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CARDIOVASCULAR

Platelet-Endothelial Cell Adhesion Molecule-1-Directed Endothelial Targeting of Superoxide Dismutase Alleviates Oxidative Stress Caused by Either Extracellular or Intracellular Superoxide

Institute for Environmental Medicine (V.V.S., S.T., V.R.M.), Department of Pharmacology (V.R.M.), and Pulmonary Critical Care Division, Department of Medicine (S.M.A.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Centocor, Malvern, Pennsylvania (M.N.)

Targeting of the antioxidant enzyme catalase to endothelial cells protects against vascular oxidative stress induced by hydrogen peroxide (H₂O₂)(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.

Address correspondence to: Vladimir Muzykantov, Institute for Environmental Medicine, University of Pennsylvania School of Medicine, 1 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6068. E-mail: muzykant{at}mail.med.upenn.edu