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 4

HDAC7 protein stability is dependent on SIK1 kinase activity.

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HDAC7 protein stability is dependent on SIK1 kinase activity. (A) Wester...
(A) Western blot for total and phosphorylated HDAC4, HDAC5, and HDAC7 in NRVMs treated with or without siRNA against Sik1 and with or without PE (100 μM, 24 hours). α-Tubulin was used as loading control (n = 5). (B) qRT-PCR expression for Hdac7 (n = 6). Bars denote mean ± SEM. (C and D) Western blot for total and phosphorylated HDAC4, HDAC5, and HDAC7 in NRVMs treated with or without HG-9-91-01 (1 μM) or YKL-05-099 (1 μM). α-Tubulin was used as loading control (n = 4). (E) Western blot for total and phosphorylated HDAC7 in WT and SIK1-KO sham/TAC LV cardiac tissue. Vinculin was used as loading control (n = 4). (F) In vitro kinase assay with recombinant HDAC7 and GST-tagged SIK1 plus YKL-05-099 (1 μM). SIK1 consensus sequence is shown below (representative Western blots, n = 3). (G) Western blot from NRVMs treated with YKL-05-099 (1 μM) and the proteasome inhibitor bortezomib (BZ) (5 nM, 16 hours) (representative Western blots, n = 3). All box plots show minimum, maximum, and median with 25th to 75th percentile range. ***P < 0.001, ****P < 0.0001, by 1-way ANOVA with Tukey’s multiple comparisons test.