RT Journal Article
SR Electronic
T1 Platelet-Endothelial Cell Adhesion Molecule-1-Directed Endothelial Targeting of Superoxide Dismutase Alleviates Oxidative Stress Caused by Either Extracellular or Intracellular Superoxide
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 450
OP 457
DO 10.1124/jpet.107.127126
VO 323
IS 2
A1 Vladimir V. Shuvaev
A1 Samira Tliba
A1 Marian Nakada
A1 Steven M. Albelda
A1 Vladimir R. Muzykantov
YR 2007
UL http://jpet.aspetjournals.org/content/323/2/450.abstract
AB Targeting of the antioxidant enzyme catalase to endothelial cells protects against vascular oxidative stress induced by hydrogen peroxide (H2O2)(Am J Physiol285:L283–L292, 2003; Nat Biotechnol21:392–398, 2003; Am J Physiol293: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. The American Society for Pharmacology and Experimental Therapeutics