Nicotinamide Mononucleotide Alleviates Cardiomyopathy Phenotypes Caused by Short-Chain Enoyl-Coa Hydratase 1 Deficiency
Ke Cai, Feng Wang, Jia-Quan Lu, Anna Shen, Shimin Zhao, Weidong Zang, Yonghao Gui, Jian‐Yuan Zhao
Abstract
Short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency plays a role in cardiomyopathy. Whether ECHS1 deficiency causes or is only associated with cardiomyopathy remains unclear. By using Echs1 heterogeneous knockout (Echs1+/-) mice, we found that ECHS1 deficiency caused cardiac dysfunction, as evidenced by diffuse myocardial fibrosis and upregulated fibrosis-related genes. Mechanistically, ECHS1 interacts with the p300 nuclear localization sequence, preventing its nuclear translocation in fibroblasts. ECHS1 deficiency promotes p300 nuclear translocation, leading to increased H3K9 acetylation, a known risk factor for cardiomyopathy. Nicotinamide mononucleotide–mediated acetylation targeting suppressed ECHS1 deficiency–induced cardiomyopathy phenotypes in Echs1+/- mice. Thus, enhancing p300-mediated H3K9ac is a potential interventional approach for preventing ECHS1 deficiency–induced cardiomyopathy.