Tumor suppressor Ras-association domain family 1 isoform A is a novel regulator of cardiac hypertrophy.
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.


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.
Oceandy
Delvac
D
Cardiovascular Medicine Research Group, School of Clinical and Laboratory Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
Pickard
Adam
A
Prehar
Sukhpal
S
Zi
Min
M
Mohamed
Tamer M A
TM
Stanley
Peter J
PJ
Baudoin-Stanley
Florence
F
Nadif
Raja
R
Tommasi
Stella
S
Pfeifer
Gerd P
GP
Armesilla
Angel L
AL
Cartwright
Elizabeth J
EJ
Neyses
Ludwig
L
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010656:Phenylephrine / Q000009:adverse effects; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000009:adverse effects
C411762:RASSF1 protein, human; C496882:RASSF1 protein, mouse; D025521:Tumor Suppressor Proteins; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D019908:Proto-Oncogene Proteins c-raf; D048052:Mitogen-Activated Protein Kinase 3