The role of aldehyde dehydrogenase 2 in cardiovascular disease

• Published in: Nature reviews cardiology 2023-07, Vol.20 (7), p.495-509
• Main Authors: Zhang, Jian, Guo, Yunyun, Zhao, Xiangkai, Pang, Jiaojiao, Pan, Chang, Wang, Jiali, Wei, Shujian, Yu, Xiao, Zhang, Cheng, Chen, Yuguo, Yin, Huiyong, Xu, Feng
• Format: Article
• Language: English
• Subjects: 692/4019/592; 692/699/75; Alcohol; Aldehyde Dehydrogenase, Mitochondrial - genetics; Aldehyde Dehydrogenase, Mitochondrial - metabolism; Aldehydes; Aldehydes - metabolism; Cardiac Imaging; Cardiac Surgery; Cardiology; Cardiovascular disease; Cardiovascular Diseases - genetics; Coronary Artery Disease; Coronary vessels; Dehydrogenases; Enzymes; Ethanol; Humans; Medicine; Medicine & Public Health; Polymorphism; Polymorphism, Genetic; Review Article; Vein & artery diseases
• ISSN: 1759-5002; 1759-5010
• DOI: 10.1038/s41569-023-00839-5

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the global population and in up to 50% of the East Asian population, is associated with increased risk of cardiovascular conditions such as coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary arterial hypertension, heart failure and drug-induced cardiotoxicity. Although numerous studies have attributed an accumulation of aldehydes (secondary to alcohol consumption, ischaemia or elevated oxidative stress) to an increased risk of cardiovascular disease (CVD), this accumulation alone does not explain the emerging protective role of ALDH2 rs671 against ageing-related cardiac dysfunction and the development of aortic aneurysm or dissection. ALDH2 can also modulate risk factors associated with atherosclerosis, such as cholesterol biosynthesis and HDL biogenesis in hepatocytes and foam cell formation and efferocytosis in macrophages, via non-enzymatic pathways. In this Review, we summarize the basic biology and the clinical relevance of the enzymatic and non-enzymatic, tissue-specific roles of ALDH2 in CVD, and discuss the future directions in the research and development of therapeutic strategies targeting ALDH2. A thorough understanding of the complex roles of ALDH2 in CVD will improve the diagnosis, management and prognosis of patients with CVD who harbour the ALDH2 rs671 polymorphism. Aldehyde dehydrogenase 2 (ALDH2), a key enzyme for the detoxification of alcohol-derived acetaldehyde, has been implicated in the pathogenesis of various types of cardiovascular disease. In this Review, Xu and colleagues present the latest evidence showing a link between the inactivating ALDH2 rs671 polymorphism and an increased or decreased risk of cardiovascular disease such as coronary artery disease. Key points Aldehyde dehydrogenase 2 (ALDH2) detoxifies alcohol-derived acetaldehyde and lipid peroxidation-generated aldehydes, and its inactivating rs671 polymorphism is present in up to 50% of the East Asian population. The ALDH2 rs671 polymorphism has been clinically and experimentally associated with an increased risk of cardiovascular disorders, including coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary artery hypertension, heart failure and drug-induced cardiotoxicity. Carriers of the ALDH2 rs671 polymorphism are at lowe