Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering With GATA6 Signaling

Title
Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering With GATA6 Signaling
Author(s)
최형철남윤석[남윤석]김윤정[김윤정]정호석[정호석]권덕화[권덕화]최낙원[최낙원]민현기[민현기]김영숙[김영숙]김형석[김형석]김돈규[김돈규]조영국[조영국]김용훈[김용훈]남광일[남광일]박동호[박동호]석경호[석경호]이인규[이인규]안영근[안영근]이철호[이철호]최흥식[최흥식]엄광현[엄광현]국현[국현]
Keywords
ACTIVATED PROTEIN-KINASE; NUCLEAR RECEPTOR SHP; SERUM RESPONSE FACTOR; HISTONE DEACETYLASE 2; GENE-EXPRESSION; TRANSCRIPTIONAL ACTIVITY; AMPK ACTIVATION; HEART; TRANSACTIVATION; METFORMIN
Issue Date
201408
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Citation
CIRCULATION RESEARCH, v.115, no.5, pp.493 - +
Abstract
Rationale: Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA-binding domain. Through interactions with other transcription factors, SHP regulates diverse biological events, including glucose metabolism in liver. However, the role of SHP in adult heart diseases has not yet been demonstrated. Objective: We aimed to investigate the role of SHP in adult heart in association with cardiac hypertrophy. Methods and Results: The roles of SHP in cardiac hypertrophy were tested in primary cultured cardiomyocytes and in animal models. SHP-null mice showed a hypertrophic phenotype. Hypertrophic stresses repressed the expression of SHP, whereas forced expression of SHP blocked the development of hypertrophy in cardiomyocytes. SHP reduced the protein amount of Gata6 and, by direct physical interaction with Gata6, interfered with the binding of Gata6 to GATA-binding elements in the promoter regions of natriuretic peptide precursor type A. Metformin, an antidiabetic agent, induced SHP and suppressed cardiac hypertrophy. The metformin-induced antihypertrophic effect was attenuated either by SHP small interfering RNA in cardiomyocytes or in SHP-null mice. Conclusions: These results establish SHP as a novel antihypertrophic regulator that acts by interfering with GATA6 signaling. SHP may participate in the metformin-induced antihypertrophic response.
URI
http://hdl.handle.net/YU.REPOSITORY/31200http://dx.doi.org/10.1161/CIRCRESAHA.115.304388
ISSN
0009-7330
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의과대학 > 약리학교실 > Articles
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