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

作者：Shen, Cheng; Wang, Cong; Han, Shasha; Wang, Zhenjun; Dong, Zhen; Zhao, Xiaona; Wang, Peng; Zhu, Hong; Sun, Xiaolei; Ma, Xin; Zhu, Hongming^*; Zou, Yunzeng; Hu, Kai; Ge, Junbo^*; Sun, Aijun^*

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2017, 1863(8): 1912-1918.

DOI：10.1016/j.bbadis.2016.11.016

• Aldehyde dehydrogenase 2
• Low-to-moderate alcohol consumption
• Reactive oxygen species
• Apoptosis
• Necroptosis

Previous studies evidenced the beneficial effects of low-to-moderate alcohol consumption on cardiovascular system by activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2), a key enzyme metabolizing acetaldehyde to innocuous acetic acid, in diabetic mice. It remains questionable whether people with inactive ALDH2 would also benefit from the 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) and ALDH2 knockout (KO) mice were exposed to low-to-moderate alcohol (EtOH) challenge for 6 weeks. Cardiac function and cell death related pathways were then measured. Although EtOH exposure did not further improve cardiac function or reduce reactive oxygen species (ROS) levels in WT mice, 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 increased myocardial fibrosis deposition as well as the excessive ROS accumulation. Above changes were related to altered cell demise (apoptosis and necroptosis), as shown by upregulated expression 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.

• 出版日期2017-8
• 单位同济大学; 山东大学; 复旦大学