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Updated: Sep 14, 2025
Isolation, Culture and Transduction of Adult Mouse Cardiomyocytes
Published on: August 28, 2016
Enzyme-independent functions of HDAC3 in the adult heart
Sichong Qian1,2, Chen Zhang3, Wenbo Li2
1Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
Insights
Histone deacetylase 3 (HDAC3) depletion in adult mice impairs heart function and gene expression, but only when its protein level is reduced, not its enzymatic activity. This suggests HDAC3
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Epigenetics
Background:
- Histone deacetylase (HDAC) inhibitors (HDIs) show cardioprotective effects, yet HDAC depletion can be detrimental.
- This contradiction highlights a gap in understanding HDAC function in the adult heart.
Purpose of the Study:
- To investigate the role of histone deacetylase 3 (HDAC3) in adult cardiac function, differentiating between its enzymatic activity and protein levels.
- To elucidate the mechanisms underlying HDAC3's influence on cardiac gene expression and contractility.
Main Methods:
- Adult-onset cardiac-specific HDAC3 depletion in mice, alongside genetic manipulation of HDAC3 enzymatic activity and protein interactions.
- High-fat diet (HFD) challenge and aortic constriction to assess cardiac hypertrophy, contractile dysfunction, and gene expression changes.
- Analysis of lipid oxidation, bioenergetic, antioxidant, and anti-apoptotic gene expression, as well as cardiomyocyte-autonomous effects.
Main Results:
- Cardiac-specific HDAC3 depletion in adult mice induced hypertrophy and dysfunction on an HFD, linked to altered gene expression.
- Loss of HDAC3 enzymatic activity alone did not cause cardiac dysfunction, indicating protein level and/or interactions are critical.
- HDAC3's interaction with lamina-associated polypeptide 2β (LAP2β) was essential for rescuing gene expression and cardiac function.
Conclusions:
- The adult cardiac function of HDAC3 is primarily mediated by its protein level and interaction with LAP2β, rather than its enzymatic activity.
- These findings challenge the direct link between HDI cardioprotection and HDAC enzymatic activity, suggesting alternative mechanisms.
- Understanding the non-enzymatic roles of HDAC3 is crucial for developing targeted cardiovascular therapies.
Abstract:
The cardioprotective effects of histone deacetylase (HDAC) inhibitors (HDIs) are at odds with the deleterious effects of HDAC depletion. Here, we use HDAC3 as a prototype HDAC to address this contradiction. We show that adult-onset cardiac-specific depletion of HDAC3 in mice causes cardiac hypertrophy and contractile dysfunction on a high-fat diet (HFD), excluding developmental disruption as a major reason for the contradiction. Genetically abolishing HDAC3 enzymatic activity without affecting its protein level does not cause cardiac dysfunction on HFD. HDAC3 depletion causes robust downregulation of lipid oxidation/bioenergetic genes and upregulation of antioxidant/anti-apoptotic genes. In contrast, HDAC3 enzyme activity abolishment causes much milder changes in far fewer genes. The abnormal gene expression is cardiomyocyte-autonomous and can be rescued by an enzyme-dead HDAC3 mutant but not by an HDAC3 mutant (Δ33-70) that lacks interaction with the nuclear-envelope protein lamina-associated polypeptide 2β (LAP2β). Tethering LAP2β to the HDAC3 Δ33-70 mutant restored its ability to rescue gene expression. Finally, HDAC3 depletion, not loss of HDAC3 enzymatic activity, exacerbates cardiac contractile functions upon aortic constriction. These results suggest that the cardiac function of HDAC3 in adults is not attributable to its enzyme activity, which has implications for understanding the cardioprotective effects of HDIs.
