title: Platelet-endothelial cell adhesion molecule-1-directed endothelial targeting of superoxide dismutase alleviates oxidative stress caused by either extracellular or intracellular superoxide.
abstract: Targeting of the antioxidant enzyme catalase to endothelial cells protects against vascular oxidative stress induced by hydrogen peroxide (H(2)O(2))(Am J Physiol 285:L283-L292, 2003; Nat Biotechnol 21:392-398, 2003; Am J Physiol 293:L162-L169, 2007). However, another reactive oxygen species, superoxide anion, is also involved in many forms of vascular oxidative stress, including ischemia/reperfusion, hypertension, and inflammation. To protect endothelium against superoxide attack, we designed and tested antibody-directed targeting of superoxide dismutase (SOD) to the endothelial surface determinant, platelet-endothelial cell adhesion molecule (PECAM)-1. We synthesized anti-PECAM/SOD conjugates that retained 70% of enzymatic activity (superoxide anion dismutation) and specifically bound to endothelial cells, but not PECAM-negative cells. The effect of anti-PECAM/SOD delivery to cells was tested in two distinct models of oxidative stress induced by either extracellular or intracellular generation of superoxide anion. In the first model, anti-PECAM/SOD, but not unconjugated SOD, protected endothelial cells against injury caused by superoxide produced in the medium by hypoxanthine-xanthine oxidase. At the optimal dose, anti-PECAM/SOD provided up to 40 to 50% protection against cell death in this model. In the second model, anti-PECAM/SOD at the optimal dose provided complete protection against necrosis caused by paraquat-induced intracellular superoxide generation. Endothelial targeting of SOD represents a new molecular antioxidant approach that could be used for the management of vascular oxidative stress.
authors: Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6068, USA.
authors: Vladimir V
authors: VV
authors: Shuvaev
authors: Samira
authors: S
authors: Tliba
authors: Marian
authors: M
authors: Nakada
authors: Steven M
authors: SM
authors: Albelda
authors: Vladimir R
authors: VR
authors: Muzykantov
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D019921:Biotinylation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D019271:Hypoxanthine / Q000494:pharmacology; D018796:Immunoconjugates / Q000494:pharmacology*; D018384:Oxidative Stress; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology*; D013482:Superoxide Dismutase / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism / Q000633:toxicity*
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013481:Superoxides; D019271:Hypoxanthine; D013482:Superoxide Dismutase