Deacetylase‐dependent and ‐independent role of HDAC3 in cardiomyopathy

• Published in: Journal of cellular physiology 2023-03, Vol.238 (3), p.647-658
• Main Authors: Ren, Jieyu, Zeng, Qun, Wu, Hongmei, Liu, Xuewen, Guida, Maria C., Huang, Wen, Zhai, Yiyuan, Li, Junjie, Ocorr, Karen, Bodmer, Rolf, Tang, Min
• Format: Article
• Language: English
• Subjects: Abnormalities; Accumulation; Animals; cardiac contractility; Cardiac muscle; Cardiomyopathies - enzymology; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathies - physiopathology; Cardiomyopathy; Coronary artery disease; deacetylase; Deposition; Disease Models, Animal; Drosophila; Drosophila melanogaster - enzymology; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - deficiency; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Fibrosis; Fruit flies; Gene Knockdown Techniques; Heart - physiology; Heart diseases; Histone Deacetylases - deficiency; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones; Histones - chemistry; Histones - metabolism; Homeostasis; Immunohistochemistry; Insects; Lipids; Muscle contraction; Muscles; Mutants; Myocardium - metabolism; Pericardin; Triglycerides; Triglycerides - metabolism
• ISSN: 0021-9541; 1097-4652; 1097-4652
• DOI: 10.1002/jcp.30957

Cardiomyopathy is a common disease of cardiac muscle that negatively affects cardiac function. HDAC3 commonly functions as corepressor by removing acetyl moieties from histone tails. However, a deacetylase‐independent role of HDAC3 has also been described. Cardiac deletion of HDAC3 causes reduced cardiac contractility accompanied by lipid accumulation, but the molecular function of HDAC3 in cardiomyopathy remains unknown. We have used powerful genetic tools in Drosophila to investigate the enzymatic and nonenzymatic roles of HDAC3 in cardiomyopathy. Using the Drosophila heart model, we showed that cardiac‐specific HDAC3 knockdown (KD) leads to prolonged systoles and reduced cardiac contractility. Immunohistochemistry revealed structural abnormalities characterized by myofiber disruption in HDAC3 KD hearts. Cardiac‐specific HDAC3 KD showed increased levels of whole‐body triglycerides and increased fibrosis. The introduction of deacetylase‐dead HDAC3 mutant in HDAC3 KD background showed comparable results with wild‐type HDAC3 in aspects of contractility and Pericardin deposition. However, deacetylase‐dead HDAC3 mutants failed to improve triglyceride accumulation. Our data indicate that HDAC3 plays a deacetylase‐independent role in maintaining cardiac contractility and preventing Pericardin deposition as well as a deacetylase‐dependent role to maintain triglyceride homeostasis. The deacetylase‐dependent and deacetylase‐independent role in maintaining cardiac performance. HDAC3 plays deacetylase‐dependent role in lipid homeostasis by promoting fatty acid (FA) oxidation. The defects of FA oxidation in HDAC3 KD would reroute the lipid intermediates to TAG synthesis. The increase of lipid intermediate S1P would promote ECM accumulation. The nonenzymatic function of HDAC3 would silence the TGF‐β signaling to directly prevent ECM accumulation. Additionally, TGF‐β signaling would indirectly promote cardiac fibrosis through increasing the lipid intermediate SIP.