PDF(Pubmed)
Abstract：
Patients with diabetes mellitus have poor prognosis after myocardial ischemic injury. However, the mechanism is unclear and there are no related therapies. We aimed to identify regulators of diabetic myocardial ischemic injury.
Mass spectrometry-based, non-targeted metabolomic approach was used to profile coronary sinus blood from diabetic and non-diabetic Bama-mini pigs at 0.5-h post coronary artery ligation. Six metabolites had a |log2 (Fold Change)|> 1.3. Among them, the most changed is arachidonic acid (AA), levels of which were 32 times lower in diabetic pigs than in non-diabetic pigs. The AA-derived products, PGI2 and 6-keto-PGF1α, were also significantly reduced. AA treatment of cultured cardiomyocytes protected against cell death by 30% at 48 h of high glucose and oxygen deprivation, which coincided with increased mitophagic activity (as indicated by increased LC3II/LC3I, decreased p62 and increased parkin & PINK1), improved mitochondrial renewal (upregulation of Drp1 and FIS1), reduced ROS generation and increased ATP production. These cardioprotective effects were abolished by PINK1(a crucial mitophagy protein) knockdown or the autophagy inhibitor 3-Methyladenine. The protective effect of AA was also inhibited by indomethacin and Cay10441, a prostacyclin receptor antagonist. Furthermore, diabetic Sprague Dawley rats were subjected to coronary ligation for 40 min and AA treatment (10 mg/day per animal gavaged) decreased myocardial infarct size, cell apoptosis index, inflammatory cytokines and improved heart function. Scanning electron microscopy showed more intact mitochondria in the border zone of infarcted myocardium in AA treated rats. Lastly, diabetic patients after myocardial infarction had lower plasma levels of AA and 6-keto-PGF1α and reduced cardiac ejection fraction, compared with non-diabetic patients after myocardial infarction. Plasma AA level was inversely correlated with fasting blood glucose.
AA protects against diabetic ischemic myocardial damage by promoting mitochondrial autophagy and renewal, which is related to AA derived PGI2 signaling. AA may represent a new strategy to treat diabetic myocardial ischemic injury.
Mass spectrometry-based, non-targeted metabolomic approach was used to profile coronary sinus blood from diabetic and non-diabetic Bama-mini pigs at 0.5-h post coronary artery ligation. Six metabolites had a |log2 (Fold Change)|> 1.3. Among them, the most changed is arachidonic acid (AA), levels of which were 32 times lower in diabetic pigs than in non-diabetic pigs. The AA-derived products, PGI2 and 6-keto-PGF1α, were also significantly reduced. AA treatment of cultured cardiomyocytes protected against cell death by 30% at 48 h of high glucose and oxygen deprivation, which coincided with increased mitophagic activity (as indicated by increased LC3II/LC3I, decreased p62 and increased parkin & PINK1), improved mitochondrial renewal (upregulation of Drp1 and FIS1), reduced ROS generation and increased ATP production. These cardioprotective effects were abolished by PINK1(a crucial mitophagy protein) knockdown or the autophagy inhibitor 3-Methyladenine. The protective effect of AA was also inhibited by indomethacin and Cay10441, a prostacyclin receptor antagonist. Furthermore, diabetic Sprague Dawley rats were subjected to coronary ligation for 40 min and AA treatment (10 mg/day per animal gavaged) decreased myocardial infarct size, cell apoptosis index, inflammatory cytokines and improved heart function. Scanning electron microscopy showed more intact mitochondria in the border zone of infarcted myocardium in AA treated rats. Lastly, diabetic patients after myocardial infarction had lower plasma levels of AA and 6-keto-PGF1α and reduced cardiac ejection fraction, compared with non-diabetic patients after myocardial infarction. Plasma AA level was inversely correlated with fasting blood glucose.
AA protects against diabetic ischemic myocardial damage by promoting mitochondrial autophagy and renewal, which is related to AA derived PGI2 signaling. AA may represent a new strategy to treat diabetic myocardial ischemic injury.
摘要：
目的：糖尿病患者心肌缺血损伤后预后不良。然而,其机制尚不清楚，也没有相关的治疗方法。我们旨在确定糖尿病心肌缺血损伤的调节因子。
结果：基于质谱，非靶向代谢组学方法用于分析冠状动脉结扎后0.5小时糖尿病和非糖尿病巴马小型猪的冠状窦血。六种代谢物具有|log2(倍数变化)|>1.3。其中,变化最大的是花生四烯酸（AA），糖尿病猪的水平比非糖尿病猪低32倍。AA衍生产品，PGI2和6-酮-PGF1α，也大大减少了。AA处理培养的心肌细胞在高糖和缺氧48小时保护细胞死亡30％，这与增加的有丝分裂活性一致(如增加的LC3II/LC3I所示，P62减少，Parkin和PINK1增加），改善线粒体更新（Drp1和FIS1的上调），减少ROS的产生和增加ATP的产生。PINK1（一种关键的线粒体自噬蛋白）敲低或自噬抑制剂3-甲基腺嘌呤消除了这些心脏保护作用。吲哚美辛和前列环素受体拮抗剂Cay10441也抑制了AA的保护作用。此外，将糖尿病SpragueDawley大鼠进行冠状动脉结扎40分钟，并进行AA治疗（每只动物10mg/天）以减少心肌梗塞的大小，细胞凋亡指数，炎症细胞因子和改善心脏功能。扫描电子显微镜显示AA处理的大鼠梗死心肌边界区线粒体更完整。最后,糖尿病患者心肌梗死后血浆AA和6-keto-PGF1α水平降低，心脏射血分数降低，与心肌梗死后的非糖尿病患者相比。血浆AA水平与空腹血糖呈负相关。
结论：AA通过促进线粒体自噬和更新来保护糖尿病缺血性心肌损伤，这与AA衍生的PGI2信号传导有关。AA可能是治疗糖尿病心肌缺血性损伤的新策略。
结果：基于质谱，非靶向代谢组学方法用于分析冠状动脉结扎后0.5小时糖尿病和非糖尿病巴马小型猪的冠状窦血。六种代谢物具有|log2(倍数变化)|>1.3。其中,变化最大的是花生四烯酸（AA），糖尿病猪的水平比非糖尿病猪低32倍。AA衍生产品，PGI2和6-酮-PGF1α，也大大减少了。AA处理培养的心肌细胞在高糖和缺氧48小时保护细胞死亡30％，这与增加的有丝分裂活性一致(如增加的LC3II/LC3I所示，P62减少，Parkin和PINK1增加），改善线粒体更新（Drp1和FIS1的上调），减少ROS的产生和增加ATP的产生。PINK1（一种关键的线粒体自噬蛋白）敲低或自噬抑制剂3-甲基腺嘌呤消除了这些心脏保护作用。吲哚美辛和前列环素受体拮抗剂Cay10441也抑制了AA的保护作用。此外，将糖尿病SpragueDawley大鼠进行冠状动脉结扎40分钟，并进行AA治疗（每只动物10mg/天）以减少心肌梗塞的大小，细胞凋亡指数，炎症细胞因子和改善心脏功能。扫描电子显微镜显示AA处理的大鼠梗死心肌边界区线粒体更完整。最后,糖尿病患者心肌梗死后血浆AA和6-keto-PGF1α水平降低，心脏射血分数降低，与心肌梗死后的非糖尿病患者相比。血浆AA水平与空腹血糖呈负相关。
结论：AA通过促进线粒体自噬和更新来保护糖尿病缺血性心肌损伤，这与AA衍生的PGI2信号传导有关。AA可能是治疗糖尿病心肌缺血性损伤的新策略。
