title: Assessment of endothelial damage and cardiac injury in a mouse model mimicking thrombotic thrombocytopenic purpura.
abstract: Essentials Endothelial injury is thought to be a key event in thrombotic thrombocytopenic purpura (TTP). Endothelial and cardiac damages were assessed in a model of TTP using ADAMTS-13 knockout mice. Damages of cardiac perfusion and function were associated with nitric oxide pathway alteration. Endothelial dysfunction constitutes a critical event in TTP development and cardiac injury.
  
  
  
  Background Cardiac alterations represent a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). Endothelial injury remains poorly defined, but seems to be a key initiating event leading to the formation of platelet-rich thrombi in TTP patients. Objectives To assess the changes in endothelial function and the induced cardiac damage in a mouse model of TTP. Patients/methods We used an animal model in which TTP-like symptoms are triggered by injection of 2000 units kg-1of recombinant von Willebrand factor in ADAMTS-13 knockout mice. Results These mice developed TTP-like symptoms, i.e. severe thrombocytopenia, schistocytosis, and anemia. On day 2, magnetic resonance imaging demonstrated a decrease in left ventricular perfusion associated with alteration of left ventricular ejection fraction, fractional shortening, and cardiac output, suggesting early systolic dysfunction. This was associated with decrease in endothelium-mediated relaxation responses to acetylcholine in mesenteric and coronary arteries, demonstrating severe early endothelial dysfunction. In parallel, we showed decreased cardiac expression of endothelial nitric oxide (NO) synthase and increased expression of antioxidant enzymes, suggesting alteration of the NO pathway. At this time, cardiac immunohistochemistry revealed an increase in the expression of VCAM-1 and E-selectin. Conclusion This study provides evidence that the heart is a sensitive target organ in TTP, and shows, for the first time, strong mesenteric and coronary endothelial dysfunction in an induced-TTP model. The mechanisms incriminated are the occurrence of a pro-oxidant state, and proadhesive and proinflammatory phenotypes. This previously largely unrecognized vascular dysfunction may represent an important contributor to the systemic organ failure occurring in TTP.
authors: Service de Médecine Interne, CHU Charles Nicolle, Rouen, France.|INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France.|Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, AP-HP, Paris, France.
authors: M
authors: M
authors: Le Besnerais
authors: INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France.
authors: J
authors: J
authors: Favre
authors: INSERM UMR S 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
authors: C V
authors: CV
authors: Denis
authors: INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France.
authors: P
authors: P
authors: Mulder
authors: INSERM U905, UFR médecine pharmacie Rouen, Rouen, France.
authors: J
authors: J
authors: Martinet
authors: INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France.
authors: L
authors: L
authors: Nicol
authors: Service de Médecine Interne, CHU Charles Nicolle, Rouen, France.|INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France.
authors: H
authors: H
authors: Levesque
authors: Service d'hématologie biologique, Hôpital Lariboisière, AP-HP, Paris, France.|EA3518, IUH Saint Louis, Université Paris-Diderot, Paris, France.
authors: A
authors: A
authors: Veyradier
authors: Baxalta Innovations GmbH, Vienna, Austria.
authors: A
authors: A
authors: Kopić
authors: Bloodworks Northwest Research Institute, Seattle, WA, USA.
authors: D G
authors: DG
authors: Motto
authors: Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, AP-HP, Paris, France.|Service d'Hématologie, Hôpital Saint-Antoine, AP-HP, Paris, France.|Institut Gustave Roussy, INSERM U1170, Villejuif, France.
authors: P
authors: P
authors: Coppo
authors: INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France.
authors: V
authors: V
authors: Richard
authors: Service de Médecine Interne, CHU Charles Nicolle, Rouen, France. ygal.benhamou@chu-rouen.fr.|INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France. ygal.benhamou@chu-rouen.fr.|Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, AP-HP, Paris, France. ygal.benhamou@chu-rouen.fr.
authors: Y
authors: Y
authors: Benhamou
mesh_terms: D000071120:ADAMTS13 Protein / Q000235:genetics*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology*; D005260:Female; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000737:chemistry; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D010477:Perfusion; D010641:Phenotype; D011697:Purpura, Thrombotic Thrombocytopenic / Q000175:diagnosis* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013927:Thrombosis / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D016277:Ventricular Function, Left; D014841:von Willebrand Factor / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D019040:E-Selectin; D016877:Oxidants; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D014841:von Willebrand Factor; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C502939:ADAMTS13 protein, mouse; D000071120:ADAMTS13 Protein
keywords: ADAMTS-13 protein; endothelium; myocardial ischemia; oxidative stress; thrombotic thrombocytopenic purpura