Document Type
Article
Publication Title
JACC: Basic to Translational Science
Abstract
Dilated cardiomyopathy (DCM) is associated with high mortality despite advanced therapies. The LMNA gene encodes lamin A/C and is the second most frequently mutated gene associated with DCM, for which therapeutic options are limited. Here we generated Lmna–/– mice and found they exhibited cardiac dysfunction at the age of 1 month but not at 2 weeks. Proteomics showed down-regulation of mitochondrial function–related pathways in Lmna–/– hearts. Moreover, early injured mitochondria with decreased cristae density and sirtuin 1 (SIRT1) down-regulation were observed in 2-week-old Lmna–/– hearts. Adenoviral overexpression of SIRT1 in lamin A/C knockdown neonatal rat ventricular myocytes improved mitochondrial oxidative respiration capacity. Adeno-associated virus–mediated SIRT1 overexpression alleviated mitochondrial injury, cardiac systolic dysfunction, ventricular dilation, and fibrosis, and prolonged lifespan in Lmna–/– mice. Mechanistically, LMNA maintains mitochondrial bioenergetics through the SIRT1-PARKIN axis. Our results suggest that targeting the SIRT1 signaling pathway is expected to be a novel therapeutic strategy for LMNA mutation–associated DCM.
DOI
10.1016/j.jacbts.2024.05.011
Publication Date
7-31-2024
Keywords
dilated cardiomyopathy, LMNA, mitochondrial bioenergetics, proteomics, SIRT1
ISSN
2452-302X
Recommended Citation
Du Z, Zhou Y, Li Q, Xie Y, Zhu T, Qiao J, Zhang R, Bao Y, Wang L, Xie Y, Quan J, Lin M, Zhang N, Jin Q, Liang W, Wu L, Yin T, Xie Y. SIRT1 Ameliorates Lamin A/C Deficiency-Induced Cardiac Dysfunction by Promoting Mitochondrial Bioenergetics. JACC: Basic to Translational Science. 2024; . doi: 10.1016/j.jacbts.2024.05.011.
