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Updated: Sep 4, 2025
In Vitro Assessment of Cardiac Function Using Skinned Cardiomyocytes
Published on: June 22, 2020
Sirtuin 5 levels are limiting in preserving cardiac function and suppressing fibrosis in response to pressure
Angela H Guo1,2, Rachael Baliira1, Mary E Skinner1
1Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
Insights
Sirtuin 5 (SIRT5) overexpression protected mice from heart failure induced by pressure overload. SIRT5 plays a key role in preserving cardiac function during stress.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Metabolic Regulation in Heart Disease
Background:
- Heart failure (HF) involves impaired cardiac function due to hypertrophy, fibrosis, and reduced contractility.
- Sirtuin 5 (SIRT5), a NAD+-dependent deacylase, is crucial for cellular metabolism and stress response.
- Previous studies on SIRT5 in the heart used loss-of-function models, showing hypersensitivity to stress.
Purpose of the Study:
- To investigate the role of SIRT5 in cardiac adaptation to chronic pressure overload.
- To evaluate the protective effects of SIRT5 overexpression (SIRT5OE) against heart failure development.
Main Methods:
- Generation of SIRT5 overexpressing (SIRT5OE) mice.
- Induction of chronic pressure overload using transverse aortic constriction (TAC).
- Assessment of cardiac function, including left ventricular dimensions and ejection fraction.
- Transcriptomic analysis to identify molecular pathways regulated by SIRT5.
Main Results:
- SIRT5OE mice showed protection against TAC-induced adverse cardiac remodeling and functional decline.
- Overexpression of SIRT5 prevented left ventricular dilation and preserved ejection fraction.
- Transcriptomic data indicated SIRT5 suppresses HF-associated metabolic shifts (glycolysis over fatty acid oxidation), immune activation, and fibrosis.
Conclusions:
- SIRT5 overexpression confers protection against experimental heart failure induced by pressure overload.
- SIRT5 acts as a critical regulator, mitigating key pathological pathways in the stressed heart.
- SIRT5 is a limiting factor for preserving cardiac function under chronic stress conditions.
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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