CONTRARY EFFECTS OF LIGHTLY AND STRONGLY OXIDIZED LDL WITH POTENT PROMOTION OF GROWTH VERSUS-APOPTOSIS ON ARTERIAL SMOOTH-MUSCLE CELLS, MACROPHAGES, AND FIBROBLASTS

The inhibition of experimental atherosclerosis by antioxidants and the presence of oxidized LDL (oxLDL) in atherosclerotic lesions indicate that oxLDL may play what is perhaps a primary role in atherogenesis. L DL promotes the growth of arterial smooth muscle cells (SMCs), and oxL DL has cytotoxic effects. Since excessive intimal growth alternating w ith necrosis is typical of atherosclerotic lesions, we wondered whethe r these extreme changes in the lesions could be related to the extreme effects of LDL and oxLDL on cells. We therefore examined the effects of increasing LDL oxidation on its capacity to induce cell growth or c ell death and whether the latter could be due to apoptosis. Cells of t he types present in the atherosclerotic artery were used, ie, SMCs (hu man arterial), macrophages (human macrophage-like cell line THP-1), an d human fibroblasts. Growth was evaluated by measuring the synthesis o f DNA and culture size (MTT method) and apoptosis by using the in situ labeling of internucleosomally degraded DNA and, in the case Of SMCs, the appearance of chromatin condensation. The oxidation of LDL was me diated by UV or Fe ions. Shortly oxidized LDL had a markedly increased growth-promoting effect on all cell types. With prolonged exposure to UV, but not to Fe, LDL became increasingly cytotoxic, and this toxici ty was paralleled by the appearance of apoptosis in all cell types. Af ter prolonged UV treatment, low-molecular-weight material from the par tially degraded LDL was responsible for the induction of apoptosis. Th e dual effect of oxLDL, ie, its strong growth-promoting effect or the induction of cell death by apoptosis, depending on the degree of chang e by oxidation, is compatible with the notion that oxLDL plays a role not only in atherogenesis but also more extensively in the development of the structure typical of the atherosclerotic lesion, with focal ex cessive growth alternating with necrosis.