脂联素通过非受体依赖途径激活HO-1/STAT-3通路恢复糖尿病心脏对缺血后处理的敏感性

Subjects with diabetes are more vulnerable to post- ischemic myocardial injury and are less or not sensitive to ischemic postconditioning (IPostC) mediated cardioprotection compared to non-diabetes, and the underlying mechanism is unclear. Adiponectin (APN) can confer cardioprotection in non-diabetes via a receptor-dependent (adiponectin receptor1) dependent activation of STAT-3, a key protein in mediating IPostC protection. However, our preliminary study shows that cardiac APN, heme oxygenase-1 (HO-1) and STAT-3 were coincidently decreased in the myocardium of type 2 diabetic rats, and that exogenous APN increased myocardial HO-1 and STAT-3 activation, and restored diabetic heart sensitivity to IPostC. Furthermore, in type-1 diabetes, cardiac STAT-3 decreased despite of the compensatory increase adiponectin receptor1, while in cultured cardiomyocytes exposed to high-glucose, APN can restore cardiomyocyte sensitivity to IPostC protection despite genetic knock-down of both APN receptors 1/2, suggesting that STAT-3 could hardly be activated via APN receptor-dependent pathway under high-glucose status. We, thus, hypothesized that APN restores diabetic heart sensitivity to IPostC via receptor-independent mechanism by activating HO-1/STAT-3 pathway. To test this hypothesis, we will conduct series experiments using in vivo and in vitro as well as cell models of myocardial ischemia/reperfusion in normal and diabetic mice with either adiponectin receptor 1/2 double knock out (KO), STAT3-KO or cardiac specific HO-1 KO, incorporating the use of adenovirus-APN and specific inhibitors to address mechanisms. This study will provide new insights regarding the molecular mechanism whereby APN restores diabetic heart sensitivity to IPostC, and facilitate the development of new and effective therapy to ischemic heart diseases.

糖尿病（DM）心脏对缺血再灌注损伤的耐受性降低，并对缺血后处理（IPostC）不敏感，其机制不清楚。脂联素（APN）可通过其受体AdipoR1激活后处理关键蛋白STAT3并具有心肌保护作用。然而我们前期研究发现，2型DM鼠APN显著降低伴随着心肌HO-1和STAT3的活性下降，而APN可恢复糖尿病HO-1与STAT3活性并恢复其对IPostC的敏感性；而1型DM鼠心脏AdipoR1代偿性增加伴随STAT3活性降低，并且心肌细胞APN受体基因沉默时APN仍能恢复高糖状态对IPostC的敏感性。我们推测APN可能通过非受体途径激活HO-1/STAT3恢复DM心脏对IPostC敏感性。因此我们将选用AdipoR、HO-1和STAT3基因敲除鼠，从整体和离体及细胞水平研究高糖状态下HO-1/STAT3信号通路变化及其在APN恢复DM心肌对IPostC敏感性的机制，为DM心肌缺血防治提供新靶点。

糖尿病（DM）心脏对缺血再灌注损伤的耐受性降低，并对缺血后处理（IPostC）不敏感，其机制不清楚。脂联素（APN）可通过其受体AdipoR1 激活后处理关键蛋白STAT3，并具有心肌保护作用。我们前期研究发现，2型DM鼠APN显著降低，同时伴随着心肌HO-1和STAT3的活性下降，而APN 可恢复糖尿病HO-1 与STAT3活性并恢复其对IPostC的敏感性；而1型DM鼠心脏AdipoR1代偿性增加伴随STAT3活性降低，并且心肌细胞APN受体基因沉默时APN仍能恢复高糖状态对IPostC的敏感性。在此基础上我们将应用脂联素基因敲除鼠结合AdipoR、HO-1 和STAT3 基因沉默，从整体和离体及细胞水平系统研究糖尿病及高糖状态下信号通路变化，及其在APN恢复DM心肌对IPostC敏感性中的的机制。我们的结果证实糖尿病状态下AdipoR1/Caveolin-3/STAT3信号通路的失活是导致糖尿病心肌对缺血后处理等保护措施不敏感的关键机理。这一发现受到国际权威杂志的推介发表，该发现为DM心肌缺血防治提供了新靶点。

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