Min Wu1, Junlan Zhou2, Min Cheng3, Chan Boriboun2, Dauren Biyashev2, Hong Wang2, Alexander Mackie2, Tina Thorne2, Jonathan Chou2, Yiping Wu4, Zhishui Chen5, Qinghua Liu6, Hongbin Yan7, Ya Yang8, Chunfa Jie9, Yao-Liang Tang10, Ting C Zhao11, Robert N Taylor12, Raj Kishore13, Douglas W Losordo2, Gangjian Qin14. 1. 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. 2. 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. 3. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. 4. Department of Plastic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. 5. Organ Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. 6. 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. 7. Cardiology Department, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 8. Department of Echocardiography, Beijing Anzhen Hospital, Capital Medical University and Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, China. 9. Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 10. Department of Medicine, Vascular Biology Center, Medical College of Georgia/Georgia Regents University, Augusta, GA, USA. 11. Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, RI, USA. 12. Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. 13. Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA. 14. 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.
Abstract
AIMS: 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. METHODS AND 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. CONCLUSION: E2F1 limits cardiac neovascularization and functional recovery after MI by suppressing VEGF and PlGF up-regulation through p53-dependent and -independent mechanisms, respectively. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND 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. CONCLUSION:E2F1 limits cardiac neovascularization and functional recovery after MI by suppressing VEGF and PlGF up-regulation through p53-dependent and -independent mechanisms, respectively. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: C Koumenis; R Alarcon; E Hammond; P Sutphin; W Hoffman; M Murphy; J Derr; Y Taya; S W Lowe; M Kastan; A Giaccia Journal: Mol Cell Biol Date: 2001-02 Impact factor: 4.272
Authors: R Ravi; B Mookerjee; Z M Bhujwalla; C H Sutter; D Artemov; Q Zeng; L E Dillehay; A Madan; G L Semenza; A Bedi Journal: Genes Dev Date: 2000-01-01 Impact factor: 11.361
Authors: X Long; M O Boluyt; M L Hipolito; M S Lundberg; J S Zheng; L O'Neill; C Cirielli; E G Lakatta; M T Crow Journal: J Clin Invest Date: 1997-06-01 Impact factor: 14.808
Authors: Monica Autiero; Johannes Waltenberger; Didier Communi; Andrea Kranz; Lieve Moons; Diether Lambrechts; Jens Kroll; Stephane Plaisance; Maria De Mol; Françoise Bono; Stefanie Kliche; Guido Fellbrich; Kurt Ballmer-Hofer; Domenico Maglione; Ulrike Mayr-Beyrle; Mieke Dewerchin; Saskia Dombrowski; Danica Stanimirovic; Paul Van Hummelen; Christoph Dehio; Daniel J Hicklin; Graziella Persico; Jean-Marc Herbert; David Communi; Masabumi Shibuya; Désiré Collen; Edward M Conway; Peter Carmeliet Journal: Nat Med Date: 2003-07 Impact factor: 53.440
Authors: Sujith Dassanayaka; Kenneth R Brittian; Andrea Jurkovic; Lauren A Higgins; Timothy N Audam; Bethany W Long; Linda T Harrison; Giuseppe Militello; Daniel W Riggs; Mitali G Chitre; Shizuka Uchida; Senthilkumar Muthusamy; Anna M Gumpert; Steven P Jones Journal: Basic Res Cardiol Date: 2019-05-31 Impact factor: 17.165
Authors: Jacqueline A Nichols; Maria Chiara Perego; Luis F Schütz; Amber M Hemple; Leon J Spicer Journal: J Anim Sci Date: 2019-07-02 Impact factor: 3.159
Authors: Shiyue Xu; Jun Tao; Liu Yang; Eric Zhang; Chan Boriboun; Junlan Zhou; Tianjiao Sun; Min Cheng; Kai Huang; Jiawei Shi; Nianguo Dong; Qinghua Liu; Ting C Zhao; Hongyu Qiu; Robert A Harris; Navdeep S Chandel; Douglas W Losordo; Gangjian Qin Journal: Circ Res Date: 2018-01-22 Impact factor: 17.367
Authors: Helena Ramos; Juliana Calheiros; Joana Almeida; Valentina Barcherini; Sónia Santos; Alexandra T P Carvalho; Maria M M Santos; Lucília Saraiva Journal: Int J Mol Sci Date: 2020-01-17 Impact factor: 5.923