Enhanced Nitric Oxide Synthase Activation via Protease-Activated Receptor 2 Is Involved in the Preserved Vasodilation in Aortas from Metabolic Syndrome Rats

Maruyama, Kana; Kagota, Satomi; McGuire, John J.; Wakuda, Hirokazu; Yoshikawa, Norishige; Nakamura, Kazuki; Shinozuka, Kazumasa

doi:10.1159/000442415

Cited by 13 publications

(16 citation statements)

References 44 publications

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“…Impaired PAR2-induced vascular relaxation was reportedly observed in rats with metabolic syndrome. [9][10][11][12] However, whether chronic hypertension affects PAR2-induced relaxation remains unclear. In this study, we focused on vasorelaxant responses induced by the PAR2 agonist 2-Fly, ACh, and SNP in aortas isolated from aged SHRs and WKY rats.…”

Section: Discussionmentioning

confidence: 99%

“…For example, PAR2 activation induced by the PAR2-activating peptide 2-furoyl-LIGRLO-amide (2-Fly) and endothelium-dependent relaxation induced by serine proteases occur by activating the endothelial nitric oxide synthase (eNOS) and eNOS-independent pathways in diverse vessels of many species. [10][11][12][13][14][15][16] Several studies compared PAR2-induced relaxation of vessels in healthy and diseased conditions such as diabetes and metabolic syndrome. [10][11][12][17][18][19] However, knowledge regarding PAR2-induced responses in the vasculature during chronic hypertension is insufficient.…”

mentioning

confidence: 99%

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Impairment of Protease-Activated Receptor 2-Induced Relaxation of Aortas of Aged Spontaneously Hypertensive Rat

Ando

Matsumoto

Kobayashi

et al. 2018

Biological & Pharmaceutical Bulletin

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Hypertension is one of the most prevalent diseases worldwide and can cause harmful complications within the vascular system. Further research on vascular responsiveness to different ligands and diverse receptors in various arteries is required to understand the mechanisms underlying the development of these vascular complications. Here, we investigated the vasorelaxant effect of the protease-activated receptor 2 (PAR2) agonist 2-furoyl-LIGRLO-amide (2-Fly) and two commonest agents, namely endothelium-dependent dilator acetylcholine (ACh) and endothelium-independent dilator sodium nitroprusside (SNP), on the thoracic aorta isolated from aged spontaneously hypertensive rats (SHR) (age, 52 1 weeks). The effects of these agents were compared between aortas isolated from SHR and age-matched normotensive Wistar Kyoto (WKY) rats. Compared with the WKY group, in the SHR group, 2-Fly-induced relaxation was impaired, ACh-induced relaxation was slightly decreased at low concentrations, and SNP-induced relaxation was similar. In addition, 2-Fly-induced aortic relaxation was largely decreased by a PAR2 antagonist (FSLLRY), endothelial denudation, and a nitric oxide (NO) synthase inhibitor N G -nitro-L-arginine (L-NNA) but not by an Akt inhibitor. These results suggested that PAR2-induced relaxations of aortas of aged SHR was impaired, and this impaired aortic relaxation may be attributed to decreased NO bioavailability rather than altered NO sensitivity unrelated to the Akt activity.Key words aorta; endothelium; hypertension; protease-activated receptor 2 (PAR2); relaxation Vascular complications often occur systemically and arise in response to hypertension-associated pathologies, leading to increased mortality and morbidity rates in hypertensive patients worldwide.1) A growing body of evidence suggests that an abnormal vascular tone, for example, augmented contraction and/or restricted relaxation that was induced by various ligands in hypertensive patients and animal models. 2-4)However, completely understanding vascular tone regulation under pathophysiological conditions is highly complex because the action of one ligand on a receptor may evoke different responses among different vessel types. Thus, a better understanding of the association between hypertension and vascular tone, as modulated by receptor activation, will help identify new therapeutic targets for preventing and treating hypertension-associated vascular complications.Protease-activated receptor 2 (PAR2) is a member of the family of protease-activated receptors and is uniquely activated by proteolysis, PAR2 plays important roles in regulating diverse cellular processes during pathophysiological conditions such as atherosclerosis, diabetes, and hypertension. [5][6][7][8][9] In the vascular system, PAR2 activation can modulate the vascular tone. For example, PAR2 activation induced by the PAR2-activating peptide 2-furoyl-LIGRLO-amide (2-Fly) and endothelium-dependent relaxation induced by serine proteases occur by activating the endothelial nitric oxide syntha...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Impairment of Protease-Activated Receptor 2-Induced Relaxation of Aortas of Aged Spontaneously Hypertensive Rat

Ando

Matsumoto

Kobayashi

et al. 2018

Biological & Pharmaceutical Bulletin

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“…20) For our own part, we have used an animal model of metabolic syndrome, SHRSP.Z-Lepr fa /IzmDmcr rats (SHRSP.ZF), to investigate the time-and age-dependent changes that occur over the time-course of metabolic syndrome. 21,22) Here in this review article, we summarize the findings from our studies of ageing/chronic exposure to metabolic abnormalities associated with metabolic syndrome on PAR2-mediated vasodilation in arteries of SHRSP.ZF. Furthermore, we discuss the role of PAR2 and the implications of its age-related changes for the circulatory function of the cardiovascular system in metabolic syndrome, and the potential for pharmaceutical development.…”

