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(Circulation. 2009;120:1213-1221.)
© 2009 American Heart Association, Inc.

Hypertension

Regulation of Vascular Contractility and Blood Pressure by the E2F2 Transcription Factor

Junlan Zhou, MD, PhD^*; Yan Zhu, PhD^*; Min Cheng, MD; Deepika Dinesh, MS; Tina Thorne, MS; Kian Keong Poh, MD; Dongxu Liu, MD, PhD; Chantal Botros, BS; Yao Liang Tang, MD, PhD; Nichole Reisdorph, PhD; Raj Kishore, PhD; Douglas W. Losordo, MD; Gangjian Qin, MD

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.).

Correspondence to Gangjian Qin, MD, Assistant Professor, Feinberg Cardiovascular Research Institute, Northwestern University, 303 E Chicago Ave, Tarry 14–751, Chicago, IL 60611. E-mail g-qin{at}northwestern.edu

Received February 20, 2009; accepted July 17, 2009.

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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 120: 1165-1167. [Extract] [Full Text]