乙醛脱氢酶 2（ALDH2）可挽救心肌缺血/再灌注损伤：自噬悖论和有毒醛的作用。
Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia/reperfusion injury: role of autophagy paradox and toxic aldehyde.
机构信息
Department of Physiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
出版信息
Eur Heart J. 2011 Apr;32(8):1025-38. doi: 10.1093/eurheartj/ehq253. Epub 2010 Aug 12.
AIMS
The present study was designed to examine the mechanism involved in mitochondrial aldehyde dehydrogenase (ALDH2)-induced cardioprotection against ischaemia/reperfusion (I/R) injury with a focus on autophagy.
METHODS
Wild-type (WT), ALDH2 overexpression, and knockout (KO) mice (n = 4-6 for each index measured) were subjected to I/R, and myocardial function was assessed using echocardiographic, Langendroff, and edge-detection systems. Western blotting was used to evaluate AMP-dependent protein kinase (AMPK), Akt, autophagy, and the AMPK/Akt upstream signalling LKB1 and PTEN.
RESULTS
ALDH2 overexpression and KO significantly attenuated and accentuated, respectively, infarct size, factional shortening, and recovery of post-ischaemic left ventricular function following I/R as well as hypoxia/reoxygenation-induced cardiomyocyte contractile dysfunction. Autophagy was induced during ischaemia and remained elevated during reperfusion. ALDH2 significantly promoted autophagy during ischaemia, which was accompanied by AMPK activation and mammalian target of rapamycin (mTOR) inhibition. On the contrary, ALDH2 overtly inhibited autophagy during reperfusion accompanied by the activation of Akt and mTOR. Inhibition and induction of autophagy mitigated ALDH2-induced protection against cell death in hypoxia and reoxygenation, respectively. In addition, levels of the endogenous toxic aldehyde 4-hydroxy-2-nonenal (4-HNE) were elevated by ischaemia and reperfusion, which was abrogated by ALDH2. Furthermore, ALDH2 ablated 4-HNE-induced cardiomyocyte dysfunction and protein damage, whereas 4-HNE directly decreased pan and phosphorylated LKB1 and PTEN expression.
CONCLUSION
Our data suggest a myocardial protective effect of ALDH2 against I/R injury possibly through detoxification of toxic aldehyde and a differential regulation of autophagy through AMPK- and Akt-mTOR signalling during ischaemia and reperfusion, respectively.
目的
本研究旨在探讨线粒体乙醛脱氢酶（ALDH2）诱导的心肌缺血/再灌注（I/R）损伤保护作用的机制，重点关注自噬。
方法
野生型（WT）、ALDH2 过表达和敲除（KO）小鼠（每种指标测量 4-6 只）进行 I/R，使用超声心动图、Langendroff 和边缘检测系统评估心肌功能。Western blot 用于评估 AMP 依赖的蛋白激酶（AMPK）、Akt、自噬以及 AMPK/Akt 上游信号 LKB1 和 PTEN。
结果
ALDH2 过表达和 KO 分别显著减轻和加重 I/R 后以及缺氧/复氧诱导的心肌细胞收缩功能障碍后梗死面积、分数缩短和缺血后左心室功能恢复。自噬在缺血期间诱导，并在再灌注期间持续升高。ALDH2 在缺血期间显著促进自噬，伴随着 AMPK 激活和哺乳动物雷帕霉素靶蛋白（mTOR）抑制。相反，ALDH2 在再灌注期间明显抑制自噬，伴随着 Akt 和 mTOR 的激活。自噬的抑制和诱导分别减轻了缺氧和复氧中 ALDH2 诱导的细胞死亡保护作用。此外，缺血和再灌注导致内源性毒性醛 4-羟基-2-壬烯醛（4-HNE）水平升高，而 ALDH2 则消除了这种升高。此外，ALDH2 消除了 4-HNE 诱导的心肌细胞功能障碍和蛋白损伤，而 4-HNE 直接降低了全和磷酸化 LKB1 和 PTEN 的表达。
结论
我们的数据表明，ALDH2 对 I/R 损伤具有心肌保护作用，可能是通过在缺血和再灌注期间分别通过 AMPK-mTOR 信号和 Akt-mTOR 信号对毒性醛进行解毒以及对自噬进行差异调节。
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