Enzyme-Independent Functions of HDAC3 in the Adult Hear

Authors

Sichong Qian
Chen Zhang
Wenbo Li
Shiyang Song
Guanqiao Lin
Zixiu Cheng
Wenjun Zhou
Huiqi Yin
Yueli Wang
Haiyang Li
Ying H Shen
Zheng Sun

Language

English

Publication Date

7-1-2025

Journal

Acta Pharmaceutica Sinica B

DOI

10.1016/j.apsb.2025.05.002

PMID

40698142

PMCID

PMC12278646

PubMedCentral® Posted Date

5-10-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Histone deacetylase, Cardiac hypertrophy, Hypertrophic cardiomyopathy, HDACi, Catalytic-independent, Fatty acid oxidation, Pressure overload, Lamina

Published Open-Access

yes

Recommended Citation

Qian, Sichong; Zhang, Chen; Li, Wenbo; et al., "Enzyme-Independent Functions of HDAC3 in the Adult Hear" (2025). Huffington Center on Aging Staff Publications. 71.
https://digitalcommons.library.tmc.edu/aging_research/71