p38α mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload
p38α mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload
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DOI：
10.1128/mcb.24.24.10611-10620.2004
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发表时间：
2004-12-01
影响因子：
5.3
通讯作者：
Otsu, K
中科院分区：
文献类型：
--
作者：
Nishida, K;Yamaguchi, O;Otsu, K
心肌肥厚是对生物力学应激的一种适应性反应，其转变为心力衰竭的分子机制还知之甚少。丝裂原活化蛋白激酶p38α是各种类型细胞中应激反应通路的关键组成部分。在本研究中，我们试图探索p38α在心脏中的体内生理功能。首先，我们建立了携带P38α等位基因的小鼠，并在α-肌球蛋白重链启动子的控制下，将它们与表达Cre重组酶的小鼠杂交，获得心脏特异的P38α基因敲除小鼠。这些心脏特异的p38pha基因敲除小鼠出生正常，发育成熟，具有生育能力，表现出正常的寿命，并表现出正常的整体心脏结构和功能。作为对左心室压力超负荷的反应，他们出现了明显的心肌肥厚，正如对照组所见，但也出现了心功能障碍和心脏扩张。这种对压力超负荷的异常反应伴随着大量的心肌纤维化和心肌细胞凋亡的出现。这些结果表明，p38α在压力超负荷反应的心肌细胞生存途径中起着关键作用，而心肌肥大生长并没有受到影响，尽管它的表达显著下调。
The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38alpha is a key component of stress response pathways in various types of cells. In this study, we attempted to explore the in vivo physiological functions of p38alpha in hearts. First, we generated mice with floxed p38alpha alleles and crossbred them with mice expressing the Cre recombinase under the control of the alpha-myosin heavy-chain promoter to obtain cardiac-specific p38alpha knockout mice. These cardiac-specific p38alpha knockout mice were born normally, developed to adulthood, were fertile, exhibited a normal life span, and displayed normal global cardiac structure and function. In response to pressure overload to the left ventricle, they developed significant levels of cardiac hypertrophy, as seen in controls, but also developed cardiac dysfunction and heart dilatation. This abnormal response to pressure overload was accompanied by massive cardiac fibrosis and the appearance of apoptotic cardiomyocytes. These results demonstrate that p38alpha plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation.