PMID- 19652091
OWN - NLM
STAT- MEDLINE
DCOM- 20090921
LR  - 20211020
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 120
IP  - 7
DP  - 2009 Aug 18
TI  - Tumor suppressor Ras-association domain family 1 isoform A is a novel regulator 
      of cardiac hypertrophy.
PG  - 607-16
LID - 10.1161/CIRCULATIONAHA.109.868554 [doi]
AB  - 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.
FAU - Oceandy, Delvac
AU  - Oceandy D
AD  - Cardiovascular Medicine Research Group, School of Clinical and Laboratory 
      Sciences, University of Manchester, Manchester Academic Health Science Centre, 
      Manchester, United Kingdom.
FAU - Pickard, Adam
AU  - Pickard A
FAU - Prehar, Sukhpal
AU  - Prehar S
FAU - Zi, Min
AU  - Zi M
FAU - Mohamed, Tamer M A
AU  - Mohamed TM
FAU - Stanley, Peter J
AU  - Stanley PJ
FAU - Baudoin-Stanley, Florence
AU  - Baudoin-Stanley F
FAU - Nadif, Raja
AU  - Nadif R
FAU - Tommasi, Stella
AU  - Tommasi S
FAU - Pfeifer, Gerd P
AU  - Pfeifer GP
FAU - Armesilla, Angel L
AU  - Armesilla AL
FAU - Cartwright, Elizabeth J
AU  - Cartwright EJ
FAU - Neyses, Ludwig
AU  - Neyses L
LA  - eng
GR  - FS/09/046/28043/BHF_/British Heart Foundation/United Kingdom
GR  - PG/05/082/BHF_/British Heart Foundation/United Kingdom
GR  - G0200020/MRC_/Medical Research Council/United Kingdom
GR  - G0500025/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090803
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (RASSF1 protein, human)
RN  - 0 (RASSF1 protein, mouse)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (Vasoconstrictor Agents)
RN  - 1WS297W6MV (Phenylephrine)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Animals
MH  - Apoptosis/physiology
MH  - Cardiomegaly/chemically induced/*metabolism/*pathology
MH  - Cell Line
MH  - *Cell Proliferation
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - Heart Failure/metabolism/pathology
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Myocytes, Cardiac/metabolism/pathology
MH  - Phenylephrine/adverse effects
MH  - Proto-Oncogene Proteins c-raf/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/*physiology
MH  - Tumor Suppressor Proteins/genetics/*metabolism
MH  - Vasoconstrictor Agents/adverse effects
EDAT- 2009/08/05 09:00
MHDA- 2009/09/22 06:00
CRDT- 2009/08/05 09:00
PHST- 2009/08/05 09:00 [entrez]
PHST- 2009/08/05 09:00 [pubmed]
PHST- 2009/09/22 06:00 [medline]
AID - CIRCULATIONAHA.109.868554 [pii]
AID - 10.1161/CIRCULATIONAHA.109.868554 [doi]
PST - ppublish
SO  - Circulation. 2009 Aug 18;120(7):607-16. doi: 10.1161/CIRCULATIONAHA.109.868554. 
      Epub 2009 Aug 3.