Section: Recent Progress In the Study Of Vasoactive Modulators In Metmentioning

confidence: 99%

“…approximately 1.2-times greater waist length to body length ratio, as an index of abdominal obesity, 1.2-times higher body weight, 1.2-times higher blood pressure, 8-times higher serum triglycerides, 1.6-times higher blood glucose than that of non-obese, normotensive control Wistar-Kyoto rats (WKY); also, these abnormalities are present at 18-23 weeks of age. 21) Using the SHRSP.ZF with metabolic syndrome, we have examined aortas and mesenteric arteries to determine the endotheliummediated vasodilator function of blood flow conductanceversus resistance-type arteries, respectively. Until 20 weeks [A] PAR2 is cleaved by serine protease (trypsin, tryptase, coagulation factor VIIa and Xa) at specific site within the N-terminus, and unmasking tethered ligands bind to the second extracellular loops, resulting in the activation.…”

Section: Changes In Par2-mediated Vasodilator Function At Early Stagementioning

confidence: 99%

“…21,22) Increased levels of reactive oxygen species (ROS), e.g. superoxide, and decreased soluble guanylyl cyclase are described as some of the mechanisms that inhibit the ability of the vascular endothelium to affect NO-mediated vascular smooth muscle in diabetic humans and related models in animals.…”

Section: Changes In Par2-mediated Vasodilator Function At Early Stagementioning

confidence: 99%

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Progression of Time-Dependent Changes to the Mechanisms of Vasodilation by Protease-Activated Receptor 2 in Metabolic Syndrome

Maruyama

McGuire

Kagota

2017

Biological & Pharmaceutical Bulletin

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Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor activated by serine proteases released from tissues or by synthetic peptide ligands administered pharmacologically. Its wide expression in the cardiovascular system, particularly within the endothelium, vasodilation activity, and link to increased expression of inflammatory cytokines positions PAR2 as a potentially important regulator of vascular pathology under conditions of tissue inflammation, and injury; and thus, a pharmaceutical target for new therapeutics. Obesity is considered a chronic low-grade systemic inflammatory condition as inflammatory cytokines released from adipocytes are closely related to development of metabolic syndrome and related disorders. Our work over the past five-years has focused on the changes in vasomotor functions of PAR2 in metabolic syndrome, using an animal model known as the SHRSP.Z-Lepr fa /IzmDmcr rats (SHRSP.ZF). In young SHRSP.ZF that had already developed impaired responses to nitric oxide, we reported that PAR2-induced endothelium-dependent vasodilation is preserved. However, this PAR2 vasodilation decreased with increasing age and further chronic exposure to the conditions of metabolism disorder. These findings raise the possibility that PAR2 regulates tissue perfusion and can protect organs from injury, which is an increasing clinical concern at later stages of metabolic syndrome. Here we present our studies on the time-dependent changes in vasoreactivity to PAR2 in metabolic syndrome and the underlying mechanisms. Furthermore, we discuss the implications of these age-related changes in PAR2 for the cardiovascular system in metabolic syndrome.

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Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease

Wang

Khalil

2018

Advances in Pharmacology

497

316

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Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade various proteins in the extracellular matrix (ECM). Typically, MMPs have a propeptide sequence, a catalytic metalloproteinase domain with catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are secreted by many cells including fibroblasts, vascular smooth muscle (VSM), and leukocytes. MMPs are regulated at the level of mRNA expression and by activation through removal of the propeptide domain from their latent zymogen form. MMPs are often secreted in an inactive proMMP form, which is cleaved to the active form by various proteinases including other MMPs. MMPs degrade various protein substrates in ECM including collagen and elastin. MMPs could also influence endothelial cell function as well as VSM cell migration, proliferation, Ca signaling, and contraction. MMPs play a role in vascular tissue remodeling during various biological processes such as angiogenesis, embryogenesis, morphogenesis, and wound repair. Alterations in specific MMPs could influence arterial remodeling and lead to various pathological disorders such as hypertension, preeclampsia, atherosclerosis, aneurysm formation, as well as excessive venous dilation and lower extremity venous disease. MMPs are often regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP ratio often determines the extent of ECM protein degradation and tissue remodeling. MMPs may serve as biomarkers and potential therapeutic targets for certain vascular disorders.

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Enhanced Nitric Oxide Synthase Activation via Protease-Activated Receptor 2 Is Involved in the Preserved Vasodilation in Aortas from Metabolic Syndrome Rats

Cited by 13 publications

References 44 publications

Impairment of Protease-Activated Receptor 2-Induced Relaxation of Aortas of Aged Spontaneously Hypertensive Rat

Impairment of Protease-Activated Receptor 2-Induced Relaxation of Aortas of Aged Spontaneously Hypertensive Rat

Progression of Time-Dependent Changes to the Mechanisms of Vasodilation by Protease-Activated Receptor 2 in Metabolic Syndrome

Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease

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