Dichloroacetate Ameliorates Cardiac Dysfunction Caused by Ischemic Insults Through AMPK Signal PathwayNot Only Shifts Metabolism
Dichloroacetate Ameliorates Cardiac Dysfunction Caused by Ischemic Insults Through AMPK Signal PathwayNot Only Shifts Metabolism
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DOI：
10.1093/toxsci/kfy272
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发表时间：
2019-02-01
影响因子：
3.8
通讯作者：
Li, Ji
中科院分区：
文献类型：
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作者：
Li, Xuan;Liu, Jia;Li, Ji
二氯乙酸二氯乙酸酯(DCA)是一种丙酮酸脱氢酶(PDK)的抑制剂，调节心脏的底物代谢。AMP活化蛋白激酶(AMPK)是一种与年龄相关的能量感受器，可保护心脏免受缺血损伤。本研究旨在探讨DCA是否通过AMPK信号通路对心肌缺血损伤起到保护作用。用青年(3~4月龄)和老年(20~24月龄)雄性C57BL/6J小鼠结扎冠状动脉左前降支(LAD)建立体内缺血模型。青年组和老年组小鼠心脏在45min缺血再灌流后心脏收缩功能均明显下降。DCA治疗显著改善了年轻和老年小鼠的心功能。心肌梗死分析表明，DCA治疗显著减少了幼年和老年小鼠的缺血/再灌注(I/R)所致的心肌梗死范围。体外心肌细胞实验表明，DCA可改善缺氧/复氧(H/R)条件下心肌细胞的收缩功能障碍，改善细胞内钙信号。DCA的这些心脏保护作用可以通过抑制AMPK的激活而减弱。此外，体外工作心脏系统的代谢测量表明，DCA处理对缺血和再灌注应激的代谢转移反应的调节作用可以通过抑制AMPK活性来减弱。免疫印迹结果显示，在假手术和I/R条件下，DCA均通过增加AMPK上游蛋白激酶LKB1的磷酸化来触发心肌AMPK信号转导通路。因此，除调节心脏代谢外，DCA在I/R过程中的心肌保护作用是通过LKB1-AMPK途径实现的。
Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), regulates substrate metabolism in the heart. AMP-activated protein kinase (AMPK) is an age-related energy sensor that protects the heart from ischemic injury. This study aims to investigate whether DCA can protect the heart from ischemic injury through the AMPK signaling pathway. Young (3-4 months) and aged (20-24 months) male C57BL/6J mice were subjected to ligation of the left anterior descending coronary artery (LAD) for an in vivo ischemic model. The systolic function of the hearts was significantly decreased in both young and aged mice after 45 min of ischemia and 24 h of reperfusion. DCA treatment significantly improved cardiac function in both young and aged mice. The myocardial infarction analysis demonstrated that DCA treatment significantly reduced the infarction size caused by ischemia/reperfusion (I/R) in both young and aged mice. The isolated-cardiomyocyte experiments showed that DCA treatment ameliorated contractile dysfunction and improved the intracellular calcium signal of cardiomyocytes under hypoxia/reoxygenation (H/R) conditions. These cardioprotective functions of DCA can be attenuated by inhibiting AMPK activation. Furthermore, the metabolic measurements with an ex vivo working heart system demonstrated that the effects of DCA treatment on modulating the metabolic shift response to ischemia and reperfusion stress can be attenuated by inhibiting AMPK activity. The immunoblotting results showed that DCA treatment triggered cardiac AMPK signaling pathway by increasing the phosphorylation of AMPK's upstream kinase liver kinase B1 (LKB1) under both sham operations and I/R conditions. Thus, except from modulating metabolism in hearts, the cardioprotective function of DCA during I/R was mediated by the LKB1-AMPK pathway.