Enzyme-independent functions of HDAC3 in the adult heart.
10.1016/j.apsb.2025.05.002
- Author:
Sichong QIAN
1
;
Chen ZHANG
2
;
Wenbo LI
3
;
Shiyang SONG
3
;
Guanqiao LIN
3
;
Zixiu CHENG
3
;
Wenjun ZHOU
3
;
Huiqi YIN
3
;
Yueli WANG
4
;
Haiyang LI
1
;
Ying H SHEN
2
;
Zheng SUN
3
Author Information
1. Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
2. Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
3. Department of Medicine-Endocrinology, Baylor College of Medicine, Houston, TX 77030, USA.
4. Echocardiography Medical Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
- Publication Type:Journal Article
- Keywords:
Cardiac hypertrophy;
Catalytic-independent;
Fatty acid oxidation;
HDACi;
Histone deacetylase;
Hypertrophic cardiomyopathy;
Lamina;
Pressure overload
- From:
Acta Pharmaceutica Sinica B
2025;15(7):3561-3574
- CountryChina
- Language:English
-
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.
