title: Erythrocyte hemolysis and hemoglobin oxidation promote ferric chloride-induced vascular injury.
abstract: The release of redox-active iron and heme into the blood-stream is toxic to the vasculature, contributing to the development of vascular diseases. How iron induces endothelial injury remains ill defined. To investigate this, we developed a novel ex vivo perfusion chamber that enables direct analysis of the effects of FeCl(3) on the vasculature. We demonstrate that FeCl(3) treatment of isolated mouse aorta, perfused with whole blood, was associated with endothelial denudation, collagen exposure, and occlusive thrombus formation. Strikingly exposing vessels to FeCl(3) alone, in the absence of perfused blood, was associated with only minor vascular injury. Whole blood fractionation studies revealed that FeCl(3)-induced vascular injury was red blood cell (erythrocyte)-dependent, requiring erythrocyte hemolysis and hemoglobin oxidation for endothelial denudation. Overall these studies define a unique mechanism of Fe(3+)-induced vascular injury that has implications for the understanding of FeCl(3)-dependent models of thrombosis and vascular dysfunction associated with severe intravascular hemolysis.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Woollard
authors.forename: Sharelle
authors.initials: S
authors.lastname: Sturgeon
authors.forename: Jaye P F
authors.initials: JP
authors.lastname: Chin-Dusting
authors.forename: Hatem H
authors.initials: HH
authors.lastname: Salem
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects*; D005260:Female; D005290:Ferric Compounds / Q000633:toxicity*; D005343:Fibrinolytic Agents / Q000633:toxicity; D005455:Fluorescent Antibody Technique; D006454:Hemoglobins / Q000378:metabolism*; D006461:Hemolysis / Q000187:drug effects*; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009676:Noxae / Q000633:toxicity*; D010084:Oxidation-Reduction; D013927:Thrombosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D005343:Fibrinolytic Agents; D006454:Hemoglobins; D009676:Noxae; C024555:ferric chloride