Simvastatin ameliorates rat cerebrovascular remodeling during hypertension via inhibition of volume-regulated chloride channel.
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 IC(50) of simvastatin on endothelin 1- and hypo-osmolarity-induced cell proliferation from 3.40+/-0.08 and 3.50+/-0.10 micromol/L to 5.30+/-0.70 and 5.60+/-0.70 micromol/L, respectively (P<0.01; n=6). Furthermore, the expression of ClC-3 was increased in basilar artery during hypertension, and simvastatin normalized the upregulation of ClC-3. Our data suggested that simvastatin ameliorates cerebrovascular remodeling in the hypertensive rat through inhibition of vascular smooth muscle cell proliferation by suppression of volume-regulated chloride channel.
Liu
Yu-Jie
YJ
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, 74 Zhongshan 2 Rd, Guangzhou 510080, China.
Wang
Xiao-Guang
XG
Tang
Yong-Bo
YB
Chen
Jing-Hui
JH
Lv
Xiao-Fei
XF
Zhou
Jia-Guo
JG
Guan
Yong-Yuan
YY
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D018118:Chloride Channels / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008798:Mevalonic Acid / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000378:metabolism
D018118:Chloride Channels; C115376:ClC-3 channel; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D019821:Simvastatin; D054460:rho-Associated Kinases; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid