Impact of HMG CoA reductase inhibition on small GTPases in the heart
- 作者：Laufs ; Ulrich ; Kilter ; Heiko ; Konkol ; Christian ; Wassmann ; Sven ; Bö ; hm ; Michael ; Nickenig ; Georg
- 关键词：Myocytes ; G-proteins ; Gene expression ; Lipid metabolism ; Hypertrophy
- 刊名：Cardiovascular Research
- 出版年：2002
- 期刊代码：48_00086363
- 类别：med
- 出版时间：March, 2002
- 卷：53
- 期：4
- 页码：911-920
- 文件大小：1.30 M
摘要
Objective: Members of the Rho GTPase family, Rac1 and RhoA have been suggested to be mediators of cardiac hypertrophy in mice. Rho proteins are posttranslationally isoprenylated. In addition to cholesterol-lowering, statins inhibit the isoprenylation of small G proteins. Therefore, it was tested if these drugs inhibit Rac1 and RhoA activity in cardiomyocytes and, thereby, prevent angiotensin II-mediated expression of atrial natriuretic factor (ANF) and myosin light chain (MLC)-2 in the heart. Methods and results: Western and Northern analysis of rat neonatal cardiomyocytes and H9C2 cells showed inhibition of basal and angiotensin-stimulated Rac1 expression, membrane-translocation and activity after statin treatment. Similarly, basal and stimulated RhoA membrane expression was inhibited. Statins concentration- and time-dependently downregulated basal as well as angiotensin-induced expression of ANF by 86±2.3%and 89±1.7%, as well as MLC-2 by 75±4.1%and 84±6%, respectively. Direct inhibition of Rac GTPase by overexpression of the dominant negative mutant RacN17 or by Clostridium sordellii lethal toxin in rat H9C2 cells inhibited ANF expression by 70±4.9%and 78±10%, respectively. Inhibition of RhoA by Clostridium botulinum C3 transferase or the dominant negative mutant RhoN19 reduced ANF mRNA by 19±11%and 23±8%, respectively. To test these findings in vivo, spontaneously hypertensive rats were treated with atorvastatin, leading to a decrease in cardiac Rac1 and RhoA activity as determined by [35S]-GTPγS-binding assays by 61±16%and 72±24%, and downregulation of MLC-2 as well as ANF mRNA expression by 31±16%and 80±24%, respectively. Conclusions: (1) Statins downregulate the activity of small G proteins in cardiomyocytes in culture as well as in vivo. (2) Inhibition of Rac1 and RhoA by statins reduces myocardial expression of ANF and MLC-2. (3) Targeting myocardial Rho GTPases by statins may be a novel treatment strategy to prevent cardiac hypertrophy.