Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes.
Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes.
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作者：
He C;Zhu H;Li H;Zou MH;Xie Z
糖尿病性心肌病与心脏自噬受抑制有关，而AMP活化蛋白激酶（AMPK）的激活可恢复糖尿病小鼠的心脏自噬并预防心肌病，尽管其机制尚不清楚。我们假设AMPK诱导的自噬通过抑制心肌细胞凋亡来改善糖尿病性心肌病，并研究了AMPK对糖尿病小鼠以及高糖处理的H9c2心肌成肌细胞中Beclin1和Bcl - 2之间相互作用的影响，Beclin1和Bcl - 2是自噬和凋亡之间的转换开关。将H9c2细胞暴露于高糖环境会降低AMPK活性，抑制c - Jun氨基末端激酶1（JNK1）- B细胞淋巴瘤2（Bcl - 2）信号传导，并促进Beclin1与Bcl - 2结合。相反，二甲双胍激活AMPK会刺激JNK1 - Bcl - 2信号传导并破坏Beclin1 - Bcl - 2复合物。AMPK的激活使心脏自噬正常化，减轻了培养的H9c2细胞中高糖诱导的凋亡。这种作用因自噬受抑制而减弱。最后，在糖尿病小鼠中长期给予二甲双胍通过激活JNK1 - Bcl - 2通路以及使Beclin1和Bcl - 2解离来恢复心脏自噬。自噬的诱导可防止心脏凋亡，并改善糖尿病小鼠的心脏结构和功能。我们得出结论，Bcl - 2从Beclin1上解离可能是通过AMPK激活来预防糖尿病性心肌病的一个重要机制，AMPK激活可恢复自噬并防止心脏凋亡。
Diabetic cardiomyopathy is associated with suppression of cardiac autophagy, and activation of AMP-activated protein kinase (AMPK) restores cardiac autophagy and prevents cardiomyopathy in diabetic mice, albeit by an unknown mechanism. We hypothesized that AMPK-induced autophagy ameliorates diabetic cardiomyopathy by inhibiting cardiomyocyte apoptosis and examined the effects of AMPK on the interaction between Beclin1 and Bcl-2, a switch between autophagy and apoptosis, in diabetic mice and high glucose–treated H9c2 cardiac myoblast cells. Exposure of H9c2 cells to high glucose reduced AMPK activity, inhibited Jun NH2-terminal kinase 1 (JNK1)–B-cell lymphoma 2 (Bcl-2) signaling, and promoted Beclin1 binding to Bcl-2. Conversely, activation of AMPK by metformin stimulated JNK1–Bcl-2 signaling and disrupted the Beclin1–Bcl-2 complex. Activation of AMPK, which normalized cardiac autophagy, attenuated high glucose–induced apoptosis in cultured H9c2 cells. This effect was attenuated by inhibition of autophagy. Finally, chronic administration of metformin in diabetic mice restored cardiac autophagy by activating JNK1–Bcl-2 pathways and dissociating Beclin1 and Bcl-2. The induction of autophagy protected against cardiac apoptosis and improved cardiac structure and function in diabetic mice. We concluded that dissociation of Bcl-2 from Beclin1 may be an important mechanism for preventing diabetic cardiomyopathy via AMPK activation that restores autophagy and protects against cardiac apoptosis.
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AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
64.8
作者：
Kuma, A;Hatano, M;Mizushima, N
通讯作者：
Mizushima, N
影响因子：
13.3
作者：
Iwai-Kanai, Eri;Yuan, Hua;Gottlieb, Roberta A.
通讯作者：
Gottlieb, Roberta A.
影响因子：
20.1
作者：
Frustaci, A;Kajstura, J;Anversa, P
通讯作者：
Anversa, P