Downregulation of angiotensin II type 1 receptor by hydrophobic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in vascular smooth muscle cells
Downregulation of angiotensin II type 1 receptor by hydrophobic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in vascular smooth muscle cells
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DOI：
10.1161/hq1201.099430
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发表时间：
2001-12-01
影响因子：
8.7
通讯作者：
Takeshita, A
中科院分区：
文献类型：
--
作者：
Ichiki, T;Takeda, K;Takeshita, A
3-羟基-3-甲基戊二酰辅酶A（HMG CoA）还原酶抑制剂，即所谓的他汀类药物，通过降低血清胆固醇水平来降低主要冠状动脉事件的相对风险。此外，他汀类药物可能通过不依赖降胆固醇的机制产生有益作用，但其特征尚不完全。由于血管紧张素II（Ang II）在心血管疾病的发病机制中起着至关重要的作用，我们研究了他汀类药物对培养的血管平滑肌细胞（VSMC）中Ang II 1型受体（AT（1）-R）表达的影响。西立伐他汀和氟伐他汀可降低AT（1）-R tRNA和AT（1）-R蛋白水平，而普伐他汀则无此作用。西立伐他汀和氟伐他汀抑制AT（1）-R启动子活性，但不影响AT（1）-R mRNA的稳定性，表明抑制发生在转录水平。将VSMC与甲羟戊酸或香叶基香叶基焦磷酸共孵育，但不与法呢基焦磷酸共孵育，逆转了西伐他汀诱导的AT（1）-R下调。显性负性Rho A的过表达也抑制AT（1）-R mRNA的表达。西立伐他汀处理24小时可降低VSMC对Ang II的钙反应。总之，他汀类药物通过甲羟戊酸依赖性、香叶基香叶基焦磷酸依赖性和Rho A依赖性方式下调AT（1）-R表达，并减弱Ang II的生物学功能。AT（1）-R的下调可能有助于他汀类药物对心血管系统的非胆固醇依赖性有益作用。
3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, so-called statins, reduce the relative risk of a major coronary event by lowering the serum cholesterol level. In addition, statins may confer beneficial effects by cholesterol-lowering independent mechanisms, which are incompletely characterized. Because angiotensin II (Ang II) plays crucial roles in the pathogenesis of cardiovascular diseases, we examined the effect of statins on the expression of the Ang II type 1 receptor (AT(1)-R) in cultured vascular smooth muscle cells (VSMCs). Cerivastatin and fluvastatin reduced the AT(1)-R tnRNA and the AT(1)-R protein levels: however, pravastatin lacked this effect. Cerivastatin and fluvastatin suppressed the AT(1)-R promoter activity measured by luciferase assay but did not affect AT(1)-R mRNA stability, suggesting that the suppression occurs at the transcriptional level. Coincubation of VSMCs with mevalonate or geranylgeranyl pyrophosphate but not with farnesyl pyrophosphate reversed the cerivastatin-induced AT(1)-R downregulation. Overexpression of dominant-negative Rho A also suppressed AT(1)-R mRNA expression. Treatment with cerivastatin for 24 hours reduced the calcium response of VSMCs to Ang II. Taken together, statins downregulate AT(1)-R expression through a mevalonate-dependent, geranylgeranyl pyrophosphate-dependent, and Rho A-dependent manner and attenuate the biological function of Ang II. Downregulation of AT(1)-R may contribute to the cholesterol-independent beneficial effect of statins on the cardiovascular system.