Simvastatin Ameliorates Rat Cerebrovascular Remodeling During Hypertension via Inhibition of Volume-Regulated Chloride Channel
Simvastatin Ameliorates Rat Cerebrovascular Remodeling During Hypertension via Inhibition of Volume-Regulated Chloride Channel
复制标题
辛伐他汀通过抑制容量调节氯通道改善高血压期间大鼠脑血管重塑
DOI：
10.1161/hypertensionaha.110.150102
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发表时间：
2010-09-01
期刊：
影响因子：
8.3
通讯作者：
Guan, Yong-Yuan
中科院分区：
文献类型：
--
作者：
Liu, Yu-Jie;Wang, Xiao-Guang;Guan, Yong-Yuan
他汀类药物对血管重构的发展和缺血性卒中的发生具有多效性作用。虽然以前的研究表明，翻译后修饰的几种蛋白质，如Rho的甲羟戊酸衍生的异戊二烯基团，香叶基香叶基焦磷酸或法呢基焦磷酸，他汀类药物的多效性作用的基础，详细的机制仍然难以捉摸。最近越来越多的证据表明，ClC-3体积调节氯通道在细胞增殖中起着重要作用，并且该通道的活性在高血压大鼠的基底动脉平滑肌细胞中增加。我们推测，抑制容量调节氯通道可能有助于他汀类药物对高血压脑血管重塑的有益作用。我们的研究表明，辛伐他汀改善高血压引起的脑血管重构。在大鼠基底动脉平滑肌细胞，辛伐他汀抑制细胞增殖和激活的体积调节氯通道，这些影响辛伐他汀被取消预处理甲羟戊酸或香叶基香叶基焦磷酸。此外，Rho A抑制剂C3外切酶和Rho激酶抑制剂Y-27632均降低细胞增殖和体积调节氯通道的激活。ClC-3过表达可降低辛伐他汀对细胞增殖的抑制作用，并使辛伐他汀对内皮素1和低渗透压诱导的细胞增殖的IC 50分别从3.40±0.08和3.50±0.10 mol/L增加到5.30±0.70和5.60±0.70 mol/L（P<0.01; n=6）。此外，高血压时基底动脉ClC-3表达增加，辛伐他汀使ClC-3的上调正常化。我们的数据表明，辛伐他汀改善高血压大鼠脑血管重构通过抑制血管平滑肌细胞增殖的容量调节氯通道。
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 &mgr;mol/L to 5.30±0.70 and 5.60±0.70 &mgr;mol/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.