Simvastatin Ameliorates Rat Cerebrovascular Remodeling During Hypertension via Inhibition of Volume-Regulated Chloride Channel

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2010-09, Vol.56 (3), p.445-452
• Main Authors: Liu, Yu-Jie, Wang, Xiao-Guang, Tang, Yong-Bo, Chen, Jing-Hui, Lv, Xiao-Fei, Zhou, Jia-Guo, Guan, Yong-Yuan
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blotting, Western; Cardiology. Vascular system; Cell Proliferation - drug effects; Cerebrovascular Circulation - drug effects; Chloride Channels - metabolism; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypertension - drug therapy; Hypertension - metabolism; Medical sciences; Mevalonic Acid - pharmacology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Polyisoprenyl Phosphates - pharmacology; Rats; rho-Associated Kinases - metabolism; Simvastatin - pharmacology; Simvastatin - therapeutic use
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.110.150102

Statins have pleiotropic actions against the development of vascular remodeling and the incidence of ischemic stroke. Although previous studies have suggested that posttranslational modification of several proteins, such as Rho by mevalonate-derived isoprene groups, geranylgeranyl pyrophosphate or farnesyl pyrophosphate, underlie the pleiotropic effects of statins, the detailed mechanisms remain elusive. Recent growing evidence demonstrated that ClC-3 volume-regulated chloride channel plays an important role in cell proliferation, and the activity of this channel is increased in basilar smooth muscle cells from a hypertensive rat. We hypothesized that inhibition of volume-regulated chloride channel may contribute to the beneficial effects of statins on cerebrovascular remodeling during hypertension. Our study here demonstrated that simvastatin ameliorated hypertension-caused cerebrovascular remodeling. In rat basilar smooth muscle cells, simvastatin inhibited cell proliferation and activation of volume-regulated chloride channel, and these effects of simvastatin were abolished by pretreatment with mevalonate or geranylgeranyl pyrophosphate. In addition, Rho A inhibitor C3 exoenzyme and Rho kinase inhibitor Y-27632 both reduced cell proliferation and activation of volume-regulated chloride channel. Moreover, ClC-3 overexpression decreased the suppressive effect of simvastatin on cell proliferation and increased estimated IC50 of simvastatin on endothelin 1- and hypo-osmolarity-induced cell proliferation from 3.40±0.08 and 3.50±0.10 μmol/L to 5.30±0.70 and 5.60±0.70 μmol/L, respectively (P