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Tumor Suppressor Ras-Association Domain Family 1 Isoform A Is a Novel Regulator of Cardiac Hypertrophy
Faculty
Pharmacy
Year:
2009
Type of Publication:
Article
Pages:
607-U125
Authors:
Mohamed, Tamer M. A, Neyses, Ludwig, Cartwright, Elizabeth J, Oceandy, Delvac, Armesilla, Angel L, Zi, Min, Prehar, Sukhpal, Pickard, Adam, Stanley, Peter J, Baudoin-Stanley, Florence, Nadif, Raja, Tommasi, Stella, Pfeifer, Gerd P
DOI:
10.1161/CIRCULATIONAHA.109.868554
Journal:
CIRCULATION LIPPINCOTT WILLIAMS \& WILKINS
Volume:
120
Research Area:
Cardiovascular System \& Cardiology
ISSN
ISI:000269051900010
Keywords :
hypertrophy, signal transduction, heart failure
Abstract:
Background-Ras signaling regulates a number of important processes in the heart, including cell growth and hypertrophy. Although it is known that defective Ras signaling is associated with Noonan, Costello, and other syndromes that are characterized by tumor formation and cardiac hypertrophy, little is known about factors that may control it. Here we investigate the role of Ras effector Ras-association domain family 1 isoform A (RASSF1A) in regulating myocardial hypertrophy. Methods and Results-A significant downregulation of RASSF1A expression was observed in hypertrophic mouse hearts, as well as in failing human hearts. To further investigate the role of RASSF1A in cardiac (patho) physiology, we used RASSF1A knock-out (RASSF1A(-/-)) mice and neonatal rat cardiomyocytes with adenoviral overexpression of RASSF1A. Ablation of RASSF1A in mice significantly enhanced the hypertrophic response to transverse aortic constriction (64.2\% increase in heart weight/body weight ratio in RASSF1A(-/-) mice compared with 32.4\% in wild type). Consistent with the in vivo data, overexpression of RASSF1A in cardiomyocytes markedly reduced the cellular hypertrophic response to phenylephrine stimulation. Analysis of molecular signaling events in isolated cardiomyocytes indicated that RASSF1A inhibited extracellular regulated kinase 1/2 activation, likely by blocking the binding of Raf1 to active Ras. Conclusions-Our data establish RASSF1A as a novel inhibitor of cardiac hypertrophy by modulating the extracellular regulated kinase 1/2 pathway. (Circulation. 2009;120:607-616.)
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