Cardiac-derived adiponectin induced by long-term insulin treatment ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic mice via AMPK signaling
Cardiac-derived adiponectin induced by long-term insulin treatment ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic mice via AMPK signaling
复制标题
长期胰岛素治疗诱导的心源性脂联素通过 AMPK 信号改善 1 型糖尿病小鼠的心肌缺血/再灌注损伤
DOI：
10.1007/s00395-012-0322-0
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发表时间：
2013-01-01
影响因子：
9.5
通讯作者：
Tao, Ling
中科院分区：
文献类型：
--
作者：
Pei, Haifeng;Qu, Yan;Tao, Ling
1型糖尿病（T1DM）预示着缺血性心脏病的不良预后。脂联素（APN）是一种具有胰岛素增敏和代谢调节作用的脂肪细胞因子，已被公认为一种有效的心脏保护分子。然而，APN与T1DM之间的关系仍存在争议，心脏来源的APN在T1DM中的作用尚不清楚。本研究旨在探讨T1DM中血浆和心脏来源的APN表达的动态变化，以及心脏来源的APN在T1DM中对抗心肌缺血/再灌注（MI/R）损伤的特殊作用。通过腹腔注射链脲佐菌素建立T1DM模型，随后每天皮下注射胰岛素或安慰剂两次，持续14天。野生型和APN基因敲除的非糖尿病小鼠接受胰岛素或安慰剂注射。在Langendorff灌注心脏中诱导MI/R。与非糖尿病小鼠相比，糖尿病小鼠的血浆APN水平在7天显著升高，在14天略有下降，而心脏来源的APN水平随时间逐渐下降。以梗死面积和心肌细胞凋亡衡量的MI/R损伤在糖尿病小鼠中几乎翻倍。14天的胰岛素治疗增加了糖尿病小鼠血浆和心脏来源的APN水平，并通过增加T1DM中的AMPK磷酸化减轻了心肌损伤，这一作用被化合物C（一种AMPK抑制剂）部分逆转。此外，APN缺乏加重了MI/R损伤，并部分消除了胰岛素治疗对MI/R损伤的保护作用，这与AMPK磷酸化降低有关。结果表明，T1DM中长期胰岛素治疗刺激的心脏来源的APN通过心肌AMPK激活对MI/R损伤发挥心脏保护作用。
Type 1 diabetes (T1DM) portends poor prognosis concerning ischemic heart disease. Adiponectin (APN), an adipocytokine possessing insulin sensitizing and metabolic regulatory effects, has been recognized as a potent cardioprotective molecule. However, the relationship between APN and T1DM remains controversial and the role of cardiac-derived APN in T1DM is unclear. This study is aimed to investigate the dynamic change of both plasma and cardiac-derived APN expressions in T1DM, and the particular role of cardiac-derived APN in T1DM against myocardial ischemia/reperfusion (MI/R) injury. T1DM was established via intraperitoneal injection of streptozocin and followed by twice-daily subcutaneous injection of insulin or vehicle for 14 days. Non-diabetic mice of wild type and APN knockout were subjected to insulin or vehicle injection. MI/R was induced in Langendorff-perfused hearts. Compared to non-diabetic mice, plasma APN levels of diabetic mice significantly increased at 7 days, and slightly decreased at 14 days, while cardiac-derived APN levels gradually decreased over time. The MI/R injury measured as infarct size and cardiomyocyte apoptosis nearly doubled in diabetic mice. 14 days of insulin treatment increased both plasma and cardiac-derived APN levels in diabetic mice and attenuated myocardial injury via increasing AMPK phosphorylation in T1DM, which was partly reversed by Compound C (an AMPK inhibitor). Moreover, APN deficiency aggravated MI/R injury and partly abolished the protective effect of insulin treatment against MI/R injury, which was associated with decreased AMPK phosphorylation. The results suggest that cardiac-derived APN stimulated by long-term insulin treatment in T1DM exerts cardioprotection against MI/R injury via myocardial AMPK activation.