Increased myocardial ischemia-reperfusion injury in renal failure involves cardiac adiponectin signal deficiency
Increased myocardial ischemia-reperfusion injury in renal failure involves cardiac adiponectin signal deficiency
复制标题
肾衰竭时心肌缺血再灌注损伤的增加涉及心脏脂联素信号缺陷。
DOI：
10.1152/ajpendo.00428.2013
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发表时间：
2014-05-01
影响因子：
5.1
通讯作者：
Tao, Ling
中科院分区：
文献类型：
--
作者：
Song, Yanbin;Yu, Qiujun;Tao, Ling
肾功能不全患者血浆脂联素（APN）水平显著升高，与心血管死亡风险呈负相关。本研究旨在探讨APN在肾功能衰竭小鼠心肌缺血再灌注（MI/R）损伤中的作用及其机制。通过肾次全切除术（SN）诱导肾衰竭。SN后腹腔注射人重组脂联素球状结构域（gAd）或全长脂联素（fAd），每天1次，连续7 d，3 wk后进行体内MI/R。SN小鼠血浆和尿APN水平均显著升高。与假手术组相比，SN组小鼠MI/R后心功能明显下降，心肌梗死面积和细胞凋亡增加。APN基因敲除小鼠MI/R损伤进一步加重，gAd治疗后MI/R损伤明显减轻，而fAd治疗后MI/R损伤明显减轻。此外，SN增加心肌NO代谢产物，超氧化物，和他们的细胞毒性反应产物过氧亚硝酸盐，上调诱导型NO合酶的表达，并降低内皮NOS磷酸化。此外，SN小鼠还表现出APN受体-1（AdipoR 1）表达和AMPK活化减少。所有这些变化在APN不存在的情况下被进一步放大，但被gAd处理逆转。本研究表明肾功能不全增加了心脏对缺血再灌注损伤的易感性，这与APN/AdipoR 1/AMPK信号转导下调和局部心肌氧化/硝化应激增加有关，并为外源性补充gAd对肾衰竭MI/R结局的保护作用提供了第一个证据。
Plasma levels of adiponectin (APN) are significantly increased in patients with renal dysfunction and are inversely related to the risk of cardiovascular mortality. The present study was designed to determine the role of APN in myocardial ischemia-reperfusion (MI/R) injury in mice with renal failure and delineate the underlying mechanisms. Renal failure was induced by subtotal nephrectomy (SN). Human recombinant globular domain of adiponectin (gAd) or full-length adiponectin (fAd) was administered via intraperitoneal injection once daily for 7 consecutive days after SN, and in vivo MI/R was introduced 3 wk later. Both plasma and urinary levels of APN increased significantly in SN mice. Compared with sham-operated mice, cardiac function was significantly depressed, and myocardial infarct size and apoptosis increased in SN mice following MI/R. The aggravated MI/R injury was further intensified in APN-knockout mice and markedly ameliorated by treatment with gAd but not fAd. Moreover, SN increased myocardial NO metabolites, superoxide, and their cytotoxic reaction product peroxynitrite, upregulated inducible NO synthase expression, and decreased endothelial NOS phosphorylation. In addition, SN mice also exhibited reduced APN receptor-1 (AdipoR1) expression and AMPK activation. All these changes were further amplified in the absence of APN but reversed by gAd treatment. The present study demonstrates that renal dysfunction increases cardiac susceptibility to ischemic-reperfusion injury, which is associated with downregulated APN/AdipoR1/AMPK signaling and increased oxidative/nitrative stress in local myocardium, and provides the first evidence for the protective role of exogenous supplement of gAd on MI/R outcomes in renal failure.