APE1功能缺失介导糖尿病性心肌损伤的作用及分子机制研究

Diabetic cardiomyopathy (DbCM) is a common critical diabetic complication with a difficult diagnosis and poor treatment efficacy, It is pivotal to clarify the pathogenesis. Oxidative stress is key factor in the pathogenesis of DbCM, however, the underlying mechanisms are unclear. Our preliminary studies showed that serum apurinic/apyrimidinic endonuclease (APE1) levels with lower enzyme activity in DbCM patients were elevated; Oxidative stress of cardiomyocytes were also elevated in the cardiac glucotoxicity in vitro model, meanwhile, its post-translational modifications changed; these results suggest that APE1 is closely associated with cardiomyocyte injury of diabetic cardiomyopathy,these modifications might induce reduced APE1 antioxidative stress and DNA repair capacity. APE1 agonists have been recently confirmed to have cytoprotective action. Thus, we hypothesize that oxidative stress and DNA damage mediated by APE1 function deficiency might be major molecular mechanisms of DbCM pathogenesis, so APE1 might be a novel therapeutic target for DbCM. In this study we shall perform the experiments in heart-specific conditional expression/knockout diabetic mice and APE1 mutant cardiomyocytes to explore: How does changes of three activities cause APE1 function deficiency? How does APE1 function deficiency induce oxidative stress and DNA damage in cardiomyocytes of DbCM? This study will be elucidate the molecular mechanisms in cardiac injury of DbCM, as well as provide a new insight into prevention and treatment of DbCM.

糖尿病心肌病(DbCM)是糖尿病常见的严重并发症，诊断困难，疗效差，阐明发病机制是关键。氧化应激是DbCM发病的中心环节，但机制不详。前期我们发现，DbCM患者血脱嘌呤/脱嘧啶核酸内切酶（APE1）水平升高而酶活性降低；糖毒性心肌细胞氧化应激增加，并APE1修饰改变；提示：APE1与DbCM心肌损伤关系密切；修饰改变可能引起糖尿病心肌APE1抗氧化应激和DNA修复能力下降。最近报道APE1功能激动剂有细胞保护作用。故推测：APE1功能缺失介导氧化应激和DNA损伤可能是糖尿病性心肌损伤的分子机制，APE1有望成为防治DbCM的新靶点。拟在心肌特异性高表达与敲除APE1的DbCM小鼠和APE1突变型心肌细胞等，探讨：糖尿病如何引起心肌APE1功能缺失？ APE1功能缺失如何引起DbCM心肌细胞氧化应激和DNA氧化性损伤？本研究有助于阐明DbCM发病的分子机制，并提供防治DbCM的新思路。

糖尿病心肌病(DbCM)是糖尿病常见的严重并发症，诊断困难，疗效差，阐明发病机制是关键。氧化应激是DbCM发病的中心环节，但机制不详。前期我们发现，DbCM患者血脱嘌呤/脱嘧啶核酸内切酶（APE1）水平升高而酶活性降低；糖毒性心肌细胞氧化应激增加，并APE1修饰改变；提示：APE1与DbCM心肌损伤关系密切；修饰改变可能引起糖尿病心肌APE1抗氧化应激和DNA修复能力下降。最近报道APE1功能激动剂有细胞保护作用。故推测：APE1功能缺失介导氧化应激和DNA损伤可能是糖尿病性心肌损伤的分子机制。本研究通过构建心肌特异性高表达与敲除APE1的DbCM小鼠和APE1突变型心肌细胞等，证实APE1功能缺失参与了糖尿病心肌损伤，主要与其氧化还原功能密切相关，有助于阐明DbCM发病的分子机制。