Mef2
激酶
组蛋白脱乙酰基酶
生物
细胞生物学
心力衰竭
发病机制
癌症研究
信号转导
心功能曲线
组蛋白
医学
内科学
免疫学
基因表达
遗传学
基因
增强子
作者
Austin Hsu,Qiming Duan,Sarah McMahon,Yu Huang,Sarah A.B. Wood,Nathanael S. Gray,Biao Wang,Benoit G. Bruneau,Saptarsi M. Haldar
摘要
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.
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