Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling
Austin Hsu, … , Benoit G. Bruneau, Saptarsi M. Haldar
Austin Hsu, … , Benoit G. Bruneau, Saptarsi M. Haldar
Published February 27, 2020
Citation Information: J Clin Invest. 2020;130(6):2966-2977. https://doi.org/10.1172/JCI133753.
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Research Article Cardiology Muscle biology

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 A.B. Wood, Nathanael S. Gray, Biao Wang, Benoit G. Bruneau, Saptarsi M. Haldar

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Figure 6

HDAC7 indirectly regulates c-Myc expression.

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HDAC7 indirectly regulates c-Myc expression. qRT-PCR (n = 6) and Western...
qRT-PCR (n = 6) and Western blotting (n = 4) for c-Myc expression in NRVMs treated with siRNA against Hdac7 (A and B), Ad-HDAC7 (C and D), or YKL-05-099 (1 μM) (E and F). All box plots show minimum, maximum, and median with 25th to 75th percentile range. (G) Western blotting of cytoplasmic (C) and nuclear (N) fractions of NRVMs treated with 1 μM YKL-05-099 plus 100 μM PE. TATA box–binding protein (TBP) and GAPDH were used as nuclear and cytoplasmic markers, respectively (representative Western blots, n = 3). (H) NRVMs treated with adenovirus harboring GFP-HDAC7 or GFP alone, followed by transfection of siRNA probes against c-Myc or scramble control. Immunostained for α-actinin (red) and nuclei (blue). Scale bars: 40 μm. (I) Cell area of NRVMs (n = 100). Bars denote mean ± SD. (J) qRT-PCR expression for Nppa and Nppb (n = 6). Data are shown as means ± SEM unless noted. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, by 1-way ANOVA with Tukey’s multiple comparisons test.