CD36在缺血后处理对糖尿病缺血/再灌注心脏失保护作用中的作用及机制

Diabetic heart is prone to myocardial ischemic-reperfusion injury (MIRI) and losses response to ischemic postconditioning(IPostC) cardioprotection, the underline mechanism is unclear. Most recent study shows that the cluster of differentiation 36 (CD36) plays a key role in the development of cardiovascular disease in patients with metabolic disorder. CD36 is over-expressed in diabetic heart which adversely affect lipid metabolism ,meanwhile, the signal transducer and activator of transcription 3(STAT3) (a key proetein in IPostC mediated cardioprotection) is reduced and cannot be activated, leading to the loss of IPostC cardioprotection. We recently found that IPostC can’t reduce myocardial infarction in Type 2 diabetic (T2DM) rats where the cardiac CD36 was over-expressed, concomitant with decreased p-STAT3. Pharmacological treatment that can restore IPostC cardioprotection in diabetic heart prevented CD36 over-expression and restored p-STAT3. The proposed study will use in vivo models of MIRI to investigate the impact of CD36 on the effectiveness of IPostC in normal and in diabetic rodents, then to confirm if CD36 over-expression is critical in compromising IPostC cardioprotection and to address the underlying mechanism. We will further study the interplay between STAT3 and CD36 and the impact on IPostC cardioprotection in diabetic rodents. The proposed research may lead to the identification of new therapeutic targets to inhibition of circulatory and/or myocardial CD36 in diabetes by either genetic or pharmacological approaches and finally provide scientific and experimental basis for prevention and cure MIRI in diabetes.

糖尿病缺血/再灌注心脏易损性增加且缺血后处理（IPostC）对其保护作用丧失，机制尚未阐明。最新发现，CD36在以代谢异常为特征的疾病心血管病变中起关键作用。糖尿病心肌CD36过表达致脂类代谢异常。且糖尿病心肌IPostC关键蛋白STAT3活性降低且不能被IPostC激活，但CD36在其中作用不确定。我们前期研究发现，药物恢复p-STAT3并恢复IPostC对糖尿病缺血心脏的保护作用伴随着对CD36的抑制。本项目拟建立2型糖尿病大鼠和转基因小鼠在体心肌缺血/再灌注损伤（MIRI）模型，探讨CD36在正常及糖尿病鼠MIRI中以及IPostC中的作用和机制。验证CD36过表达是否是致使IPostC在糖尿病心脏失去保护作用中的关键机制。诠释激活STAT3与/或抑制CD36是恢复糖尿病心脏IPostC保护作用的重要机制。为糖尿病MIRI的防治探索有效治疗措施提供实验依据。

糖尿病缺血/再灌注心脏易损性增加且缺血后处理（IPostC）对其保护作用丧失，机制尚未阐.明。最新发现，CD36在以代谢异常为特征的疾病的心血管病变中起关键作用。糖尿病心肌CD36过表达致脂类代谢异常。且糖尿病心肌IPostC关键蛋白STAT3表达降低且不能被IPostC激活成p-STAT3，但CD36在其中作用不确定。我们前期研究发现，药物恢复p-STAT3并恢复IPostC对糖尿病缺血心脏的保护作用伴随着对CD36的抑制。本项目建立1型糖尿病大鼠在体心肌缺血/再灌注损伤（MIRI）模型和IPostC模型，纳入CD36的抑制剂磺基-N-琥珀酰亚胺酯油酸(SSO)，探讨CD36在正常及糖尿病鼠MIRI中以及IPostC中的作用和机制。研究发现：在糖尿病缺血后处理组，SSO抑制糖尿病心肌CD36过表达，血清胰岛素水平、TGs和FFAs浓度都降低，大鼠的心肌梗死面积也减少，且心肌p-STAT3表达增高，提示抑制CD36可能可以恢复STAT3磷酸化水平。验证CD36过表达是致使IPostC在糖尿病心脏失去保护作用中的关键机制。抑制CD36过表达，减少酯类积聚和脂质过氧化水平，减轻氧化应激，恢复STAT3磷酸化水平是恢复糖尿病心脏IPostC保护作用的重要机制。为糖尿病MIRI的防治探索有效治疗措施提供实验依据。