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. De sign and setting-The effects of native and modified LDL on cultured hu man coronary artery smooth muscle cells (SMC) and endothelial cells (E Cs) were investigated. Main outcome measures-Four indices of cytotoxic ity were studied: (i) chromium-51 release; (ii) 5-bromo-2'-deoxyuridin e (BrDUrd) uptake; (iii) morphological appearance; and (iv) EC migrati on. Results-(i) Minimally modified (mm) LDL (400 mu g/ml) causes signi ficant Cr-51 release; the cytotoxic effect was significantly greater f or copper oxidised (ox) LDL (400 mu g/ml). Native LDL had no effect. ( ii) BrDUrd uptake studies showed significant inhibition of cell prolif eration by 100 mu g/ml of oxLDL and to a lesser extent by mmLDL; nativ e 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 greate r than or equal to 200 mu g/ml. (iv) EC migration was significantly in hibited by oxLDL (100 mu g/ml), but not by native or mmLDL. Conclusion -The extent of oxidation of LDL determined its cytotoxicity to coronar y 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 athe rogenicity of modified LDL by enhancing cellular injury and inflammati on, and by inhibiting re-endothelialisation of areas of coronary arter y damaged during the atherogenic process.