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

Ke Cai; Feng Wang; Jia-Quan Lu; An-Na Shen; Shi-Min Zhao; Wei-Dong Zang; Yong-Hao Gui; Jian-Yuan Zhao

doi:10.1016/j.jacbts.2021.12.007

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

JACC Basic Transl Sci. 2022 Apr 25;7(4):348-362. doi: 10.1016/j.jacbts.2021.12.007. eCollection 2022 Apr.

Authors

Ke Cai¹, Feng Wang¹, Jia-Quan Lu¹, An-Na Shen¹, Shi-Min Zhao^{1

2}, Wei-Dong Zang³, Yong-Hao Gui¹, Jian-Yuan Zhao^{1

3}

Affiliations

¹ NHC Key Laboratory of Neonatal Diseases, Cardiovascular Center, Children's Hospital of Fudan University, State Key Laboratory of Genetic Engineering, and School of Life Sciences, Fudan University, Shanghai, China.
² Key Laboratory of Reproduction Regulation of NPFPC, Fudan University, Shanghai, China.
³ School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.

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.

Keywords: ANP, atrial natriuretic peptide; BCAA, branched-chain amino acid; BNP, brain natriuretic peptide; DCM, dilated cardiomyopathy; ECHS1, short-chain enoyl-CoA hydratase 1; FA, fatty acid; HCM, hypertrophic cardiomyopathy; HFF, human foreskin fibroblast; IVSd, interventricular septum in end-diastole; IVSs, interventricular septum in end-systole; LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; LVIDd, left ventricular internal dimension in end-diastole; LVIDs, left ventricular internal dimension in end-systole; LVPWd, left ventricular posterior wall in end-diastole; LVPWs, left ventricular posterior wall in end-systole; NMN, nicotinamide mononucleotide; acetylation of H3K9; cardiomyopathy; enoyl-CoA hydratase 1; nicotinamide mononucleotide; p300; α-SMA, smooth muscle actin-α.