Aldh2, or aldehyde dehydrogenase 2, is a non-cytochrome P450 mitochondrial enzyme. Its key function is to oxidize acetaldehyde, a common metabolite from alcohol drinking, into acetate. This process is crucial in alcohol metabolism and also in the metabolism of other endogenous and exogenous aldehydes, especially under oxidative stress. It is involved in multiple biological pathways related to metabolism and oxidative stress response, which are of great significance for maintaining normal physiological functions [1]. Genetic models, such as gene knockout (KO) mouse models, have been valuable in studying Aldh2.

In KO mouse models, Aldh2 deficiency has been linked to various disease-related phenotypes. In septic acute respiratory distress syndrome (ARDS), Aldh2 -/- mice and Aldh2rs671 knock-in mice showed pulmonary and circulating NETosis, which promoted endothelial destruction and exacerbated septic ARDS [2]. In alcohol-related conditions, Aldh2-KO mice were more sensitive to binge alcohol-induced oxidative stress, gut leakiness, endotoxemia, and acute liver injury, suggesting that Aldh2 plays a protective role against alcohol-mediated gut and liver injury [3]. In the context of atherosclerosis, transplanting bone marrow from APOE -/-ALDH2 -/- to APOE -/- mice increased atherosclerosis plaques, as macrophages from ALDH2 -/- mice had impaired efferocytotic activity [4].

In conclusion, Aldh2 is essential for aldehyde metabolism and plays a protective role in multiple disease conditions. Studies using Aldh2 KO mouse models have revealed its significance in diseases such as septic ARDS, alcohol-related liver and gut injuries, and atherosclerosis, providing insights into the underlying disease mechanisms and potential therapeutic targets.

References:

1. Chen, Che-Hong, Ferreira, Julio C B, Mochly-Rosen, Daria. . ALDH2 and Cardiovascular Disease. In Advances in experimental medicine and biology, 1193, 53-67. doi:10.1007/978-981-13-6260-6_3. https://pubmed.ncbi.nlm.nih.gov/31368097/

2. Xu, Changchang, Zhang, Lin, Xu, Shaoyu, Pang, Jiaojiao, Chen, Yuguo. 2024. Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS. In Cellular & molecular immunology, 21, 510-526. doi:10.1038/s41423-024-01146-w. https://pubmed.ncbi.nlm.nih.gov/38472357/

3. Rungratanawanich, Wiramon, Lin, Yuhong, Wang, Xin, Chidambaram, Saravana Babu, Song, Byoung-Joon. 2022. ALDH2 deficiency increases susceptibility to binge alcohol-induced gut leakiness, endotoxemia, and acute liver injury in mice through the gut-liver axis. In Redox biology, 59, 102577. doi:10.1016/j.redox.2022.102577. https://pubmed.ncbi.nlm.nih.gov/36528936/

4. Zhang, Jian, Zhao, Xiangkai, Guo, Yunyun, Chen, Yuguo, Xu, Feng. 2022. Macrophage ALDH2 (Aldehyde Dehydrogenase 2) Stabilizing Rac2 Is Required for Efferocytosis Internalization and Reduction of Atherosclerosis Development. In Arteriosclerosis, thrombosis, and vascular biology, 42, 700-716. doi:10.1161/ATVBAHA.121.317204. https://pubmed.ncbi.nlm.nih.gov/35354308/