PT - JOURNAL ARTICLE AU - Angela H. Guo AU - Rachael K. Baliira AU - Mary E. Skinner AU - Surinder Kumar AU - Anthony Andren AU - Li Zhang AU - Shaday Michan AU - Norma J. Davis AU - Merissa W. Maccani AU - Sharlene M. Day AU - David A. Sinclair AU - Costas A. Lyssiotis AU - Adam B. Stein AU - David B. Lombard TI - Sirtuin 5 levels are limiting in preserving cardiac function and suppressing fibrosis in response to pressure overload AID - 10.1101/2021.06.15.448619 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.06.15.448619 4099 - http://biorxiv.org/content/early/2021/06/16/2021.06.15.448619.short 4100 - http://biorxiv.org/content/early/2021/06/16/2021.06.15.448619.full AB - Heart failure (HF) is defined as an inability of the heart to pump blood adequately to meet the body’s metabolic demands. 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 induced by TAC. Compared to littermate controls, SIRT5OE mice were protected from left ventricular dilation and impaired ejection fraction, adverse functional consequences of TAC. Transcriptomic analyses revealed that SIRT5 suppresses key HF sequelae, including the metabolic switch from fatty acid oxidation to glycolysis, immune activation, and increased fibrotic signaling. We conclude that SIRT5 is a limiting factor in the preservation of cardiac function in response to experimental pressure overload.Competing Interest StatementDAS is a consultant to MetroBiotech, a company developing NAD+ boosters to treat rare diseases; a complete list of DAS activities is at https://sinclair.hms.harvard.edu/david-sinclairs-affiliations. CAL has received consulting fees from Astellas Pharmaceuticals and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach. DBL reports ownership of the equivalent in voting stock or share of ABBV and GILD.