Distinct roles of autophagy in the heart during ischemia and reperfusion - Roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy
Distinct roles of autophagy in the heart during ischemia and reperfusion - Roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy
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DOI：
10.1161/01.res.0000261924.76669.36
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发表时间：
2007-03-30
影响因子：
20.1
通讯作者：
Sadoshima, Junichi
中科院分区：
文献类型：
--
作者：
Matsui, Yutaka;Takagi, Hiromitsu;Sadoshima, Junichi
自噬是蛋白质和细胞器的细胞内整体降解过程。在心脏中，心肌缺血刺激自噬。然而，自噬在心肌细胞存活中的作用和潜在的信号传导机制知之甚少。模拟心肌缺血的葡萄糖剥夺（GD）诱导培养的心肌细胞自噬。自噬抑制剂3-甲基腺嘌呤降低了心肌细胞的存活率，表明自噬对心肌细胞中的GD具有保护作用。GD诱导的自噬与AMP激活的蛋白激酶（AMPK）的激活和mTOR（雷帕霉素的哺乳动物靶标）的失活相一致。通过腺嘌呤9-β-D-阿拉伯呋喃糖苷或显性阴性AMPK抑制AMPK可显著降低GD诱导的自噬，而雷帕霉素刺激自噬未能对GD诱导的自噬产生累加效应，表明AMPK的激活和mTOR的抑制介导了GD诱导的自噬。自噬也诱导缺血和再灌注小鼠心脏，在体内进一步增强。缺血引起的自噬伴随着AMPK的激活，并被显性负性AMPK抑制。与此相反，再灌注过程中的自噬伴随着Beclin 1的上调，但不激活AMPK。在再灌注阶段，自噬和心脏损伤的诱导在beclin 1（+/-）小鼠中显著减弱。这些结果表明，在心脏中，缺血通过AMPK依赖性机制刺激自噬，而缺血/再灌注通过Beclin 1依赖性但AMPK非依赖性机制刺激自噬。此外，自噬在缺血和再灌注期间起着不同的作用：自噬在缺血期间可能是保护性的，而在再灌注期间可能是有害的。
Autophagy is an intracellular bulk degradation process for proteins and organelles. In the heart, autophagy is stimulated by myocardial ischemia. However, the causative role of autophagy in the survival of cardiac myocytes and the underlying signaling mechanisms are poorly understood. Glucose deprivation ( GD), which mimics myocardial ischemia, induces autophagy in cultured cardiac myocytes. Survival of cardiac myocytes was decreased by 3-methyladenine, an inhibitor of autophagy, suggesting that autophagy is protective against GD in cardiac myocytes. GD-induced autophagy coincided with activation of AMP-activated protein kinase ( AMPK) and inactivation of mTOR ( mammalian target of rapamycin). Inhibition of AMPK by adenine 9-beta-D-arabinofuranoside or dominant negative AMPK significantly reduced GD-induced autophagy, whereas stimulation of autophagy by rapamycin failed to cause an additive effect on GD-induced autophagy, suggesting that activation of AMPK and inhibition of mTOR mediate GD-induced autophagy. Autophagy was also induced by ischemia and further enhanced by reperfusion in the mouse heart, in vivo. Autophagy resulting from ischemia was accompanied by activation of AMPK and was inhibited by dominant negative AMPK. In contrast, autophagy during reperfusion was accompanied by upregulation of Beclin 1 but not by activation of AMPK. Induction of autophagy and cardiac injury during the reperfusion phase was significantly attenuated in beclin 1(+/-) mice. These results suggest that, in the heart, ischemia stimulates autophagy through an AMPK-dependent mechanism, whereas ischemia/reperfusion stimulates autophagy through a Beclin 1-dependent but AMPK-independent mechanism. Furthermore, autophagy plays distinct roles during ischemia and reperfusion: autophagy may be protective during ischemia, whereas it may be detrimental during reperfusion.