The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy.
The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy.
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DOI：
10.1172/jci14938
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发表时间：
2002-07
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影响因子：
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通讯作者：
J. Sadoshima;O. Montagne;Qian Wang;Guiping Yang;Jill Warden;Jing Liu;G. Takagi;V. Karoor;C. Hong;G. Johnson;D. Vatner;S. Vatner
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文献类型：
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作者：
J. Sadoshima;O. Montagne;Qian Wang;Guiping Yang;Jill Warden;Jing Liu;G. Takagi;V. Karoor;C. Hong;G. Johnson;D. Vatner;S. Vatner
丝裂原活化蛋白激酶（MEKK 1）介导c-Jun NH（2）-末端激酶（JNK）的活化。虽然先前使用培养的心肌细胞的研究表明MEKK 1-JNK通路在肥大和凋亡中起关键作用，但其在成年动物体内心脏肥大和凋亡中的作用尚未完全了解。我们使用MEKK 1缺陷的小鼠研究了MEKK 1-JNK通路在压力超负荷心脏中的作用。我们发现，在Mekk 1（+/+）小鼠中，横主动脉结扎显著增加了JNK活性，但在Mekk 1（-/-）小鼠中没有，表明MEKK 1通过压力超负荷介导JNK激活。然而，压力超负荷导致Mekk 1（-/-）动物的心脏肥大和心钠素表达水平显著升高，其死亡率和肺/体重比高于对照组。结扎后14天，Mekk 1（-/-）心脏扩张，左心室射血分数低。压力超负荷导致这些小鼠的凋亡和炎症病变水平升高，并产生比野生型对照组更小的TGF-β和TNF-α表达增加。因此，MEKK 1似乎是压力超负荷诱导的JNK激活和细胞因子上调所需的，但对于压力超负荷诱导的心脏肥大是必需的。MEKK 1还可以防止细胞凋亡和炎症，从而防止心脏压力超负荷后的心力衰竭和猝死。
Mitogen-activated protein kinase kinase kinase (MEKK1) mediates activation of c-Jun NH(2)-terminal kinase (JNK). Although previous studies using cultured cardiac myocytes have suggested that the MEKK1-JNK pathway plays a key role in hypertrophy and apoptosis, its effects in cardiac hypertrophy and apoptosis are not fully understood in adult animals in vivo. We examined the role of the MEKK1-JNK pathway in pressure-overloaded hearts by using mice deficient in MEKK1. We found that transverse aortic banding significantly increased JNK activity in Mekk1(+/+) but not Mekk1(-/-) mice, indicating that MEKK1 mediates JNK activation by pressure overload. Nevertheless, pressure overload caused significant levels of cardiac hypertrophy and expression of atrial natriuretic factor in Mekk1(-/-) animals, which showed higher mortality and lung/body weight ratio than were seen in controls. Fourteen days after banding, Mekk1(-/-) hearts were dilated, and their left ventricular ejection fraction was low. Pressure overload caused elevated levels of apoptosis and inflammatory lesions in these mice and produced a smaller increase in TGF-beta and TNF-alpha expression than occurred in wild-type controls. Thus, MEKK1 appears to be required for pressure overload-induced JNK activation and cytokine upregulation but to be dispensable for pressure overload-induced cardiac hypertrophy. MEKK1 also prevents apoptosis and inflammation, thereby protecting against heart failure and sudden death following cardiac pressure overload.