Artigo Acesso aberto Revisado por pares

Sirtuin 5 levels are limiting in preserving cardiac function and suppressing fibrosis in response to pressure overload

2022; Nature Portfolio; Volume: 12; Issue: 1 Linguagem: Inglês

10.1038/s41598-022-16506-7

ISSN

2045-2322

Autores

Angela H. Guo, Rachael K. Baliira, Mary E. Skinner, Surinder Kumar, Anthony Andren, Li Zhang, Robert Goldsmith, Shaday Michán, Norma J. Davis, Merissa W. Maccani, Sharlene M. Day, David Sinclair, Matthew J. Brody, Costas A. Lyssiotis, Adam Stein, David B. Lombard,

Tópico(s)

Calcium signaling and nucleotide metabolism

Resumo

Abstract Heart failure (HF) is the inability of the heart to pump blood sufficiently to meet the metabolic demands of the body. HF with reduced systolic function is characterized by cardiac hypertrophy, ventricular fibrosis and remodeling, and decreased cardiac contractility, leading to cardiac functional impairment and death. Transverse aortic constriction (TAC) is a well-established model for inducing hypertrophy and HF in rodents. Mice globally deficient in sirtuin 5 (SIRT5), a NAD + -dependent deacylase, are hypersensitive to cardiac stress and display increased mortality after TAC. Prior studies assessing SIRT5 functions in the heart have all employed loss-of-function approaches. In this study, we generated SIRT5 overexpressing (SIRT5OE) mice, and evaluated their response to chronic pressure overload using TAC. Compared to littermate controls, SIRT5OE mice were protected against adverse functional consequences of TAC, left ventricular dilation and impaired ejection fraction. Transcriptomic analysis revealed that SIRT5 suppresses key HF sequelae, including the metabolic switch from fatty acid oxidation to glycolysis, immune activation, and fibrotic signaling pathways. We conclude that SIRT5 is a limiting factor in the preservation of cardiac function in response to experimental pressure overload.

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