Oceandy Delvac, Pickard Adam, Prehar Sukhpal, Zi Min, Mohamed Tamer M A, Stanley Peter J, Baudoin-Stanley Florence, Nadif Raja, Tommasi Stella, Pfeifer Gerd P, Armesilla Angel L, Cartwright Elizabeth J, Neyses Ludwig
Cardiovascular Medicine Research Group, School of Clinical and Laboratory Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
Circulation. 2009 Aug 18;120(7):607-16. doi: 10.1161/CIRCULATIONAHA.109.868554. Epub 2009 Aug 3.
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.
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.
Our data establish RASSF1A as a novel inhibitor of cardiac hypertrophy by modulating the extracellular regulated kinase 1/2 pathway.
Ras信号通路调节心脏中的许多重要过程，包括细胞生长和肥大。尽管已知Ras信号通路缺陷与努南综合征、科斯特洛综合征以及其他以肿瘤形成和心脏肥大为特征的综合征相关，但对于可能控制该通路的因素却知之甚少。在此，我们研究Ras效应分子Ras关联结构域家族1同工型A（RASSF1A）在调节心肌肥大中的作用。
在肥厚的小鼠心脏以及衰竭的人类心脏中均观察到RASSF1A表达显著下调。为进一步研究RASSF1A在心脏（病理）生理学中的作用，我们使用了RASSF1A基因敲除（RASSF1A(-)(/)(-)）小鼠以及过表达RASSF1A的腺病毒转染的新生大鼠心肌细胞。敲除小鼠体内的RASSF1A可显著增强对主动脉缩窄的肥大反应（RASSF1A(-)(/)(-)小鼠的心脏重量/体重比增加64.2%，而野生型小鼠为32.4%）。与体内实验数据一致，在心肌细胞中过表达RASSF1A可显著降低对去氧肾上腺素刺激的细胞肥大反应。对分离的心肌细胞中分子信号事件的分析表明，RASSF1A可能通过阻断Raf1与活性Ras的结合来抑制细胞外调节激酶1/2的激活。
我们的数据表明，RASSF1A通过调节细胞外调节激酶1/2通路，是一种新型的心肌肥大抑制剂。
