Aldehyde dehydrogenase 2 deficiency negates chronic low-to-moderate alcohol consumption-induced cardioprotecion possibly via ROS-dependent apoptosis and RIP1/RIP3/MLKL-mediated necroptosis

Previous studies evidenced the beneficial effects of low-to-moderate alcohol consumption on cardiovascular sys- temby activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2), a key enzyme metabolizing acetalde- hyde to innocuous acetic acid, in diabetic mice. It remains questionable whether people with inactive ALDH2 would also benefit fromthe drinking habit. Present study was therefore designed to examine the influence of ALDH2 deficiency on low-to-moderate alcohol consumption related myocardial alternations. Wildtype (WT) andALDH2knockout (KO) micewere exposedto low-to-moderate alcohol (EtOH) challenge for 6weeks. Cardiac function and cell death related pathwayswere thenmeasured. Although EtOHexposure did not further improve cardiac function or reduce reactive oxygen species (ROS) levels inWTmice, levels of high density lipoprotein- cholesterol (HDL-c) and expression of heme oxygenase-1 (HO-1) were significantly elevated in WT-EtOH group. However, EtOH exposure in KO mice depressed cardiac function as indicated by reduced left ventricular ejection fraction (EF) and increasedmyocardial fibrosis deposition as well as the excessive ROS accumulation. Above changeswere related to altered cell demise (apoptosis and necroptosis), as shown by upregulated expres- sion of cleaved caspase 9, cleaved caspase 3 and RIP1/RIP3/MLKL cascade.Our results thus suggest that ALDH2 is indispensable for the favorable cardiac effect of low-to-moderate alcohol consumption and ALDH2 deficiency may lead to unexpected cardiac dysfunctions via enhancing myocardial apoptosis and necroptosis.