PINK1下调致线粒体自噬障碍加重糖尿病心肌缺血易损性及长期摄食α-亚麻酸对其改善作用

With about 11.6 adults in the stage of diabetes mellitus in 100 Chinese, China is now home to the most cases worldwide. Mitochondrial dysfunction has been demonstrated to be one of the major risk factors contributing to increased vulnerability in diabetic heart, but the mechanism is not fully understood. In our preliminary study, mitophagic dysfunction due to down-regulated PINK1 contributed to aggravated myocardial ischemia/reperfusion injury while up-regulated PINK1 helped to reverse it. Clinically, alpha-linolenic acid (ALA) can be used in the adjuvant treatment of diabetes, but no mechanism of ALA intake helping human myocardial protection has been reported in the world. Our previous founding and latest preliminary experiments suggested that long-term dietary supplement of ALA attenuated myocardial ischemia/reperfusion injury in diabetic animals, increased PINK1 expression and restored mitophagy. Based on these data, we hypothesize that mitophagic dysfunction due to down-regulated PINK1 in cardiomyocytes contributes to increased heart vulnerability. Furthermore, ALA intake can improve ischemic myocardial function in diabetic state through changing the above-mentioned mechanisms. The aim of this research is to clarify the existence and significance of the PINK1 pathway in diabetic state and the influence of ALA intake on myocardial ischemia by pharmacological and genetic intervention means. It may guide the public a reasonable diet, thus provide a theoretical basis and novel possible targets for preventing diabetic ischemic cardiomyopathy.

目前我国成年人糖尿病患病率达11.6%，已成为第一糖尿病大国。糖尿病心肌缺血易损性显著增加，亟需阐明其机制并寻求有效防治策略。已证实线粒体及其功能异常是重要致病因素之一，但其具体机制尚未完全阐明。我们预实验显示，糖尿病心肌存在PTEN induced putative kinase 1（PINK1）表达下调，从而诱导线粒体自噬障碍，加重心肌缺血/再灌注损伤。另外，临床研究证实必需脂肪酸α-亚麻酸（ALA）可辅助治疗糖尿病，但国内外尚未见ALA保护缺血心肌的报道。我们前期发现和预实验提示，长期摄食ALA可显著减轻糖尿病心肌缺血/再灌注损伤，并上调心肌PINK1，有效恢复线粒体自噬。本研究拟通过药理学和基因干预方法，阐明PINK1在糖尿病缺血心肌易损性中的作用及机制，以及ALA可否通过改善此信号而保护缺血心肌，为深入认识糖尿病心肌损伤机理、并为指导大众合理饮食而防治糖尿病性冠心病提供实验证据。

目前我国成年人糖尿病患病率达11.6%，已成为第一糖尿病大国。糖尿病心肌缺血易损性显著增加，亟需阐明其机制并寻求有效防治策略。已证实线粒体及其功能异常是重要致病因素之一，但其具体机制尚未完全阐明。本课题中，我们通过建立糖尿病小鼠动物模型和高糖/高脂心肌细胞模型，体内动物实验结合体外细胞实验，分析糖尿病心肌缺血的分子机制，同时给予α-亚麻酸预处理，观察α-亚麻酸对于糖尿病心肌的保护作用。我们的研究结果表明，糖尿病状态下，与线粒体自噬障碍相关的分子PINK1、Mfn2、Parkin，以及p62、LC3-II/I均参与了上述病理性过程，降低PINK1分子表达，可显著影响上述信号通路，引起线粒体自噬障碍，从而加重糖尿病心肌缺血的程度。这一病理性过程与心肌细胞凋亡密切相关，caspase-3、caspase-9的活性受到显著影响。给予α-亚麻酸预处理，可以上调心肌PINK1，显著改善线粒体自噬障碍，缓解并抑制心肌细胞凋亡的发生，从而显著减轻上述糖尿病心肌缺血的程度。上述结果提示，α-亚麻酸预处理，对于糖尿病心肌缺血具有显著的改善作用，为深入认识糖尿病心肌损伤机理、并为指导大众合理饮食而防治糖尿病性冠心病提供实验证据，具有一定的临床应用价值，有望为临床心肌缺血的治疗提供新的思路和策略。