PKCε/Caveolin-3对自噬与necroptosis的调控决定糖尿病心肌对缺血后处理的敏感性

Subjects with diabetes are more vulnerable to ischemic myocardial injury (IRI) and less or not sensitive to ischemic postconditioning (IPostC) mediated cardioprotection, and the underlying mechanism is unclear. Most recent studys showed that restoration of autophagic flux was essential in IPostC cardioprotection and that inhibition of autophagy induced necroptosis and exacerbated myocardial IRI. Our preliminary studies showed that post-ischemic myocardial injury was increased while IPostC cardioprotection was lost in hearts from diabetes, which was associated with PKCε over-activation and reduction of the association of PKCε with caveolin-3 (Cav3) as well as impairment of autophagic flux and induction of necroptosis. Further, in cultured cardiomyocytes exposed to high glucose, post-hypoxic cellular injury was increased and the protective effects of hypoxic postconditioning were lost. All these can be reversed by PKCε inhibition, while this beneficial effect of PKCε inhibition was abolished by Cav3 gene knockdown. The above preliminary findings prompted us to postulate that hyperglycemia-induced over-activation in PKCε, leads to the disassociation of PKCε and Cav3, and the subsequent impairment of autophagic flux, resulting in induction of necroptosis, and leads to the loss of IPostC cardioprotection in diabetes. We, therefore, aim to examine the role of PKCε/Cav3 in IPostC cardioprotection against myocardial IRI and to explore the underlying mechanism in relation to autophagy and necroptosis in diabetic rodents. We will conduct series experiments using in vivo and in vitro cell models of myocardial IRI in normal and diabetic mice with PKCε gene knock out(KO), Cav3 KO, Atg5 KO (autophagy deficiency) mice, incorporating the use of PKCε, Cav3, and Atg5 adenoviruses and PKCε siRNA to address mechanisms. This study will provide new insights regarding the molecular mechanism whereby PKCε/Cav3 restores diabetic hearts sensitivity to IPostC, and facilitate the development of effective therapy to combat ischemic heart diseases.

糖尿病（DM）心脏缺血再灌注损伤（IRI）易损性敏感，对缺血后处理（IPostC）保护不敏感，机制不明。新近发现适度的自噬流是IPostC发挥作用必须，而抑制自噬可诱发necroptosis加重IRI。 我们前期发现，DM鼠心脏PKCε过度活化并与Cav3结合减少，自噬流受损，necroptosis升高，心肌IRI加重且对IPostC不敏感。高糖培养的心肌细胞IRI加重，且后处理保护作用消失，抑制PKCε减轻细胞损伤且恢复后处理保护，但该保护被Cav3基因沉默取消。我们推测DM心肌PKCε过度活化阻断与Cav3结合及信号转导，破坏自噬流，导致 IPostC失效。我们将用PKCε、Cav3和自噬缺失的Atg基因敲除鼠，从整体和离体及细胞水平研究高糖状态下PKCε/ Cav3信号通路及其对自噬流和necroptosis的调控对DM心肌IPostC敏感性的影响，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（IRI）易损性增加，对缺血后处理（IPostC）保护不敏感，机制不明。新近发现适度的自噬流是IPostC发挥作用必须，而抑制自噬可诱发necroptosis加重IRI。 我们前期发现， DM鼠心脏，PKCε过度活化并与Cav3结合减少，自噬流受损，necroptosis升高，心肌IRI加重且对IPostC不敏感。高糖培养的心肌细胞IRI加重，且后处理保护作用消失，抑制PKCε减轻细胞损伤且恢复后处理保护，但该保护被Cav3基因沉默取消。我们推测DM心肌PKCε过度活化阻断与Cav3结合及信号转导，破坏自噬流，导致 IPostC失效。我们将用PKCε、Cav3和自噬缺失的Atg基因敲除鼠，从整体和离体及细胞水平研究高糖状态下PKCε/ Cav3信号通路及其对自噬流和necroptosis的调控对DM心肌IPostC敏感性的影响，为DM心肌缺血防治提供新靶点。我们的结果证实PKCε过度活化通过下调Cav3，抑制STAT3激活，从而损坏自噬流，诱导necroptosis，加重糖尿病心肌IRI. 我们的发现将为研发抗糖尿病心脏对缺血再灌注损伤药物提供理论依据。

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