Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque

// Chang Pan 1,2,3,4,* , Jun-hui Xing 1,2,3,4,* , Cheng Zhang 2,5,* , Ying-mei Zhang 6,* , Lue-tao Zhang 1,2,3,4,* , Shu-jian Wei 1,2,3,4 , Ming-xiang Zhang 2 , Xu-ping Wang 2 , Qiu-huan Yuan 1,2,3,4 , Li Xue 1,2,3,4 , Jia-li Wang 1,2,3,4 , Zhao-qiang Cui 2 , Yun Zhang 2,5 , Feng Xu 1,2,3,4 and Yu-guo Chen 1,2,3,4 1 Department of Emergency and Chest Pain Center, Qilu Hospital, Shandong University, Ji’nan, China 2 Key Laboratory of Cardiovascular Remodeling and Function Research, Ministry of Education and Ministry of Public Health of People’s Republic of China, Qilu Hospital, Shandong University, Ji’nan, China 3 Institute of Emergency and Critical Care Medicine, Qilu Hospital, Shandong University, Ji’nan, China 4 The Key Laboratory of Emergency and Critical Care Medicine affiliated to Health Commission of Shandong Province, Qilu Hospital, Shandong University, Ji’nan, China 5 Department of Cardiology, Qilu Hospital, Shandong University, Ji’nan, China 6 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Feng Xu, email: // Yu-guo Chen, email: // Keywords : ALDH2, polymorphism, atherosclerotic plaque vulnerability, inflammation, MAPK signaling pathway, Pathology Section Received : April 22, 2016 Accepted : May 06, 2016 Published : May 15, 2016 Abstract Previous studies demonstrated that aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which eliminates ALDH2 activity down to 1%-6%, is a susceptibility gene for coronary disease. Here we investigated the underlying mechanisms based on our prior clinical and experimental studies. Male apoE-/- mice were transfected with GFP, ALDH2-overexpression and ALDH2-RNAi lentivirus respectively (n=20 each) after constrictive collars were placed around the right common carotid arteries. Consequently, ALDH2 gene silencing led to an increased en face plaque area, more unstable plaque with heavier accumulation of lipids, more macrophages, less smooth muscle cells and collagen, which were associated with aggravated inflammation. However, ALDH2 overexpression displayed opposing effects. We also found that ALDH2 activity decreased in atherosclerotic plaques of human and aged apoE-/- mice. Moreover, in vitro experiments with human umbilical vein endothelial cells further illustrated that, inhibition of ALDH2 activity resulted in elevating inflammatory molecules, an increase of nuclear translocation of NF-κB, and enhanced phosphorylation of NF-κB p65, AP-1 c-Jun, Jun-N terminal kinase and p38 MAPK, while ALDH2 activation could trigger contrary effects. These findings suggested that ALDH2 can influence plaque development and vulnerability, and inflammation via MAPK, NF-κB and AP-1 signaling pathways.