AdipoR1/STAT3通路的激活是丙泊酚后处理减轻糖尿病心肌缺血再灌注损伤的主要机制

Restoration of the blood supply is the main treatment for ischemic heart while it resulted in lethal ischemia reperfusion injury (IRI). Ischemic postconditioning (IPostC) confers cardioprotection against IRI by STAT3 activation. However, IPostC lost cardioprotection in diabetic subjects and the mechanism is not clear. Propofol, an anaesthetic with cardiac protective effect and was reported to induce STAT3 phosphorylation in H9C2 cells. However, whether propofol given during early reperfusion (propofol post-conditioning, PPC) can reduce myocardial IRI, especially in diabetic model, is not studied. Our preliminary data showed that PPC reduced IRI in non-diabetic rats, accompanied by increased cardiac adiponectin (APN) level, HO-1 and STAT3 phosphorylation (p-STAT3) expression. However, the cardioprotective effects of PPC was diminished in diabetic myocardium subjected to IRI, with impaired cardiac HO-1/STAT3 signaling and decreased adiponectin receptor1(AdipoR1) level. APN supplementation restored PPC cardioprotection under diabetic or hyperglycemic conditions and STAT3 or AdipoR1 gene knockdown abolished APN-mediated restoration of PPC cardioprotection. We will incorporate the uses of STAT3 and AdipoR1 gene knockout mice and the uses of adenovirus APN and HO-1 overexpression as well as AdipoR1, STAT3, and HO-1 genes silences to explore the role of AdipoR1/STAT3 signaling in PPC-mediated cardiac protection against IRI in diabetes using in vivo IRI models and in vitro in primarily cultured cardiomyocyte and H9C2 cells exposed to hypoxia and reoxygenation.

再灌注是挽救缺血心肌最主要手段，但其本身可导致致死性缺血再灌注损伤（IRI）。缺血后处理通过激活STAT3减轻IRI，但糖尿病心脏中STAT3含量降低导致了后处理失效。丙泊酚是常用麻醉药，可激活心肌细胞STAT3。我们前期发现丙泊酚后处理（PPC）可减轻正常心肌IRI并伴随HO-1，p-STAT3和脂联素表达增加，但不能在糖尿病发挥类似保护作用。脂联素具有抗心肌缺血作用且可以激活STAT3，但在糖尿病患者循环中脂联素降低。补充脂联素可恢复糖尿病心肌对丙泊酚后处理的敏感性，并增加脂联素1型受体(AdipoR1)和p-STAT3表达，但不增加HO-1及AdipoR2的表达。由此我们假设，PPC在糖尿病心肌中通过AdipoR1依赖途径激活STAT3来抗IRI。本项目拟用AdipoR1及STAT3敲除小鼠结合脂联素转染，从整体和细胞水平阐明PPC对心肌IRI的保护作用，为临床治疗提供理论依据。