Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling.

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 cardiomyocytes derived from human induced pluripotent stem cells. 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 prohypertrophic signaling effector that can induce c-Myc expression, indicating a functional departure from the canonical MEF2 corepressor 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.

• Authors: Austin Hsu, Qiming Duan, Sarah McMahon, Yu Huang, Sarah Ab Wood, Nathanael S Gray, Biao Wang, Benoit G Bruneau, Saptarsi M Haldar
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 130 Issue 6 Pg. 2966-2977 (06 01 2020) ISSN: 1558-8238 [Electronic] United States
• PMID: 32106109 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Serine-Threonine Kinases
• Sik1 protein, mouse
• Sik1 protein, rat
• HDAC7 protein, rat
• Hdac7 protein, mouse
• Histone Deacetylases

Topics

• Animals
• Histone Deacetylases (metabolism)
• Humans
• Mice
• Myocytes, Cardiac (metabolism, pathology)
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• Rats
• Rats, Sprague-Dawley
• Ventricular Remodeling