A small molecule AMPK activator protects the heart against ischemia-reperfusion injury.
A small molecule AMPK activator protects the heart against ischemia-reperfusion injury.
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DOI：
10.1016/j.yjmcc.2011.03.003
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发表时间：
2011-07
影响因子：
5
通讯作者：
Young LH
中科院分区：
文献类型：
--
作者：
Kim AS;Miller EJ;Wright TM;Li J;Qi D;Atsina K;Zaha V;Sakamoto K;Young LH
AMP活化蛋白激酶（AMPK）是一种应激信号酶，协调能量产生和消耗途径的调节。内源性AMPK激活可保护心脏免受缺血性损伤和细胞凋亡，但药理学AMPK刺激是否减轻缺血再灌注损伤尚不清楚。本研究的目的是确定使用小分子激活剂A-769662直接刺激AMPK是否减轻心肌缺血-再灌注损伤，并检查其心脏保护机制。与对照心脏相比，用A-769662预处理的离体小鼠心脏在缺血后再灌注期间具有更好的左心室收缩功能恢复（基线速率-压力乘积的55% vs. 29%; p=0.03）和更少的心肌坏死（梗死面积减少56%; p<0.01）。与溶媒相比，A-769662体内预处理可减少经历左冠状动脉闭塞和再灌注的C57 B1/6小鼠的梗死面积（36% vs. 18%，p=0.025）。具有遗传失活AMPK的小鼠心脏不受A-769662的保护，表明该化合物具有特异性。A-769662预处理增加了真核细胞延伸因子2（eEF 2）的磷酸化和失活，保存了缺血期间的能量电荷，延迟了缺血性挛缩的发生，并减少了心肌细胞凋亡和坏死。A-769662还增强了缺血期间内皮型一氧化氮合酶（eNOS）的激活，这部分减弱了心肌顿抑，但不能防止坏死。AMPK是一种治疗靶点，可以通过直接作用的小分子刺激，以防止缺血-再灌注期间的损伤。AMPK激活剂的使用可能代表了保护心脏和其他实体器官免受缺血的新策略。
AMP-activated protein kinase (AMPK) is a stress signaling enzyme that orchestrates the regulation of energy-generating and -consuming pathways. Intrinsic AMPK activation protects the heart against ischemic injury and apoptosis, but whether pharmacologic AMPK stimulation mitigates ischemia-reperfusion damage is unknown. The aims of this study were to determine whether direct stimulation of AMPK using a small molecule activator, A-769662, attenuates myocardial ischemia-reperfusion injury, and to examine its cardioprotective mechanisms. Isolated mouse hearts pre-treated with A-769662 had better recovery of left ventricular contractile function (55% vs. 29% of baseline rate-pressure product; p=0.03) and less myocardial necrosis (56% reduction in infarct size; p<0.01) during post-ischemic reperfusion compared to control hearts. Pre-treatment with A-769662 in vivo attenuated infarct size in C57Bl/6 mice undergoing left coronary artery occlusion and reperfusion compared to vehicle (36% vs. 18%, p=0.025). Mouse hearts with genetically inactivated AMPK were not protected by A-769662, indicating the specificity of this compound. Pre-treatment with A-769662 increased the phosphorylation and inactivation of eukaryotic elongation factor 2 (eEF2), preserved energy charge during ischemia, delayed the development of ischemic contracture, and reduced myocardial apoptosis and necrosis. A-769662 also augmented endothelial nitric oxide synthase (eNOS) activation during ischemia, which partially attenuated myocardial stunning, but did not prevent necrosis. AMPK is a therapeutic target that can be stimulated by a direct-acting small molecule in order to prevent injury during ischemia-reperfusion. The use of AMPK activators may represent a novel strategy to protect the heart and other solid organs against ischemia.
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