title: Targeted detoxification of selected reactive oxygen species in the vascular endothelium.
abstract: Oxidative stress underlies diverse vascular diseases, but its management remains elusive, in part because of our inability to selectively detoxify reactive oxygen species (ROS) in pathological sites and our limited understanding which species need to be eliminated. The antioxidant enzymes (AOEs) superoxide dismutase (SOD) and catalase (which decompose and H(2)O(2), respectively), conjugated with an antibody to platelet-endothelial cell adhesion molecule-1 (PECAM-1), bind to endothelial cells and alleviate oxidative stress in cell culture models. Here, we studied the effects of these antioxidant conjugates in mouse models of vascular oxidative stress. Anti-PECAM/catalase and anti-PECAM/SOD conjugates, in contrast to control IgG/AOE conjugates, accumulated in the lungs and vascularized organs after intravenous injection in wild-type, but not PECAM KO mice. Anti-PECAM/catalase, but not anti-PECAM/SOD, protected mice from lung injury induced by H(2)O(2) produced by glucose oxidase deposited in the pulmonary vasculature. Anti-PECAM/catalase also reduced alveolar edema and attenuated decline in arterial oxygen in mice that underwent unilateral lung ischemia/reperfusion, whereas anti-PECAM/SOD was not effective, implying the key role of H(2)O(2) in tissue damage in this pathology. In contrast, anti-PECAM/SOD, but not anti-PECAM/catalase prevented oxidation of tetrahydrobiopterin and normalized vasoreactivity in the vessels of mice rendered hypertensive by pretreatment with angiotensin-II. This outcome agrees with reports implicating superoxide and peroxynitrite in altered endothelium-dependent vasodilatation in hypertension. Therefore, the use of endothelial cell-targeted antioxidants identifies the key specific species of ROS involved in various forms of vascular disease and holds promise for the mechanistically tailored treatment of these pathologies.
authors.affiliation: Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6068, USA.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Shuvaev
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
authors.forename: Faiz
authors.initials: F
authors.lastname: Bhora
authors.forename: Karine
authors.initials: K
authors.lastname: Laude
authors.forename: Hua
authors.initials: H
authors.lastname: Cai
authors.forename: Sergei
authors.initials: S
authors.lastname: Dikalov
authors.forename: Evguenia
authors.initials: E
authors.lastname: Arguiri
authors.forename: Charalambos C
authors.initials: CC
authors.lastname: Solomides
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001708:Biopterins / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002374:Catalase / Q000008:administration & dosage / Q000494:pharmacology*; D003432:Cross-Linking Reagents; D004730:Endothelium, Vascular / Q000378:metabolism*; D005949:Glucose Oxidase / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D011652:Pulmonary Circulation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000633:toxicity*; D015427:Reperfusion Injury / Q000517:prevention & control; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
chemical_list: D000906:Antibodies; D000975:Antioxidants; D003432:Cross-Linking Reagents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017382:Reactive Oxygen Species; D013481:Superoxides; D000804:Angiotensin II; D001708:Biopterins; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D002374:Catalase; D013482:Superoxide Dismutase
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