title: Simvastatin ameliorates angiotensin II-induced endothelial dysfunction through restoration of Rho-BH4-eNOS-NO pathway.
abstract: Endothelial dysfunction contributes to the initiation and development of hypertension. We previously found that simvastatin moderately decreases blood pressure in 2-kidney-2-clip (2k2c) renal hypertension, but the precise mechanisms are still unclear. The present study was designed to examine the protective actions of simvastatin in 2k2c-evoked endothelial dysfunction and also delineate the underlying mechanisms. Here we show that 2k2c-induced elevation in plasma angiotensin II impaired acetylcholine-induced endothelium-dependent vascular relaxation, suppressed endothelial NO synthase (eNOS) activity and reduced nitric oxide (NO) production. Additionally, the levels of tetrahydrobiopterin (BH4), an essential cofactor of eNOS, as well as the activity of GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme for BH4 synthesis, were markedly reduced. Administration of simvastatin significantly improved acetylcholine-induced endothelium-dependent carotid arteries relaxation at 9 weeks in reno-hypertensive rats. Notably, GTPCH I activity, BH4 production, p-eNOS expression and NO levels in the vascular endothelium were elevated as a result of simvastatin administration. In cultured rat arterial endothelial cells, simvastatin restored BH4, GTPCH I activity and NO release impaired by angiotensin II, and pretreatment with mevalonate (MVA) or geranylgeranyl pyrophosphate (GGPP) abolished the beneficial effects exerted by simvastatin. Moreover, RhoA inhibitor C3 exoenzyme, Rho kinase inhibitor Y-27632 and dominant negative mutant of RhoA prevented BH4 and NO loss due to Ang II treatment. Taken together, normalization of BH4-eNOS-NO pathway at least in part accounts for the beneficial actions of simvastatin on vascular endothelium during 2k2c hypertension, and RhoA-Rho kinase pathway is involved in regulation of BH4 production.
authors.affiliation: Department of pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Mi
authors.initials: M
authors.lastname: Wang
authors.forename: Sheng-Jiang
authors.initials: SJ
authors.lastname: Xue
authors.forename: Dong-Hong
authors.initials: DH
authors.lastname: Liu
authors.forename: Yong-Bo
authors.initials: YB
authors.lastname: Tang
mesh_terms: D000109:Acetylcholine; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000166:cytology / Q000503:physiopathology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006136:GTP Cyclohydrolase / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006977:Hypertension, Renal / Q000378:metabolism / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000804:Angiotensin II; D001708:Biopterins; D009569:Nitric Oxide; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D054460:rho-Associated Kinases; D006136:GTP Cyclohydrolase; C003402:sapropterin; D000109:Acetylcholine