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

• Published in: Canadian journal of physiology and pharmacology 2017-04, Vol.95 (4), p.356-364
• Main Authors: Maruyama, Kana, Kagota, Satomi, McGuire, John J, Wakuda, Hirokazu, Yoshikawa, Noriko, Nakamura, Kazuki, Shinozuka, Kazumasa
• Format: Article
• Language: English
• Subjects: Age; Aging - metabolism; Animals; Aorta - metabolism; Cyclic GMP - analogs & derivatives; Cyclic GMP - metabolism; Cyclic GMP - pharmacology; Disease Models, Animal; Down-Regulation; Endothelium; Endothelium, Vascular - metabolism; endothelium-dependent vasodilation; expression des récepteurs; Gene Expression - physiology; Health aspects; Male; Metabolic syndrome; Metabolic Syndrome - metabolism; Nitric Oxide - metabolism; Nitroprusside - pharmacology; Oligopeptides - pharmacology; Oxidative stress; Oxidative Stress - physiology; protease-activated receptor 2; Proteases; Proteins; Rats; Rats, Inbred Strains; receptor expression; Receptor, PAR-2 - agonists; Receptor, PAR-2 - metabolism; RNA, Messenger - metabolism; récepteur activé par les protéases 2; stress oxydatif; syndrome métabolique; Thiobarbituric Acid Reactive Substances - analysis; Thionucleotides - pharmacology; Trypsin - pharmacology; vasodilatation dépendante de l’endothélium; Vasodilation; Vasodilation - physiology; Vasodilator Agents - pharmacology
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2016-0298

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-Lepr fa /IzmDmcr (SHRSP.ZF) rats with metabolic syndrome. Here we investigated mechanisms linking PAR2’s vascular effects to phenotypic characteristics of male SHRSP.ZF rats at 10, 20, and 30 weeks of age. We found vasodilation responses to either 2fLIGRLO or enzyme-mediated PAR2 activation by trypsin were sustained until 20 weeks and lessened at 30 weeks. PAR2 protein and mRNA levels were lower in aortas at 30 weeks than at 10 and 20 weeks. PAR2-mediated responses positively correlated with PAR2 protein and mRNA levels. Decreased cGMP accumulation in the presence of 2fLIGRLO paralleled the decreased relaxations elicited by nitroprusside and the cGMP analog 8-pCPT-cGMP, and the less soluble guanylyl cyclase protein at 30 weeks. 2fLIGRLO-induced relaxation was negatively correlated with serum thiobarbituric acid reactive substances, an index of oxidative stress, which increased with age. Forward stepwise data regression supported a model of age-related decreases in PAR2 function resulting from decreased PAR2 mRNA and increased oxidative stress. We conclude that decreased responsiveness of aortic smooth muscle to NO and downregulation of receptor expression impair PAR2 functions at later stages of metabolic syndrome in SHRSP.ZF rats.