AMP-activated protein kinase deficiency enhances myocardial ischemia/reperfusion injury but has minimal effect on the antioxidant/antinitrative protection of adiponectin.
AMP-activated protein kinase deficiency enhances myocardial ischemia/reperfusion injury but has minimal effect on the antioxidant/antinitrative protection of adiponectin.
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DOI：
10.1161/circulationaha.108.815043
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发表时间：
2009-02-17
期刊：
影响因子：
37.8
通讯作者：
Ma XL
中科院分区：
文献类型：
--
作者：
Wang Y;Gao E;Tao L;Lau WB;Yuan Y;Goldstein BJ;Lopez BL;Christopher TA;Tian R;Koch W;Ma XL
糖尿病增加缺血性心脏病的发病率/死亡率，但其潜在机制尚不完全清楚。糖尿病患者同时存在AMPK和脂联素的缺陷，但AMPK在体内是否具有心脏保护作用或脂联素心脏保护作用的中心介导剂仍不清楚。对心肌细胞特异性过表达突变型AMPKα2亚基（AMPK-DN）或野生型（WT）同窝雄性成年小鼠进行体内心肌缺血/再灌注（MI/R），并使用溶剂或脂联素进行治疗。与WT相比，遭受MI/R的AMPK-DN小鼠遭受更大的心脏损伤（更大的梗死面积、更多的细胞凋亡和更差的心脏功能），这可能是这些动物中氧化应激增加的结果。用脂联素处理AMPK-DN小鼠不能使心脏乙酰辅酶A羧化酶磷酸化，就像在WT小鼠心脏中一样。然而，脂联素对MI/R损伤的心脏保护作用的重要部分在AMPK-DN小鼠中保留。此外，用脂联素治疗AMPK-DN小鼠可降低MI/R诱导的心脏氧化和硝化应激，其程度与WT小鼠相同。最后，脂联素处理AMPK-DN心肌细胞可减少模拟MI/R诱导的氧化/硝化应激和减少细胞死亡（P<0.01）。总的来说，我们的研究结果表明，AMPK缺乏显着增加MI/R损伤在体内，但脂联素的抗氧化/抗硝化保护的影响很小。
Diabetes increases the morbidity/mortality of ischemic heart disease, but the underlying mechanisms are incompletely understood. Deficiency of both AMP-activated protein kinase (AMPK) and adiponectin occurs in diabetes, but whether AMPK is cardioprotective or a central mediator of adiponectin cardioprotection in vivo remains unknown. Male adult mice with cardiomyocyte-specific overexpression of a mutant AMPKα2 subunit (AMPK-DN) or wild-type (WT) littermates were subjected to in vivo myocardial ischemia/reperfusion (MI/R) and treated with vehicle or adiponectin. In comparison to WT, AMPK-DN mice subjected to MI/R endured greater cardiac injury (larger infarct size, more apoptosis, and poorer cardiac function) likely as a result of increased oxidative stress in these animals. Treatment of AMPK-DN mice with adiponectin failed to phosphorylate cardiac acetyl-CoA carboxylase as it did in WT mouse heart. However, a significant portion of the cardioprotection of adiponectin against MI/R injury was retained in AMPK-DN mice. Furthermore, treatment of AMPK-DN mice with adiponectin reduced MI/R-induced cardiac oxidative and nitrative stress to the same degree as that seen in WT mice. Finally, treating AMPK-DN cardiomyocytes with adiponectin reduced simulated MI/R-induced oxidative/nitrative stress and decreased cell death (P<0.01). Collectively, our results demonstrated that AMPK deficiency significantly increases MI/R injury in vivo but has minimal effect on the antioxidative/antinitrative protection of adiponectin.