Apoptosis signal-regulating kinase 1/p38 signaling pathway negatively regulates physiological hypertrophy
Apoptosis signal-regulating kinase 1/p38 signaling pathway negatively regulates physiological hypertrophy
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DOI：
10.1161/circulationaha.107.710434
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发表时间：
2008-01-29
期刊：
影响因子：
37.8
通讯作者：
Otsu, Kinya
中科院分区：
文献类型：
--
作者：
Taniike, Masayuki;Yamaguchi, Osamu;Otsu, Kinya
背景-心脏上的机械应力可能导致截然不同的结果。生理刺激如运动引起适应性心肌肥厚，其特征是心脏结构正常，心功能正常或增强。病理性刺激，如高血压和主动脉瓣狭窄，可引起适应性不良的心脏重构，最终导致心力衰竭。凋亡信号调节激酶1 （Apoptosis signal-regulating kinase 1, ASK1）已知参与病理性心脏重构，但ASK1通路是否协调导致生理性心脏生长的信号级联尚未确定。方法和结果-为了评估ASK1在心脏生长的生理形式中的作用，缺乏ASK1（ASK1(-/-)）的小鼠通过游泳锻炼4周。ASK1（-/-）小鼠表现出心脏过度生长并伴有典型的生理性肥大特征。游泳诱导的Akt（生理肥大信号级联的关键分子）的激活比野生型对照组增加得更多。p38 （ASK1的下游激酶）的激活在游泳运动的ASK1（-/-）小鼠中被选择性抑制。此外，ASK1或p38活性的抑制可增强大鼠新生心室心肌细胞中胰岛素样生长因子1诱导的蛋白质合成，p38特异性抑制剂可增强Akt的激活，抑制蛋白磷酸酶2A的激活。心脏特异性p38 α缺陷小鼠对游泳运动的反应是心脏肥厚的加重形式。结论-这些结果表明ASK1/p38信号通路负性调节生理性肥大。
Background - Mechanical stress on the heart can lead to crucially different outcomes. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy, characterized by a normal cardiac structure and normal or enhanced cardiac function. Pathological stimuli such as hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Apoptosis signal-regulating kinase 1 (ASK1) is known to be involved in pathological cardiac remodeling, but it has not been determined whether ASK1 pathways coordinate the signaling cascade leading to physiological type cardiac growth.Methods and Results - To evaluate the role of ASK1 in the physiological form of cardiac growth, mice lacking ASK1 (ASK1(-/-)) were exercised by swimming for 4 weeks. ASK1(-/-) mice showed exaggerated growth of the heart accompanied by typical characteristics of physiological hypertrophy. Their swimming-induced activation of Akt, a key molecule in the signaling cascade of physiological hypertrophy, increased more than that seen in wild-type controls. The activation of p38, a downstream kinase of ASK1, was suppressed selectively in the swimming-exercised ASK1(-/-) mice. Furthermore, the inhibition of ASK1 or p38 activity enhanced insulin-like growth factor 1-induced protein synthesis in rat neonatal ventricular cardiomyocytes, and the treatment with a specific inhibitor of p38 resulted in enhancement of Akt activation and suppression of protein phosphatase 2A activation. The cardiac-specific p38 alpha-deficient mice developed an exacerbated form of cardiac hypertrophy in response to swimming exercise.Conclusions - These results indicate that the ASK1/p38 signaling pathway negatively regulates physiological hypertrophy.