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(Circulation. 2009;120:607-616.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Tumor Suppressor Ras-Association Domain Family 1 Isoform A Is a Novel Regulator of Cardiac Hypertrophy

Delvac Oceandy, MD, PhD^*; Adam Pickard, PhD^*; Sukhpal Prehar, MSc; Min Zi, MD; Tamer M.A. Mohamed, PhD; Peter J. Stanley, BSc; Florence Baudoin-Stanley, MRes; Raja Nadif, PhD; Stella Tommasi, PhD; Gerd P. Pfeifer, PhD; Angel L. Armesilla, PhD; Elizabeth J. Cartwright, PhD; Ludwig Neyses, MD

From the Cardiovascular Medicine Research Group, School of Clinical and Laboratory Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom (D.O., A.P., S.P., M.Z., T.M.A.M., P.J.S., F.B.-S., R.N., E.J.C., L.N.); Division of Biology, Beckman Research Institute of the City of Hope, Duarte, Calif (S.T., G.P.P.); Molecular Pharmacology Group, Research Institute in Healthcare Sciences, School of Applied Sciences, University of Wolverhampton, Wolverhampton, United Kingdom (A.L.A.); and Biochemistry Department, Faculty of Pharmacy, Zagazig University, Egypt (T.M.A.M.).

Correspondence to Dr Ludwig Neyses, 1.302 Stopford Bldg, Oxford Rd, Manchester M13 9PT, United Kingdom. E-mail Ludwig.Neyses{at}cmft.nhs.uk

Received March 26, 2009; accepted June 9, 2009.

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.

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CLINICAL PERSPECTIVE

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