Transgenic G alpha q overexpression induces cardiac contractile failure in mice
Transgenic G alpha q overexpression induces cardiac contractile failure in mice
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DOI：
10.1073/pnas.94.15.8121
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发表时间：
1997-07-22
影响因子：
11.1
通讯作者：
Dorn, GW
中科院分区：
文献类型：
--
作者：
DAngelo, DD;Sakata, Y;Dorn, GW
触发心脏肥大和调节向心力衰竭转变的关键细胞信号尚不清楚。为了确定G α q介导的信号通路在这些事件中的作用，构建了转基因小鼠，其使用α-肌球蛋白重链启动子在心脏中过表达野生型G α q。G α q过表达2倍未显示出可检测的效应，而4倍过表达导致心脏重量和心肌细胞大小增加，同时心房自然因子显著增加，沿着增加。（约55倍），β-肌球蛋白重链（大约8倍），和α-骨架肌动蛋白（约8倍）表达，并减少（约3倍）β-肾上腺素能受体刺激的腺苷酸环化酶活性，所有这些信号都被认为是其他实验系统或人类心力衰竭中肥大或衰竭的标志物。超声心动图和体内心脏血液动力学研究确实揭示了表现为缩短分数降低的固有收缩力受损（19 +/-2%vs，41 +/- 3%），dP/dt max，负的力-频率反应，改变的Starling关系，以及对β-肾上腺素能激动剂多巴酚丁胺的收缩反应减弱，在较高水平的G α q过表达下，6只动物中有3只发生明显的心脏失代偿，并发生双心室衰竭，肺充血和死亡，该通路中似乎对这些事件至关重要的因素是蛋白激酶C β的激活。有趣的是，有丝分裂原活化蛋白激酶，这是一些假设是重要的肥大程序，没有被激活，G α q过表达表现出生化和生理表型类似的补偿和失代偿期的人类心脏肥大，并提出了一个共同的发病机制。
The critical cell signals that trigger cardiac hypertrophy and regulate the transition to heart failure are not known. To determine the role of G alpha q-mediated signaling pathways in these events, transgenic mice were constructed that overexpressed wild-type G alpha q in the heart using the alpha-myosin heavy chain promoter. Two-fold overexpression of G alpha q showed no detectable effects, whereas 4-fold overexpression resulted in increased heart weight and myocyte size along with marked increases in atrial naturietic factor (approximate to 55-fold), beta-myosin heavy chain (approximate to 8-fold), and alpha-skeletal actin (approximate to 8-fold) expression, and decreased (approximate to 3-fold) beta-adrenergic receptor-stimulated adenylyl cyclase activity, All of these signals have been considered markers of hypertrophy or failure in other experimental systems or human heart failure, Echocardiography and in vivo cardiac hemodynamic studies indeed revealed impaired intrinsic contractility manifested as decreased fractional shortening (19 +/- 2% vs, 41 +/- 3%), dP/dt max, a negative force-frequency response, an altered Starling relationship, and blunted contractile responses to the beta-adrenergic agonist dobutamine, At higher levels of G alpha q overexpression, frank cardiac decompensation occurred in 3 of 6 animals with development of biventricular failure, pulmonary congestion, and death, The element within the pathway that appeared to be critical for these events was activation of protein kinase C epsilon. Interestingly, mitogen-activated protein kinase, which is postulated by some to be important in the hypertrophy program, was not activated, The G alpha q overexpressor exhibits a biochemical and physiologic phenotype resembling both the compensated and decompensated phases of human cardiac hypertrophy and suggests a common mechanism for their pathogenesis.