (non-diabetic) rats were studied in a wire myograph. GK non-pregnant uterine arteries had reduced responses to acetylcholine (ACh) and sodium nitroprusside (SNP) but increased responses to propylamine propylamine NONOate and greater sensitivity to sildenafil compared to Wistar non-pregnant arteries. In late pregnancy, Wistar rats had reduced uterine vascular smooth muscle responsiveness to SNP but GK rats failed to show this adaptation and had reduced expression of sGC as compared to the non-pregnant state. GK rats had a smaller litter size (13.9 ± 0.48 vs. 9.8 ± 0.75, p<0.05) and a greater number of resorptions compared to Wistar controls (0.8 ± 0.76% vs. 19.9 ± 6.06%, p<0.05). These results suggest that uterine arteries from rats with T2D show reduced sensitivity of uterine vascular smooth muscle sGC to NO. During pregnancy, the GK uterine vascular smooth muscle fails to show relaxation responses similar to those of arteries from non-diabetic rats.
    AJP Heart and Circulatory Physiology 12/2013; 306(4). DOI:10.1152/ajpheart.00588.2013 · 4.01 Impact Factor
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    ABSTRACT: There is a growing body of evidence suggesting that epigallocatechin gallate (EGCG), a major catechin isolated from green tea, has several beneficial effects, such as anti-oxidant and anti-inflammatory activities. However, whether treatment with EGCG can suppress the endothelin-1 (ET-1)-induced contraction in carotid arteries from type 2 diabetic rats is unknown, especially at the chronic stage of the disease. We hypothesized that long-term treatment with EGCG would attenuate ET-1-induced contractions in type 2 diabetic arteries. Otsuka Long-Evans Tokushima fatty (OLETF) rats (43weeks old) were treated with EGCG (200mg/kg/day for 2months, p.o.), and the responsiveness to ET-1, phenylephrine (PE), acetylcholine (ACh) and sodium nitroprusside (SNP) was measured in common carotid artery (CA) from EGCG-treated and -untreated OLETF rats and control Long-Evans Tokushima Otsuka (LETO) rats. In OLETF rats, EGCG attenuated responsiveness to ET-1 in CA compared to untreated groups. However, EGCG did not alter PE-induced contractions in CA from OLETF rats. In endothelium-denuded arteries, EGCG did not affect ET-1-induced contractions in either the OLETF or LETO group. Acetylcholine-induced relaxation was increased by EGCG treatment in CA from the OLETF group. The expressions of ET receptors, endothelial nitric oxide synthase, superoxide dismutases, and gp91(phox) [an NAD(P)H oxidase component] in CA were not altered by EGCG treatment in either group. Our data suggest that, within the timescale investigated here, EGCG attenuates ET-1-induced contractions in CA from type 2 diabetic rats, and one of the mechanisms may involve normalizing endothelial function.
    Life sciences 11/2013; 118(2). DOI:10.1016/j.lfs.2013.11.016 · 2.30 Impact Factor
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    ABSTRACT: Low-grade systemic inflammation is a common manifestation of hypertension; however, the exact mechanisms that initiate this pathophysiological response, thereby contributing to further increases in blood pressure, are not well understood. Aberrant vascular inflammation and reactivity via activation of the innate immune system may be the first step in the pathogenesis of hypertension. One of the functions of the innate immune system is to recognize and respond to danger. Danger signals can arise from not only pathogenic stimuli but also endogenous molecules released following cell injury and/or death [damage-associated molecular patterns (DAMPs)]. In the short-term, activation of the innate immune system is beneficial in the vasculature by providing cytoprotective mechanisms and facilitating tissue repair following injury or infection. However, sustained or excessive immune system activation, such as in autoimmune diseases, may be deleterious and can lead to maladaptive, irreversible changes to vascular structure and function. An initial source of DAMPs that enter the circulation to activate the innate immune system could arise from modest elevations in peripheral vascular resistance. These stimuli could subsequently lead to ischemic- or pressure-induced events aggravating further cell injury and/or death, providing more DAMPs for innate immune system activation. This review will address and critically evaluate the current literature on the role of the innate immune system in hypertension pathogenesis. The role of Toll-like receptor (TLR) activation on somatic cells of the vasculature in response to the release of DAMPs and the consequences of this activation on inflammation, vasoreactivity, and vascular remodeling will be specifically discussed.
    AJP Heart and Circulatory Physiology 10/2013; 306(2). DOI:10.1152/ajpheart.00328.2013 · 4.01 Impact Factor
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    ABSTRACT: Background: We previously reported that σ1-receptor (σ1R) expression in the thoracic aorta decreased after pressure overload (PO) induced by abdominal aortic banding in ovariectomized (OVX) rats. Here, we asked whether stimulation of σ1R with the selective agonist SA4503 elicits functional recovery of aortic vasodilation and constriction following vascular injury in OVX rats with PO. Methods and Results: SA4503 (0.3-1.0mg/kg) and NE-100 (a σ1R antagonist, 1.0mg/kg) were administered orally for 4 weeks (once daily) to OVX-PO rats. Vascular functions of isolated descending aorta were measured following phenylephrine (PE)- or endothelin-1 (ET-1)-induced vasoconstriction and acetylcholine (ACh)- or clonidine-induced vasodilation. SA4503 administration rescued PO-induced σ1R decreases in aortic smooth muscle and endothelial cells. SA4503 treatment also rescued PO-induced impairments in ACh- and clonidine-induced vasodilation without affecting PE- and ET-1-induced vasoconstriction. Ameliorated ACh- and clonidine-induced vasodilation was closely associated with increased Akt activity and in turn endothelial nitric oxide synthase (eNOS) phosphorylation. The SA4503-mediated improvement of vasodilation was blocked by NE-100 treatment. Conclusions: σ1R is downregulated following PO-induced endothelial injury in OVX rats. The selective σ1R agonist SA4503 rescues impaired endothelium-dependent vasodilation in the aorta from OVX-PO rats through σ1R stimulation, enhancing eNOS-cGMP signaling in vascular endothelial cells. These observations encourage development of novel therapeutics targeting σ1R to prevent vascular endothelial injury in vascular diseases.
    Circulation Journal 08/2013; 77(11). DOI:10.1253/circj.CJ-13-0256 · 3.69 Impact Factor