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Circulation. 2009 Sep 29;120(13):1213-21. doi: 10.1161/CIRCULATIONAHA.109.859207. Epub 2009 Sep 14.

Regulation of vascular contractility and blood pressure by the E2F2 transcription factor.

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  • 1Assistant Professor, Feinberg Cardiovascular Research Institute, Northwestern University, 303 E Chicago Ave, Tarry 14-751, Chicago, IL 60611, USA.

Abstract

BACKGROUND:

Recent studies have identified a polymorphism in the endothelin-converting enzyme (ECE)-1b promoter (-338C/A) that is strongly associated with hypertension in women. The polymorphism is located in a consensus binding sequence for the E2F family of transcription factors. E2F proteins are crucially involved in cell-cycle regulation, but their roles in cardiovascular function are poorly understood. Here, we investigated the potential role of E2F2 in blood pressure regulation.

METHODS AND RESULTS:

Tail-cuff measurements of systolic and diastolic blood pressures were significantly higher in E2F2-null (E2F2(-/-)) mice than in their wild-type littermates, and in ex vivo ring assays, aortas from the E2F2(-/-) mice exhibited significantly greater contractility in response to big endothelin-1. Big endothelin-1 is activated by ECE-1, and mRNA levels of ECE-1b, the repressive ECE-1 isoform, were significantly lower in E2F2(-/-) mice than in wild-type mice. In endothelial cells, chromatin immunoprecipitation assays confirmed that E2F2 binds the ECE-1b promoter, and promoter-reporter assays indicated that E2F2 activates ECE-1b transcription. Furthermore, loss or downregulation of E2F2 led to a decline in ECE-1b levels, to higher levels of the membranous ECE-1 isoforms (ie, ECE-1a, -1c, and -1d), and to deregulated ECE-1 activity. Finally, Sam68 coimmunoprecipitated with E2F2, occupied the ECE-1b promoter (chromatin immunoprecipitation), and repressed E2F2-mediated ECE-1b promoter activity (promoter-reporter assays).

CONCLUSIONS:

Our results identify a cell-cycle-independent mechanism by which E2F2 regulates endothelial function, arterial contractility, and blood pressure.

PMID:
19752322
[PubMed - indexed for MEDLINE]
PMCID:
PMC2785027
Free PMC Article

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