Impact of HMG CoA reductase inhibition on small GTPases in the heart.

Abstract

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 gamma 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.

• Authors: Ulrich Laufs, Heiko Kilter, Christian Konkol, Sven Wassmann, Michael Böhm, Georg Nickenig
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 53 Issue 4 Pg. 911-20 (Mar 2002) ISSN: 0008-6363 [Print] England
• PMID: 11922901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heptanoic Acids
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Hypolipidemic Agents
• Myosin Light Chains
• Pyrroles
• RNA, Messenger
• myosin light chain 2
• Angiotensin II
• Atrial Natriuretic Factor
• Atorvastatin
• Simvastatin
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases
• Cardiac Myosins
• GTP Phosphohydrolases
• rac1 GTP-Binding Protein
• rhoA GTP-Binding Protein

Topics

• Angiotensin II (pharmacology)
• Animals
• Atorvastatin
• Atrial Natriuretic Factor (genetics, metabolism)
• Cardiac Myosins (metabolism)
• Cardiomegaly (metabolism)
• Cell Membrane (metabolism)
• Cells, Cultured
• GTP Phosphohydrolases (antagonists & inhibitors, metabolism)
• Gene Expression Regulation (drug effects)
• Heptanoic Acids (pharmacology)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Hypolipidemic Agents (pharmacology)
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Male
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Myocardium (cytology, enzymology)
• Myosin Light Chains (metabolism)
• Pyrroles (pharmacology)
• RNA, Messenger (genetics)
• Rats
• Rats, Sprague-Dawley
• Simvastatin (pharmacology)
• rac1 GTP-Binding Protein (antagonists & inhibitors, metabolism)
• rhoA GTP-Binding Protein (antagonists & inhibitors, metabolism)