Prevention of cardiac hypertrophy by atorvastatin in a transgenic rabbit model of human hypertrophic cardiomyopathy.
Cardiac hypertrophy, a major determinant of morbidity and mortality in hypertrophic cardiomyopathy (HCM), is considered a secondary phenotype and potentially preventable. To test this hypothesis, we screened 30 5- to 6-month-old beta-myosin heavy chain Q403 transgenic rabbits by echocardiography and selected 26 without cardiac hypertrophy. We randomized the transgenic rabbits to treatment with atorvastatin (2.5 mg/Kg/d), known to block hypertrophic signaling or a placebo. We included 15 nontransgenic rabbits as controls. Cardiac phenotype was analyzed serially before, 6 and 12 months after randomization. Serum total cholesterol levels were reduced by 49% with atorvastatin administration. Left-ventricular mass, wall thickness; myocyte size, myocardial levels of molecular markers of hypertrophy, lipid peroxides, and oxidized mitochondrial DNA; and the number of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive myocytes were increased significantly in the placebo but not in the atorvastatin group. Myocardium catalase mRNA levels were decreased by 5-fold in the placebo but were normal in the atorvastatin group. Catalase protein level and activity were not significantly changed. Levels of membrane-bound Ras and phospho-p44/42 mitogen-activated-protein kinase (MAPK) were increased in the placebo group (approximately 2.5 fold) but were reduced in the atorvastatin group. Levels of GTP- and membrane-bound RhoA and Rac1, phospho-p38, and phospho-c-Jun NH2-terminal kinases were unchanged. Thus, atorvastatin prevented development of cardiac hypertrophy; determined at organ, cellular, and molecular levels, partly through reducing active Ras and p44/42 MAPK. The results indicate potential beneficial effects of atorvastatin in prevention of cardiac hypertrophy, a major determinant of morbidity in all forms of cardiovascular diseases, and beckon clinical studies in humans with HCM.
Senthil
Vinitha
V
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, 519D, Houston, TX 77030, USA.
Chen
Suet N
SN
Tsybouleva
Natalie
N
Halder
Tripti
T
Nagueh
Sherif F
SF
Willerson
James T
JT
Roberts
Robert
R
Marian
A J
AJ
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D000069059:Atorvastatin; D002312:Cardiomyopathy, Hypertrophic / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D004272:DNA, Mitochondrial / Q000032:analysis; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control; D008297:Male; D032383:Myocytes, Cardiac / Q000473:pathology; D018995:Myosin Heavy Chains / Q000502:physiology; D018384:Oxidative Stress; D011758:Pyrroles / Q000627:therapeutic use*; D011817:Rabbits; D016277:Ventricular Function, Left; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis
D004272:DNA, Mitochondrial; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018995:Myosin Heavy Chains