Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review

Proteinase-activated receptor 2 (PAR2) is a cell surface receptor activated by serine proteinases or specific synthetic compounds. Interest in PAR2 as a pharmaceutical target for various diseases is increasing. Here we asked two questions relevant to endothelial dysfunction and diabetes: How is PAR2 function affected in blood vessels? What role does PAR2 have in promoting obesity, diabetes, and/or metabolic syndrome, specifically via the endothelium and adipose tissues? We conducted a systematic review of the published literature in PubMed and Scopus (July 2015; search terms: par2, par-2, f2lr1, adipose, obesity, diabetes, and metabolic syndrome). Seven studies focused on PAR2 and vascular function. The obesity, diabetes, or metabolic syndrome animal models differed amongst studies, but each reported that PAR2-mediated vasodilator actions were preserved in the face of endothelial dysfunction. The remaining studies focused on nonvascular functions and provided evidence supporting the concept that PAR2 activation promoted obesity. Key studies showed that PAR2 activation regulated cellular metabolism, and PAR2 antagonists inhibited adipose gain and metabolic dysfunction in rats.We conclude that PAR2 antagonists for treatment of obesity indeed show early promise as a therapeutic strategy; however, endothelial-specific PAR2 functions, which may offset mechanisms that produce vascular dysfunction in diabetes, warrant additional study

過酸化ベンゾイルの一般薬理学的研究

The pharmacological actions of benzoyl peroxide were investigated using the screening methods of general pharmacology. The results obtained in the present study were as follows: (1) In in vivo study, benzoyl peroxide did not exhibit analgesic, anti-convulsive, muscle-relaxant or hypnotic effects in mice. (2) Benzoyl peroxide did not affect the twitch response to electrical stimulation in isolated phrenic nerve-diaphragm preparation of rats. (3) Benzoyl peroxide did not affect the contractile response to acetylcholine in the isolated bronchus of rats, but significantly depressed the contractile responses to acetylcholine and Ba^ in isolated ileum of rats. (4) Benzoyl peroxide did not exhibit diuretic effects or hemolytic effects in rabbits. The in vivo results indicated that benzoyl peroxide has no effect on the central nervous system or the somatic nervous system of rats. However, at higher concentrations benzoyl peroxide depressed the contractile response of ileal smooth muscles. Therefore, our results suggest that excess benzoyl peroxide changes some physiological functions of smooth muscle tissue without changing the behavior or external appearance in vivo experiments

Protection of protease-activated receptor 2 mediated vasodilatation against angiotensin II-induced vascular dysfunction in mice

Background: Under conditions of cardiovascular dysfunction, protease-activated receptor 2 (PAR2) agonists maintain vasodilatation activity, which has been attributed to increased cyclooxygenase-2, nitric oxide synthase and calcium-activated potassium channel (SK3.1) activities. Protease-activated receptor 2 agonist mediated vasodilatation is unknown under conditions of dysfunction caused by angiotensin II. The main purpose of our study was to determine whether PAR2-induced vasodilatation of resistance arteries was attenuated by prolonged angiotensin II treatment in mice. We compared the vasodilatation of resistance-type arteries (mesenteric) from angiotensin II-treated PAR2 wild-type mice (WT) induced by PAR2 agonist 2-furoyl-LIGRLO-amide (2fly) to the responses obtained in controls (saline treatment). We also investigated arterial vasodilatation in angiotensin IItreated PAR2 deficient (PAR2-/-) mice. Results: 2fly-induced relaxations of untreated arteries from angiotensin II-treated WT were not different than salinetreated WT. Treatment of arteries with nitric oxide synthase inhibitor and SK3.1 inhibitor (L-NAME + TRAM-34) blocked 2fly in angiotensin II-treated WT. Protein and mRNA expression of cyclooxygenase-1 and -2 were increased, and cyclooxygenase activity increased the sensitivity of arteries to 2fly in only angiotensin II-treated WT. These protective vasodilatation mechanisms were selective for 2fly compared with acetylcholine- and nitroprussideinduced relaxations which were attenuated by angiotensin II; PAR2-/- were protected against this attenuation of nitroprusside. Conclusions: PAR2-mediated vasodilatation of resistance type arteries is protected against the negative effects of angiotensin II-induced vascular dysfunction in mice. In conditions of endothelial dysfunction, angiotensin II induction of cyclooxygenases increases sensitivity to PAR2 agonist and the preserved vasodilatation mechanism involves activation of SK3.1

Participation of peroxynitrite in oxidative modification of LDL by aqueous extracts of cigarette smoke

AbstractAqueous extracts of cigarette smoke (CSE) can oxidatively modify plasma low-density lipoprotein (LDL). The aim of the present study was to elucidate the participation of peroxynitrite in LDL oxidation. When LDL was incubated with CSE, its oxidative modification was dependent on time and concentration. It could be effectively prevented by vitamin E, partially by superoxide dismutase, but hardly by catalase, mannitol and metal chelators. CSE also increased the 3-nitrotyrosine content in LDL. A similar increase of 3-nitrotyrosine occurred after incubation of LDL with a peroxynitrite generating agent, 3-morpholinosydnonimine, thus suggesting that prominent pro-oxidants in CSE are peroxynitrite-generating species

Age-related changes to vascular protease-activated receptor 2 in metabolic syndrome: A relationship between oxidative stress, receptor expression and endothelium-dependent vasodilation.

Protease-activated receptor 2 (PAR2) is expressed in vascular endothelium. Nitric oxide (NO)-cyclic GMP mediated vasodilation in response to 2-furoyl-LIGRLO-amide (2fLIGRLO), a PAR2-activating peptide, is impaired in aortas from aged SHRSP.Z-LeprThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author