Depending on their concentration oxidized low density lipoproteins stimulate extracellular matrix synthesis or induce apoptosis in human coronary artery smooth muscle cells

Various lines of evidence indicate that oxidative stress resulting in lipid peroxidation and protein modification is involved in the pathogenesis of a therosclerosis and coronary heart disease. We have investigated the effect of modified (oxidized) low-density lipoproteins (oxLDL) on collagen and fib ronectin synthesis in cultured human coronary artery smooth muscle cells (H CA-SMC). As shown by immunofluorescence microscopy and time-resolved fluore scence immunoassay, oxLDL dose-dependently stimulated collagen type I and f ibronectin synthesis in cultured HCA-SMC. The effect on matrix synthesis wa s biphasic, with a maximum effect at concentrations between 1 and 10 mu g/m l oxLDL. Higher oxLDL concentrations (>25 mu g/ml) were cytotoxic. Beside o xLDL, malondialdehyde-modified LDL also stimulated extracellular matrix syn thesis. In the presence of 100 mu g/ml ascorbic acid, 25, 50 and 100 mu g/m l oxLDL induced apoptosis within 6-8 hours (demonstrated by TUNEL-reaction, annexin-V binding and APO-2.7-expression) Apoptosis was not induced by nor mal (unmodified) LDL and malondialdehydemodified LDL. The radical scavenger s and antioxidants TROLOX and probucol and the hydrogen peroxide eliminator catalase significantly reduced oxLDL-induced apoptosis. Our results demons trate that low concentrations of oxLDL are profibrogenic by stimulating ext racellular matrix synthesis, whereas higher oxLDL concentrations induce oxi dative stress and apoptosis in coronary artery smooth muscle cells. The pro fibrogenic effect might be relevant in the formation of atherosclerotic pla ques, and the proapoptotic effect might contribute to an increased plaque v ulnerability.