© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Impact of HMG CoA reductase inhibition on small GTPases in the heart
Medizinische Klinik und Poliklinik der Universität des Saarlandes, Innere Medizin III, 66421 Homburg/Saar, Germany
ulrich{at}laufs.com
* Corresponding author. Tel.: +49-6841-162-3436; fax: +49-6841-162-3637
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]-GTP
S-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.
KEYWORDS Myocytes; G-proteins; Gene expression; Lipid metabolism; Hypertrophy
1 Ulrich Laufs and Heiko Kilter contributed equally to this study.
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