title: 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.
  
  
  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.affiliation: Medizinische Klinik und Poliklinik der Universität des Saarlandes, Innere Medizin III, 66421 Homburg/Saar, Germany. ulrich@laufs.com
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
authors.forename: Heiko
authors.initials: H
authors.lastname: Kilter
authors.forename: Christian
authors.initials: C
authors.lastname: Konkol
authors.forename: Sven
authors.initials: S
authors.lastname: Wassmann
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000069059:Atorvastatin; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D024722:Cardiac Myosins / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D018994:Myosin Light Chains / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D018994:Myosin Light Chains; D011758:Pyrroles; D012333:RNA, Messenger; C107184:myosin light chain 2; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D000069059:Atorvastatin; D019821:Simvastatin; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D024722:Cardiac Myosins; D020558:GTP Phosphohydrolases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein