title: Selective Vascular Endothelial Protection Reduces Cardiac Dysfunction in Chronic Heart Failure.
abstract: BACKGROUND
  Chronic heart failure (CHF) induces endothelial dysfunction in part because of decreased nitric oxide (NO(·)) production, but the direct link between endothelial dysfunction and aggravation of CHF is not directly established. We previously reported that increased NO production via inhibition of protein tyrosine phosphatase 1B (PTP1B) is associated with reduced cardiac dysfunction in CHF. Investigation of the role of endothelial PTP1B in these effects may provide direct evidence of the link between endothelial dysfunction and CHF.
  
  
  RESULTS
  Endothelial deletion of PTP1B was obtained by crossing LoxP-PTP1B with Tie2-Cre mice. CHF was assessed 4 months after myocardial infarction. In some experiments, to exclude gene extinction in hematopoietic cells, Tie2-Cre/LoxP-PTP1B mice were lethally irradiated and reconstituted with bone marrow from wild-type mice, to obtain mouse with endothelial-specific deletion of PTP1B. Vascular function evaluated ex vivo in mesenteric arteries showed that in wild-type mice, CHF markedly impaired NO-dependent flow-mediated dilatation. CHF-induced endothelial dysfunction was less marked in endoPTP1B(-/-) mice, suggesting restored NO production. Echocardiographic, hemodynamic, and histological evaluations demonstrated that the selectively improved endothelial function was associated with reduced left ventricular dysfunction and remodeling, as well as increased survival, in the absence of signs of stimulated angiogenesis or increased cardiac perfusion.
  
  
  CONCLUSIONS
  Prevention of endothelial dysfunction, by endothelial PTP1B deficiency, is sufficient to reduce cardiac dysfunction post myocardial infarction. Our results provide for the first time a direct demonstration that endothelial protection per se reduces CHF and further suggest a causal role for endothelial dysfunction in CHF development.
authors.affiliation: From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Department of Pharmacology, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., O.B., L.N., P.M., J.M., V.R.); Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., L.N., P.M., V.R.); and Inserm (Institut National de la Santé et de la Recherche Médicale) U905, Department of Immunology, Rouen, France (O.B., J.M.).
authors.forename: Julie
authors.initials: J
authors.lastname: Maupoint
authors.affiliation: From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Department of Pharmacology, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., O.B., L.N., P.M., J.M., V.R.); Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., L.N., P.M., V.R.); and Inserm (Institut National de la Santé et de la Recherche Médicale) U905, Department of Immunology, Rouen, France (O.B., J.M.).
authors.forename: Marie
authors.initials: M
authors.lastname: Besnier
authors.affiliation: From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Department of Pharmacology, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., O.B., L.N., P.M., J.M., V.R.); Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., L.N., P.M., V.R.); and Inserm (Institut National de la Santé et de la Recherche Médicale) U905, Department of Immunology, Rouen, France (O.B., J.M.).
authors.forename: Elodie
authors.initials: E
authors.lastname: Gomez
authors.affiliation: From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Department of Pharmacology, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., O.B., L.N., P.M., J.M., V.R.); Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., L.N., P.M., V.R.); and Inserm (Institut National de la Santé et de la Recherche Médicale) U905, Department of Immunology, Rouen, France (O.B., J.M.).
authors.forename: Najime
authors.initials: N
authors.lastname: Bouhzam
authors.affiliation: From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Department of Pharmacology, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., O.B., L.N., P.M., J.M., V.R.); Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., L.N., P.M., V.R.); and Inserm (Institut National de la Santé et de la Recherche Médicale) U905, Department of Immunology, Rouen, France (O.B., J.M.).
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Henry
authors.affiliation: From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Department of Pharmacology, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., O.B., L.N., P.M., J.M., V.R.); Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., L.N., P.M., V.R.); and Inserm (Institut National de la Santé et de la Recherche Médicale) U905, Department of Immunology, Rouen, France (O.B., J.M.).
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
authors.affiliation: From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Department of Pharmacology, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., O.B., L.N., P.M., J.M., V.R.); Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., L.N., P.M., V.R.); and Inserm (Institut National de la Santé et de la Recherche Médicale) U905, Department of Immunology, Rouen, France (O.B., J.M.).
authors.forename: Lionel
authors.initials: L
authors.lastname: Nicol
authors.affiliation: From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Department of Pharmacology, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., O.B., L.N., P.M., J.M., V.R.); Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., L.N., P.M., V.R.); and Inserm (Institut National de la Santé et de la Recherche Médicale) U905, Department of Immunology, Rouen, France (O.B., J.M.).
authors.forename: Paul
authors.initials: P
authors.lastname: Mulder
authors.affiliation: From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Department of Pharmacology, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., O.B., L.N., P.M., J.M., V.R.); Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., L.N., P.M., V.R.); and Inserm (Institut National de la Santé et de la Recherche Médicale) U905, Department of Immunology, Rouen, France (O.B., J.M.).
authors.forename: Jérémie
authors.initials: J
authors.lastname: Martinet
authors.affiliation: From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Department of Pharmacology, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., O.B., L.N., P.M., J.M., V.R.); Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., L.N., P.M., V.R.); and Inserm (Institut National de la Santé et de la Recherche Médicale) U905, Department of Immunology, Rouen, France (O.B., J.M.). vincent.richard@univ-rouen.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002908:Chronic Disease; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000503:physiopathology; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D008638:Mesenteric Arteries / Q000201:enzymology* / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014664:Vasodilation; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D009569:Nitric Oxide; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
keywords: bone marrow; endothelium; heart failure; myocardial infarction; nitric oxide