OVEREXPRESSION OF HUMAN SUPEROXIDE-DISMUTASE INHIBITS OXIDATION OF LOW-DENSITY-LIPOPROTEIN BY ENDOTHELIAL-CELLS

Oxidation of LDL in the subendothelial space has been proposed to play a key role in atherosclerosis. Endothelial cells produce superoxide a nions (0(2)(.-)) and oxidize LDL in vitro; however, the role of O: - i n endothelial cell-induced LDL oxidation is unclear. Incubation of hum an LDL (200 mu g/mL) with bovine aortic endothelial cells (BAECs) for 18 hours resulted in a 4-fold increase in LDL oxidation compared with cell-free incubation (22.5+/-1.1 versus 6.3+/-0.2 [mean+/-SEM] nmol ma londialdehyde/mg LDL protein, respectively; P<0.05). Under similar con ditions, incubation of LDL with porcine aortic endothelial cells resul ted in a 5-fold increase in LDL oxidation. Inclusion of exogenous copp er/zinc superoxide dismutase (Cu/ZnSOD, 100 mu g/mL) in the medium red uced BAEC-induced LDL oxidation by 79%. To determine whether the intra cellular SOD content can have a similar protective effect, BAECs were infected with adenoviral vectors containing cDNA for human Cu/ZnSOD (A dCu/ZnSOD) or manganese SOD (AdMnSOD). Adenoviral infection increased the content and activity of either Cu/ZnSOD or MnSOD in the cells and reduced cellular O-2(.-) release by two thirds. When cells infected wi th AdCu/ZnSOD or AdMnSOD were incubated with LDL, formation of malondi aldehyde was decreased by 77% and 32%, respectively. Two other indices of LDL oxidation, formation of conjugated dienes and increased LDL el ectrophoretic mobility, were similarly reduced by SOD transduction. Th ese data suggest that production of O-2(.-) contributes to endothelial cell-induced oxidation of LDL in vitro, Furthermore, adenovirus-media ted transfer of cDNA for human SOD, particularly Cu/ZnSOD, effectively reduces oxidation of LDL by endothelial cells.