Cdc42 is an antihypertrophic molecular switch in the mouse heart
Cdc42 is an antihypertrophic molecular switch in the mouse heart
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DOI：
10.1172/jci37694
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发表时间：
2009-10-01
影响因子：
15.9
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
--
作者：
Maillet, Marjorie;Lynch, Jeffrey M.;Molkentin, Jeffery D.
为了改善收缩功能，心肌经历肥大生长，而没有响应于病理和生理刺激的肌细胞增殖。各种膜结合受体和中间信号转导途径调节心肌肥厚的诱导，但心脏保护性调节途径或拮抗心肌肥厚的效应器仍然知之甚少。在这里，我们确定了小GTdR Cdc 42作为抑制心脏生长反应的生理和病理刺激的信号中间体。cdc 42在压力超负荷后的心脏和培养的心肌细胞中被多种激动剂特异性激活。心脏特异性缺失Cdc 42的小鼠在刺激2周和8周时发生了更大的心脏肥大，并且比野生型对照组更快地转变为心力衰竭。这些小鼠还表现出更大的心脏肥大，以响应神经内分泌激动剂输注2周，更显着的是，增强运动诱导的肥大和猝死。这些病理与通过MEKK 1/MKK 4/MKK 7途径刺激后不能激活JNK相关，导致更大的心脏活化T细胞核因子（NFAT）活性。用Mkk 7心脏特异性转基因恢复心脏JNK信号传导逆转了增强的生长效应。这些结果确定了我们认为是一种新的抗肥大和保护性心脏信号通路，Cdc 42依赖性JNK激活拮抗钙调神经磷酸酶-NFAT活性，以减少肥大，防止过渡到心力衰竭。
To improve contractile function, the myocardium undergoes hypertrophic growth without myocyte proliferation in response to both pathologic and physiologic stimulation. Various membrane-bound receptors and intermediate signal transduction pathways regulate the induction of cardiac hypertrophy, but the cardioprotective regulatory pathways or effectors that antagonize cardiac hypertrophy remain poorly understood. Here we identify the small GTPase Cdc42 as a signaling intermediate that restrained the cardiac growth response to physiologic and pathologic stimuli. Cdc42 was specifically activated in the heart after pressure overload and in cultured cardiomyocytes by multiple agonists. Mice with a heart-specific deletion of Cdc42 developed greater cardiac hypertrophy at 2 and 8 weeks of stimulation and transitioned more quickly into heart failure than did wild-type controls. These mice also displayed greater cardiac hypertrophy in response to neuroendocrine agonist infusion for 2 weeks and, more remarkably, enhanced exercise-induced hypertrophy and sudden death. These pathologies were associated with an inability to activate JNK following stimulation through a MEKK1/MKK4/MKK7 pathway, resulting in greater cardiac nuclear factor of activated T cells (NFAT) activity. Restoration of cardiac JNK signaling with an Mkk7 heart-specific transgene reversed the enhanced growth effect. These results identify what we believe to be a novel antihypertrophic and protective cardiac signaling pathway, whereby Cdc42-dependent JNK activation antagonizes calcineurin-NFAT activity to reduce hypertrophy and prevent transition to heart failure.