Extent of oxidative modification of low density lipoprotein determines the degree of cytotoxicity to human coronary artery cells

Objective-To assess whether the extent of LDL oxidation influences its cytotoxic effects, thus contributing to its atherogenic potential. Design and setting-The effects of native and modified LDL on cultured human coronary artery smooth muscle cells (SMC) and endothelial cells (ECs) were investigated. Main outcome measures-Four indices of cytotoxicity were studied: (i) chromium-51 release; (ii) 5-bromo-2'-deoxyuridine (BrDUrd) uptake; (iii) morphological appearance; and (iv) EC migration. Results-(i) Minimally modified (mm) LDL (400 mu g/ml) causes significant Cr-51 release; the cytotoxic effect was significantly greater for copper oxidised (ox) LDL (400 mu g/ml). Native LDL had no effect. (ii) BrDUrd uptake studies showed significant inhibition of cell proliferation by 100 mu g/ml of oxLDL and to a lesser extent by mmLDL; native LDL had no effect. (iii) Morphological appearance was not altered by native LDL. Changes in cell morphology were induced by mmLDL (400 mu g/ml), and were more pronounced with oxLDL in concentrations of greater than or equal to 200 mu g/ml. (iv) EC migration was significantly inhibited by oxLDL (100 mu g/ml), but not by native or mmLDL. Conclusion-The extent of oxidation of LDL determined its cytotoxicity to coronary artery cells. Native LDL had no cytotoxic effect. In contrast, oxLDL and to a lesser extent mmLDL caused cytotoxicity at concentrations to which cells in vivo might be exposed. This may contribute to the atherogenicity of modified LDL by enhancing cellular injury and inflammation, and by inhibiting re-endothelialisation of areas of coronary artery damaged during the atherogenic process.