Manling Zhang1, Xue Yang2, Raymond J Zimmerman3, Qin Wang4, Mark A Ross5, Jonathan M Granger6, Elizabeth D Luczak6, Djahida Bedja6, Hong Jiang7, Ning Feng8. 1. Department of Medicine, Division of Cardiology, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States; Division of Cardiology, Veteran Affair Pittsburgh Healthcare System, Pittsburgh, PA, United States. 2. Department of Medicine, Division of Cardiology, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. 3. Department of Medicine, Division of Cardiology, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States. 4. Department of Medicine, Division of Cardiology, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States; Echocardiography lab at Heart Center, Ningxia General Hospital, Ningxia Medical University, Ningxia, China. 5. Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, United States of America. 6. Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, United States. 7. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. 8. Department of Medicine, Division of Cardiology, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States; Division of Cardiology, Veteran Affair Pittsburgh Healthcare System, Pittsburgh, PA, United States. Electronic address: fengn@pitt.edu.
Abstract
BACKGROUND: Persistent cardiac Ca2+/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.
BACKGROUND: Persistent cardiac Ca2+/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 CaMKIIhyperactivity induced cardiac dysfunction.
Authors: Maicon Landim-Vieira; Matthew C Childers; Amanda L Wacker; Michelle Rodriquez Garcia; Huan He; Rakesh Singh; Elizabeth A Brundage; Jamie R Johnston; Bryan A Whitson; P Bryant Chase; Paul M L Janssen; Michael Regnier; Brandon J Biesiadecki; J Renato Pinto; Michelle S Parvatiyar Journal: Elife Date: 2022-05-03 Impact factor: 8.713