Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 323, Issue 2, Pages 450-457Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.107.127126
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Funding
- NHLBI NIH HHS [HL71175, HL079063, HL071174] Funding Source: Medline
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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.
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