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

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.

• Authors: Junlan Zhou, Yan Zhu, Min Cheng, Deepika Dinesh, Tina Thorne, Kian Keong Poh, Dongxu Liu, Chantal Botros, Yao Liang Tang, Nichole Reisdorph, Raj Kishore, Douglas W Losordo, Gangjian Qin
• Journal: Circulation (Circulation) Vol. 120 Issue 13 Pg. 1213-21 (Sep 29 2009) ISSN: 1524-4539 [Electronic] United States
• PMID: 19752322 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• E2F2 Transcription Factor
• E2f2 protein, mouse
• Endothelin-1
• Khdrbs1 protein, mouse
• RNA-Binding Proteins
• Aspartic Acid Endopeptidases
• Metalloendopeptidases
• Ece1 protein, mouse
• Endothelin-Converting Enzymes

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Aorta (physiology)
• Aspartic Acid Endopeptidases (genetics, metabolism)
• Blood Pressure (physiology)
• Cell Cycle (physiology)
• Cell Membrane (metabolism)
• Down-Regulation (physiology)
• E2F2 Transcription Factor (genetics, metabolism)
• Endothelin-1 (pharmacology)
• Endothelin-Converting Enzymes
• Female
• Male
• Metalloendopeptidases (genetics, metabolism)
• Mice
• Mice, Mutant Strains
• Promoter Regions, Genetic (physiology)
• RNA-Binding Proteins (metabolism)
• Transcriptional Activation (physiology)
• Vasoconstriction (drug effects, physiology)