title: Endothelial deletion of protein tyrosine phosphatase-1B protects against pressure overload-induced heart failure in mice.
abstract: Cardiac angiogenesis is an important determinant of heart failure. We examined the hypothesis that protein tyrosine phosphatase (PTP)-1B, a negative regulator of vascular endothelial growth factor (VEGF) receptor-2 activation, is causally involved in the cardiac microvasculature rarefaction during hypertrophy and that deletion of PTP1B in endothelial cells prevents the development of heart failure.
  
  
  
  Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in mice with endothelial-specific deletion of PTP1B (End.PTP1B-KO) and controls (End.PTP1B-WT). Survival up to 20 weeks after TAC was significantly improved in mice lacking endothelial PTP1B. Serial echocardiography revealed a better systolic pump function, less pronounced cardiac hypertrophy, and left ventricular dilation compared with End.PTP1B-WT controls. Histologically, banded hearts from End.PTP1B-KO mice exhibited increased numbers of PCNA-positive, proliferating endothelial cells resulting in preserved cardiac capillary density and improved perfusion as well as reduced hypoxia, apoptotic cell death, and fibrosis. Increased relative VEGFR2 and ERK1/2 phosphorylation and greater eNOS expression were present in the hearts of End.PTP1B-KO mice. The absence of PTP1B in endothelial cells also promoted neovascularization following peripheral ischaemia, and bone marrow transplantation excluded a major contribution of Tie2-positive haematopoietic cells to the improved angiogenesis in End.PTP1B-KO mice. Increased expression of caveolin-1 as well as reduced NADPH oxidase-4 expression, ROS generation and TGFβ signalling were observed and may have mediated the cardioprotective effects of endothelial PTP1B deletion.
  
  
  
  Endothelial PTP1B deletion improves cardiac VEGF signalling and angiogenesis and protects against chronic afterload-induced heart failure. PTP1B may represent a useful target to preserve cardiac function during hypertrophy.
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Rajinikanth
authors.initials: R
authors.lastname: Gogiraju
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Marco R
authors.initials: MR
authors.lastname: Schroeter
authors.affiliation: Center for Cardiology, Department of Cardiology I, University Medical Center Mainz, Mainz, Germany Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.
authors.forename: Magdalena L
authors.initials: ML
authors.lastname: Bochenek
authors.affiliation: Center for Cardiology, Department of Cardiology I, University Medical Center Mainz, Mainz, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Hubert
authors.affiliation: Center for Cardiology, Department of Cardiology I, University Medical Center Mainz, Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany Center for Cardiology, Department of Cardiology I, University Medical Center Mainz, Mainz, Germany katrin.schaefer@unimedizin-mainz.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schäfer
mesh_terms: D000818:Animals; D001011:Aorta / Q000503:physiopathology / Q000601:surgery; D017209:Apoptosis; D062186:Arterial Pressure; D051242:Caveolin 1 / Q000378:metabolism; D003250:Constriction; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D006614:Hindlimb; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D007511:Ischemia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency* / Q000235:genetics; D042787:Receptor, TIE-2 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C000592875:Kdr protein, mouse; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
keywords: Angiogenesis; Fibrosis; Heart failure; Hypertrophy; PTP1B