Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling
- 1 June 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (6), 2966-2977
- https://doi.org/10.1172/jci133753
Abstract
Salt inducible kinases (SIKs) are key regulators of cellular metabolism and growth, but their role in cardiomyocyte plasticity and heart failure pathogenesis remains unknown. Here, we showed that loss of SIK1 kinase activity protected against adverse cardiac remodeling and heart failure pathogenesis in rodent models and human iPSC-derived cardiomyocytes. We found that SIK1 phosphorylated and stabilized histone deacetylase 7 (HDAC7) protein during cardiac stress, an event that is required for pathologic cardiomyocyte remodeling. Gain- and loss-of-function studies of HDAC7 in cultured cardiomyocytes implicated HDAC7 as a pro-hypertrophic signaling effector that can induce c-Myc expression, indicating a functional departure from the canonical MEF2 co-repressor function of class IIa HDACs. Taken together, our findings reveal what we believe to be a previously unrecognized role for a SIK1-HDAC7 axis in regulating cardiac stress responses and implicate this pathway as a potential target in human heart failure.Funding Information
- Tobacco Related Disease Research Program (28DT-008)
- NIH (HL127240)
- NIH (C06 RR018928)
- UCSF (Discovery Fellows Program)
- American Heart Association (17PRE33670181)
This publication has 29 references indexed in Scilit:
- A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathwayNature Medicine, 2018
- Development of Chemical Probes for Investigation of Salt-Inducible Kinase Function in VivoACS Chemical Biology, 2016
- A Hormone-Dependent Module Regulating Energy BalanceCell, 2011
- Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in miceJCI Insight, 2010
- Cardiac PlasticityThe New England Journal of Medicine, 2008
- SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytesNature Medicine, 2007
- Histone Deacetylases 5 and 9 Govern Responsiveness of the Heart to a Subset of Stress Signals and Play Redundant Roles in Heart DevelopmentMolecular and Cellular Biology, 2004
- Class II Histone Deacetylases Act as Signal-Responsive Repressors of Cardiac HypertrophyCell, 2002
- The c-myc proto-oncogene regulates cardiac development in transgenic mice.Molecular and Cellular Biology, 1990
- Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines.Circulation Research, 1982