title: Hemopexin therapy improves cardiovascular function by preventing heme-induced endothelial toxicity in mouse models of hemolytic diseases.
abstract: BACKGROUND
  Hemolytic diseases are characterized by enhanced intravascular hemolysis resulting in heme-catalyzed reactive oxygen species generation, which leads to endothelial dysfunction and oxidative damage. Hemopexin (Hx) is a plasma heme scavenger able to prevent endothelial damage and tissue congestion in a model of heme overload. Here, we tested whether Hx could be used as a therapeutic tool to counteract heme toxic effects on the cardiovascular system in hemolytic diseases.
  
  
  RESULTS
  By using a model of heme overload in Hx-null mice, we demonstrated that heme excess in plasma, if not bound to Hx, promoted the production of reactive oxygen species and the induction of adhesion molecules and caused the reduction of nitric oxide availability. Then, we used β-thalassemia and sickle cell disease mice as models of hemolytic diseases to evaluate the efficacy of an Hx-based therapy in the treatment of vascular dysfunction related to heme overload. Our data demonstrated that Hx prevented heme-iron loading in the cardiovascular system, thus limiting the production of reactive oxygen species, the induction of adhesion molecules, and the oxidative inactivation of nitric oxide synthase/nitric oxide, and promoted heme recovery and detoxification by the liver mainly through the induction of heme oxygenase activity. Moreover, we showed that in sickle cell disease mice, endothelial activation and oxidation were associated with increased blood pressure and altered cardiac function, and the administration of exogenous Hx was found to almost completely normalize these parameters.
  
  
  CONCLUSIONS
  Hemopexin treatment is a promising novel therapy to protect against heme-induced cardiovascular dysfunction in hemolytic disorders.
authors: Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors: Francesca
authors: F
authors: Vinchi
authors: Lucia
authors: L
authors: De Franceschi
authors: Alessandra
authors: A
authors: Ghigo
authors: Tim
authors: T
authors: Townes
authors: James
authors: J
authors: Cimino
authors: Lorenzo
authors: L
authors: Silengo
authors: Emilio
authors: E
authors: Hirsch
authors: Fiorella
authors: F
authors: Altruda
authors: Emanuela
authors: E
authors: Tolosano
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006418:Heme / Q000009:adverse effects* / Q000378:metabolism; D006466:Hemopexin / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009569:Nitric Oxide / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016896:Treatment Outcome; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D006418:Heme; D006466:Hemopexin