Related Experiment Video
Updated: Jun 27, 2026
Epigenetic Regulation of Cardiac Differentiation of Embryonic Stem Cells and Tissues
Published on: June 3, 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, 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
- Epigenetics
- Molecular Cardiology
Background:
- Histone deacetylase inhibitors (HDIs) show cardioprotective effects, yet histone deacetylase (HDAC) depletion can be detrimental.
- This study investigates the contradictory roles of HDACs in cardiac function using HDAC3 as a model.
Purpose of the Study:
- To resolve the paradox between the beneficial effects of HDIs and the harmful effects of HDAC depletion in the adult heart.
- To elucidate the specific role of HDAC3 protein level versus its enzymatic activity in maintaining cardiac function.
Main Methods:
- Adult-onset cardiac-specific HDAC3 depletion in mice.
- Genetic manipulation to abolish HDAC3 enzymatic activity or disrupt its interaction with LAP2β.
- High-fat diet (HFD) challenge and aortic constriction to assess cardiac function.
- Analysis of gene expression related to lipid oxidation, bioenergetics, and oxidative stress.
Main Results:
- Cardiac-specific HDAC3 depletion in adult mice on HFD induced cardiac hypertrophy and dysfunction.
- Loss of HDAC3 protein, not its enzymatic activity, altered gene expression of lipid oxidation and antioxidant pathways.
- Interaction with lamina-associated polypeptide 2β (LAP2β) is crucial for HDAC3's function in gene regulation.
- HDAC3 depletion, independent of its enzymatic activity, worsened cardiac function under pressure overload.
Conclusions:
- The cardiac function of HDAC3 in adult mammals is primarily mediated by its protein interactions, not its enzymatic activity.
- These findings challenge the direct link between HDAC enzymatic activity and the cardioprotective effects of HDIs.
- HDAC3's role in the adult heart involves protein-level functions critical for maintaining cardiac homeostasis and response to stress.
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.
