on September 14, 2009
Published online before print September 14, 2009, doi: 10.1161/CIRCULATIONAHA.109.859207
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Submitted on February 20, 2009
From the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Ill (J.Z., M.C., T.T., C.B., R.K., D.W.L., G.Q.); Molecular Cardiology Research Institute, Tufts University School of Medicine, Tufts Medical Center, Boston, Mass (Y.Z.); Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass (D.D., K.K.P.); Center for Infection and Immunity Research, School of Life Sciences, Hubei University, Wuhan, Hubei, P.R. China (D.L.); Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio (Y.L.T.); and Proteomics Facility, National Jewish Medical and Research Center, Denver, Colo (N.R.). * To whom correspondence should be addressed. E-mail: g-qin{at}northwestern.edu.
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). Conclusion—Our results identify a cell-cycle–independent mechanism by which E2F2 regulates endothelial function, arterial contractility, and blood pressure.
Accepted on July 17, 2009
Regulation of Vascular Contractility and Blood Pressure by the E2F2 Transcription Factor
Junlan Zhou MD, PhD,
Key words: blood pressure • endothelin • endothelium • E2F transcription factors • Sam68 protein, mouse
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