Nicotinamide Mononucleotide Alleviates Cardiomyopathy Phenotypes Caused by Short-Chain Enoyl-Coa Hydratase 1 Deficiency

Short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency plays a rote in cardiomyopathy. Whether ECHS1 deficiency causes or is only associated with cardiomyopathy remains unclear. By using Echs1 heterogeneous knockout (Echsr(+/-)) 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. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Automated summary

ECHS1 deficiency causes cardiac dysfunction through promoting p300 nuclear translocation and increasing H3K9 acetylation. Targeting acetylation can alleviate the cardiomyopathy phenotypes induced by ECHS1 deficiency.