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Simvastatin Ameliorates Angiotensin II-Induced Endothelial Dysfunction Through Restoration of Rho-BH4-eNOS-NO Pathway

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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.

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Sources of Funding

This work was supported by the National Natural Science Foundation of China (No.30900530), Science and Technology Planning Project of Guangdong Province, China (No.2008B030303061; No.2008B080703056; NO.2010B080701044; 2011B080701012), and Doctoral Fund of Ministry of Education of China (for young teachers, No.20090171120055).

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Authors and Affiliations

  1. Department of pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China, 510080

    Zheng Zhang, Mi Wang, Sheng-Jiang Xue & Yong-Bo Tang

  2. Department of Ultrasound, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China, 510080

    Dong-Hong Liu

  3. Institute of Pharmacy and Pharmacology, Nanhua University, Hengyang, Hunan, People’s Republic of China, 421001

    Sheng-Jiang Xue

Authors
  1. Zheng Zhang
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  2. Mi Wang
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Correspondence to Dong-Hong Liu or Yong-Bo Tang.

Additional information

Zheng Zhang and Mi Wang contributed equally to this work.

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Zhang, Z., Wang, M., Xue, SJ. et al. Simvastatin Ameliorates Angiotensin II-Induced Endothelial Dysfunction Through Restoration of Rho-BH4-eNOS-NO Pathway. Cardiovasc Drugs Ther 26, 31–40 (2012). https://doi.org/10.1007/s10557-011-6351-3

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