Zhu Yi, He Ya-Jun, Yu Yuan, Xu Dan, Yuan Shi-Ying, Yan Hong
Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Intensive Care Unit, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China; and.
J Cardiovasc Pharmacol. 2024 Jan 1;83(1):93-104. doi: 10.1097/FJC.0000000000001499.
Aldehyde dehydrogenase 2 (ALDH2) protects the ischemic heart by activating adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling. However, the molecular mechanisms linking ALDH2 and AMPK signaling are not fully understood. This study aimed to explore the potential mechanisms linking ALDH2 and AMPK in myocardial ischemic injury. An ischemic model was established by ligating the left anterior descending coronary artery in rats. The overexpression or knockdown of ALDH2 in H9c2 cells treated with oxygen-glucose deprivation was obtained through lentivirus infection. Transferase-mediated dUTP nick-end labeling was used to evaluate apoptosis in an ischemic rat model and oxygen-glucose deprivation cells. ALDH2 activity, mitochondrial oxidative stress markers, adenosine triphosphate, respiratory control ratio, and cell viability in H9c2 cells were evaluated using a biological kit and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide. Protein expression of ALDH2 , 4-hydroxynonenal, thioredoxin-1 (Trx-1), and AMPK-proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling pathway was detected through Western blotting. ALDH2 activation reduced ischemic-induced myocardial infarct size and apoptosis. ALDH2 protected mitochondrial function by enhancing mitochondrial respiratory control ratio and adenosine triphosphate production, alleviated mitochondrial oxidative stress, and suppressed myocardial apoptosis. Moreover, ALDH2 attenuated ischemia-induced oxidative stress and maintained Trx-1 levels by reducing 4-hydroxynonenal, thereby promoting AMPK-PGC-1α signaling activation. Inhibiting Trx-1 or AMPK abolished the cardioprotective effect of ALDH2 on ischemia. ALDH2 alleviates myocardial injury through increased mitochondrial biogenesis and reduced oxidative stress, and these effects were achieved through Trx1-mediating AMPK-PGC1-α signaling activation.
乙醛脱氢酶2（ALDH2）通过激活5'-单磷酸腺苷激活的蛋白激酶（AMPK）信号通路保护缺血心脏。然而，连接ALDH2和AMPK信号通路的分子机制尚未完全阐明。本研究旨在探讨心肌缺血损伤中连接ALDH2和AMPK的潜在机制。通过结扎大鼠左冠状动脉前降支建立缺血模型。通过慢病毒感染在氧糖剥夺处理的H9c2细胞中实现ALDH2的过表达或敲低。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法评估缺血大鼠模型和氧糖剥夺细胞中的细胞凋亡。使用生物试剂盒和3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐评估H9c2细胞中的ALDH2活性、线粒体氧化应激标志物、三磷酸腺苷、呼吸控制率和细胞活力。通过蛋白质印迹法检测ALDH2、4-羟基壬烯醛、硫氧还蛋白-1（Trx-1）和AMPK-增殖激活受体γ共激活因子-1α（PGC-1α）信号通路的蛋白表达。ALDH2激活可减少缺血诱导的心肌梗死面积和细胞凋亡。ALDH2通过提高线粒体呼吸控制率和三磷酸腺苷生成来保护线粒体功能，减轻线粒体氧化应激，并抑制心肌细胞凋亡。此外，ALDH2通过降低4-羟基壬烯醛减轻缺血诱导的氧化应激并维持Trx-1水平，从而促进AMPK-PGC-1α信号通路激活。抑制Trx-1或AMPK可消除ALDH2对缺血的心脏保护作用。ALDH2通过增加线粒体生物合成和减少氧化应激来减轻心肌损伤，这些作用是通过Trx1介导的AMPK-PGC1-α信号通路激活实现的。
