Small heterodimer partner blocks cardiac hypertrophy by interfering with GATA6 signaling

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Title
Small heterodimer partner blocks cardiac hypertrophy by interfering with GATA6 signaling
Author(s)
Y S Nam; Y Kim; H Joung; D H Kwon; N Choe; H K Min; Y S Kim; H S Kim; D K Kim; Y K Cho; Yong-Hoon Kim; K I Nam; H C Choi; D H Park; K Suk; I K Lee; Y Ahn; Chul Ho Lee; H S Choi; G H Eom; H Kook
Bibliographic Citation
Circulation Research, vol. 115, no. 5, pp. 493-503
Publication Year
2014
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.
Keyword
GATA6 transcription factorhypertrophymetforminnuclear receptor subfamily 0, group B, member 2orphan nuclear receptors
ISSN
0009-7330
Publisher
Kluwer
DOI
http://dx.doi.org/10.1161/CIRCRESAHA.115.304388
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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