Abstract | BACKGROUND: 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.
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Authors | Manling Zhang, Xue Yang, Raymond J Zimmerman, Qin Wang, Mark A Ross, Jonathan M Granger, Elizabeth D Luczak, Djahida Bedja, Hong Jiang, Ning Feng |
Journal | Journal of molecular and cellular cardiology
(J Mol Cell Cardiol)
Vol. 149
Pg. 73-81
(12 2020)
ISSN: 1095-8584 [Electronic] England |
PMID | 32971072
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2020 Elsevier Ltd. All rights reserved. |
Chemical References |
- Histone Deacetylase Inhibitors
- Hydroxamic Acids
- SIN3A transcription factor
- quisinostat
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
- Histone Deacetylases
- Sin3 Histone Deacetylase and Corepressor Complex
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Topics |
- Animals
- Animals, Newborn
- Autophagy
(drug effects, genetics)
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
(metabolism)
- Cardiomegaly
(complications, genetics, pathology, physiopathology)
- Disease Progression
- Down-Regulation
(drug effects, genetics)
- Enzyme Activation
(drug effects)
- Heart Failure
(enzymology, genetics, pathology, physiopathology)
- Histone Deacetylase Inhibitors
(pharmacology)
- Histone Deacetylases
(metabolism)
- Hydroxamic Acids
(pharmacology)
- Mice, Transgenic
- Models, Biological
- Myocytes, Cardiac
(metabolism, pathology)
- Phosphorylation
(drug effects)
- Rats
- Sin3 Histone Deacetylase and Corepressor Complex
(metabolism)
- Up-Regulation
(drug effects, genetics)
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