CaMKII exacerbates heart failure progression by activating class I HDACs. (December 2020)

• Record Type: Journal Article
• Authors: Zhang, Manling; Yang, Xue; Zimmerman, Raymond J.; Wang, Qin; Ross, Mark A.; Granger, Jonathan M.; Luczak, Elizabeth D.; Bedja, Djahida; Jiang, Hong; Feng, Ning
• Is Part Of: Journal of molecular and cellular cardiology. Volume 149(2020)
• Page Start: 73
• Page End: 81
• Publication Date: 2020-12
• Subjects: Ca2+/calmodulin dependent Kinase II -- Histone deacetylase -- Heart failure; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2020.09.007
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background: Persistent cardiac Ca 2+ /calmodulin dependent Kinase II (CaMKII) activation plays an essential role in heart failure development. However, the molecular mechanisms underlying CaMKII induced heart failure progression remains incompletely understood. Histone deacetylases (HDACs) are critical for transcriptional responses to stress, and contribute to expression of pathological genes causing adverse ventricular remodeling. Class I HDACs, including HDAC1, HDAC2 and HDAC3, promote pathological cardiac hypertrophy, whereas class IIa HDACs suppress cardiac hypertrophy. While it is known that CaMKII deactivates class IIa HDACs to enhance cardiac hypertrophy, the role of CaMKII in regulating class I HDACs during heart failure progression is unclear. Methods and results: CaMKII increases the deacetylase activity of recombinant HDAC1, HDAC2 and HDAC3 via in vitro phosphorylation assays. Phosphorylation sites on HDAC1 and HDAC3 are identified with mass spectrometry. HDAC1 activity is also increased in cardiac-specific CaMKIIδC transgenic mice (CaMKIIδC -tg). Beyond post-translational modifications, CaMKII induces HDAC1 and HDAC3 expression. HDAC1 and HDAC3 expression are significantly increased in CaMKIIδC -tg mice. Inhibition of CaMKII by overexpression of the inhibitory peptide AC3-I in the heart attenuates the upregulation of HDAC1 after myocardial infarction surgery. Importantly, a potent HDAC1 inhibitor Quisinostat improves downregulated autophagy genes and cardiac dysfunction in CaMKIIδC -tg mice. In addition to Quisinostat, selective class I HDACs inhibitors, Apicidin and Entinostat, HDAC3 specific inhibitor RGFP966, as well as HDAC1 and HDAC3 siRNA prevent CaMKII overexpression induced cardiac myocyte hypertrophy. Conclusion: CaMKII activates class I HDACs in heart failure, which may be a central mechanism for heart failure progression. Selective class I HDACs inhibition may be a novel therapeutic avenue to alleviate CaMKII hyperactivity induced cardiac dysfunction. Graphical abstract: Unlabelled Image Highlights: CaMKII directly enhances HDAC1 and HDAC3 deacetylase activity. CaMKII induces HDAC1 and HDAC3 expression in the heart. CaMKII promotes HDAC1/HDAC2/Sin3a repressive complex formation. Class I HDAC inhibitors improve CaMKII hyperactivity induced cardiac hypertrophy. HDAC inhibitor recovers CaMKII hyperactivity induced autophagy genes downregulation.