title: E2F1 suppresses cardiac neovascularization by down-regulating VEGF and PlGF expression.
abstract: OBJECTIVE
  The E2F transcription factors are best characterized for their roles in cell-cycle regulation, cell growth, and cell death. Here we investigated the potential role of E2F1 in cardiac neovascularization.
  
  
  RESULTS
  We induced myocardial infarction (MI) by ligating the left anterior descending artery in wild-type (WT) and E2F1(-/-) mice. E2F1(-/-) mice demonstrated a significantly better cardiac function and smaller infarct sizes than WT mice. At infarct border zone, capillary density and endothelial cell (EC) proliferation were greater, apoptotic ECs were fewer, levels of VEGF and placental growth factor (PlGF) were higher, and p53 level was lower in E2F1(-/-) than in WT mice. Blockade of VEGF receptor 2 (VEGFR2) signalling with the selective inhibitor SU5416 or with the VEGFR2-blocking antibody DC101 abolished the differences between E2F1(-/-) mice and WT mice in cardiac function, infarct size, capillary density, EC proliferation, and EC apoptosis. In vitro, hypoxia-induced VEGF and PlGF up-regulation was significantly greater in E2F1(-/-) than in WT cardiac fibroblasts, and E2F1 overexpression suppressed PlGF up-regulation in both WT and p53(-/-) cells; however, VEGF up-regulation was suppressed only in WT cells. E2F1 interacted with and stabilized p53 under hypoxic conditions, and both E2F1 : p53 binding and the E2F1-induced suppression of VEGF promoter activity were absent in cells that expressed an N-terminally truncated E2F1 mutant.
  
  
  CONCLUSIONS
  E2F1 limits cardiac neovascularization and functional recovery after MI by suppressing VEGF and PlGF up-regulation through p53-dependent and -independent mechanisms, respectively.
authors.affiliation: Department of Plastic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Tarry 14-721, Chicago, IL 60611, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Tarry 14-721, Chicago, IL 60611, USA.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Tarry 14-721, Chicago, IL 60611, USA.
authors.forename: Chan
authors.initials: C
authors.lastname: Boriboun
authors.affiliation: Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Tarry 14-721, Chicago, IL 60611, USA.
authors.forename: Dauren
authors.initials: D
authors.lastname: Biyashev
authors.affiliation: Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Tarry 14-721, Chicago, IL 60611, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Tarry 14-721, Chicago, IL 60611, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mackie
authors.affiliation: Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Tarry 14-721, Chicago, IL 60611, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.affiliation: Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Tarry 14-721, Chicago, IL 60611, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chou
authors.affiliation: Department of Plastic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Organ Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Zhishui
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Cardiology Department, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Echocardiography, Beijing Anzhen Hospital, Capital Medical University and Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Chunfa
authors.initials: C
authors.lastname: Jie
authors.affiliation: Department of Medicine, Vascular Biology Center, Medical College of Georgia/Georgia Regents University, Augusta, GA, USA.
authors.forename: Yao-Liang
authors.initials: YL
authors.lastname: Tang
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, RI, USA.
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Taylor
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.affiliation: Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Tarry 14-721, Chicago, IL 60611, USA.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.affiliation: Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Tarry 14-721, Chicago, IL 60611, USA g-qin@northwestern.edu.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020127:Recovery of Function; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000072483:Placenta Growth Factor; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D046988:Proteasome Endopeptidase Complex
keywords: E2F1; Heart; PlGF; VEGF; p53