17β-Estradiol-induced interaction of ERα with NPPA regulates gene expression in cardiomyocytes.

Abstract:

AIMS:17β-Oestradiol (E2) and its receptors (ERα and ERβ) are important regulators of physiological and pathological processes in the cardiovascular system. ER act in concert with other regulatory factors mediating oestrogenic effects. However, the underlying mechanisms modulating ER transcriptional activity are not fully elucidated. To gain better understanding of E2-induced ERα action in the human heart, we aimed to identify and functionally analyse interaction partners of ERα. METHODS AND RESULTS:Using yeast two-hybrid assays with a human heart cDNA library, we identified atrial natriuretic peptide precursor A (NPPA), a well-known cardiac hypertrophy marker, as a novel ERα interaction partner interacting in an E2-dependent manner. Mutation analyses and immunofluorescence data indicated that the LXXLL motif within NPPA is necessary for its E2-induced interaction with ERα, its action as a co-repressor of ERα, and its translocation into the nucleus of human and rat cardiomyocytes. Expression analysis and chromatin immunoprecipitation assays in a human left ventricular cardiomyocyte cell line, AC16, showed that NPPA interacts with E2/ERα, suppressing the transcriptional activity of ERα on E2-target genes, such as NPPA, connexin43, αactinin-2, nuclear factor of activated T-cells, and collagens I and III. CONCLUSION:We characterize for the first time an E2-regulated interaction of NPPA with ERα in cardiomyocytes, that may be crucial in physiological and/or pathological cardiac processes, thereby representing a potential therapeutic target.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Mahmoodzadeh S,Pham TH,Kuehne A,Fielitz B,Dworatzek E,Kararigas G,Petrov G,Davidson MM,Regitz-Zagrosek V

doi

10.1093/cvr/cvs281

subject

Has Abstract

pub_date

2012-12-01 00:00:00

pages

411-21

issue

3

eissn

0008-6363

issn

1755-3245

pii

cvs281

journal_volume

96

pub_type

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