Doggen Kris, Ray Lynn, Mathieu Myrielle, Mc Entee Kathleen, Lemmens Katrien, De Keulenaer Gilles W
Laboratory of Physiology, University of Antwerp, Antwerp, Belgium.
J Mol Cell Cardiol. 2009 Jan;46(1):33-8. doi: 10.1016/j.yjmcc.2008.10.010. Epub 2008 Oct 28.
The neuregulin-1 (NRG-1)/ErbB system has emerged as a cardioprotective system that becomes activated during myocardial stress, most convincingly shown in response to cardiotoxic chemotherapy. Direct evidence of increased ventricular ErbB receptor activity in heart failure unrelated to cardiotoxic drugs is, however, limited. We investigated changes in NRG-1 expression, ErbB receptor phosphorylation and downstream activation of intracellular ErbB targets during rapid pacing and progressive ventricular dysfunction in the dog. Heart failure was induced in dogs by 7 weeks of rapid pacing. Ventricular function was assessed by echocardiography. Messenger RNA expression was investigated in ventricular biopsies using quantitative PCR. Activation of NRG-1/ErbB signaling and of downstream targets was investigated using immunoprecipitation and/or Western blotting. Over the course of 7 weeks of pacing and ventricular dilatation, ventricular levels of NRG-1, but not of other ErbB4 ligands, and of ADAM19, a protease promoting NRG-1 release, progressively increased. In parallel, levels of activated ErbB2 and ErbB4, phosphorylated at tyrosine residues 877/1248 and 1284 respectively, became progressively higher. Similarly, levels of total and phosphorylated PI-3 kinase increased. Surprisingly, however, and in contrast with activation of downstream targets of ErbB receptors in normal hearts, Akt and ERK1/2, remained inactivated. This study shows that ventricular ErbB2 and ErbB4 receptors become activated during the development of pacing-induced heart failure, but that downstream signaling is, at least partly, abrogated. Abrogation of cardioprotective signaling after ErbB activation is an unanticipated phenomenon in the progression of heart failure with possibly major pathophysiological significance. The underlying mechanisms should be further elucidated.
神经调节蛋白-1（NRG-1）/表皮生长因子受体（ErbB）系统已成为一种心脏保护系统，在心肌应激时被激活，这在对心脏毒性化疗的反应中表现得最为明显。然而，与心脏毒性药物无关的心力衰竭患者心室ErbB受体活性增加的直接证据有限。我们研究了犬快速起搏和进行性心室功能障碍过程中NRG-1表达、ErbB受体磷酸化以及细胞内ErbB靶点下游激活的变化。通过7周的快速起搏诱导犬发生心力衰竭。通过超声心动图评估心室功能。使用定量PCR研究心室活检组织中的信使核糖核酸表达。使用免疫沉淀和/或蛋白质印迹法研究NRG-1/ErbB信号传导及其下游靶点的激活情况。在7周的起搏和心室扩张过程中，心室中NRG-1的水平逐渐升高，而其他ErbB4配体以及促进NRG-1释放的蛋白酶ADAM19的水平并未升高。同时，分别在酪氨酸残基877/1248和1284处磷酸化的活化ErbB2和ErbB4的水平逐渐升高。同样，总磷脂酰肌醇-3激酶和磷酸化磷脂酰肌醇-3激酶的水平也升高。然而，令人惊讶的是，与正常心脏中ErbB受体下游靶点的激活情况相反，蛋白激酶B（Akt）和细胞外信号调节激酶1/2（ERK1/2）仍处于失活状态。这项研究表明，在起搏诱导的心力衰竭发展过程中，心室ErbB2和ErbB4受体被激活，但下游信号传导至少部分被阻断。ErbB激活后心脏保护信号的阻断是心力衰竭进展中一个意外的现象，可能具有重要的病理生理学意义。其潜在机制应进一步阐明。
