Published online before print July 14, 2005, doi: 10.1161/01.RES.0000177090.07296.ac
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on April 12, 2005
Revised on June 29, 2005
Accepted on June 30, 2005
Prevention of Cardiac Hypertrophy by Atorvastatin in a Transgenic Rabbit Model of Human Hypertrophic Cardiomyopathy
Vinitha Senthil ;
* To whom correspondence should be addressed. E-mail: amarian{at}bcm.tmc.edu.
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 
-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 (
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.
Key words: hypertrophy • genetics • prevention • gene expression • statins
This article has been cited by other articles:
 |
|
 |
|
  J. M. Bos, J. A. Towbin, and M. J. Ackerman Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J. Am. Coll. Cardiol., July 14, 2009; 54(3): 201 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Lombardi, G. Rodriguez, S. N. Chen, C. M. Ripplinger, W. Li, J. Chen, J. T. Willerson, S. Betocchi, S. A. Wickline, I. R. Efimov, et al. Resolution of Established Cardiac Hypertrophy and Fibrosis and Prevention of Systolic Dysfunction in a Transgenic Rabbit Model of Human Cardiomyopathy Through Thiol-Sensitive Mechanisms Circulation, March 17, 2009; 119(10): 1398 - 1407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Lombardi, A. Bell, V. Senthil, J. Sidhu, M. Noseda, R. Roberts, and A. J. Marian Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies Cardiovasc Res, July 1, 2008; 79(1): 109 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dandona and R. Roberts Identification of Myofilament Mutations: Its Role in the Diagnosis and Management of Hypertrophic Cardiomyopathy Mayo Clin. Proc., June 1, 2008; 83(6): 626 - 627. [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. McMurtry, S. Bonnet, E. D. Michelakis, S. Bonnet, A. Haromy, and S. L. Archer Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamcyin-atorvastatin-simvastatin study Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L933 - L940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Brown, D. P. Del Re, and M. A. Sussman The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits Circ. Res., March 31, 2006; 98(6): 730 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Marian, V. Senthil, S. N. Chen, and R. Lombardi Antifibrotic Effects of Antioxidant N-Acetylcysteine in a Mouse Model of Human Hypertrophic Cardiomyopathy Mutation J. Am. Coll. Cardiol., February 21, 2006; 47(4): 827 - 834. [Abstract] [Full Text] [PDF]
|
|