THE SPHINGOMYELIN-CERAMIDE SIGNALING PATHWAY IS INVOLVED IN OXIDIZED LOW-DENSITY LIPOPROTEIN-INDUCED CELL-PROLIFERATION

Development of atherosclerosis is believed to involve proliferation of smooth muscle cells (SMC). Our laboratory previously demonstrated tha t the growth of bovine aortic SMC was stimulated by mildly oxidized lo w density lipoproteins (oxLDL) and that the mitogenic effect of oxLDL was greater than that induced by native LDL (AugB, N., Pieraggi, M. T. , Thiers, J. C., Negre-Salvayre, A., and Salvayre R. (1995) Biochem. J . 309, 1015-1020). Since the lipid mediator ceramide has been describe d to be proliferative, the present work aimed at studying the potentia l involvement of the so-called sphingomyelin ceramide pathway in the S ignal transduction cascade induced by oxLDL. Incubation of SMC with UV -oxidized LDL induced sphingomyelin hydrolysis (32%), which peaked at 60 min and was accompanied by a concomitant increase of intracellular ceramide level. The effect of oxidized LDL on sphingomyelin turnover e xhibited the same LDL dose dependence as their mitogenic effect, Exoge nous bacterial sphingomyelinase induced sphingomyelin hydrolysis and c eramide generation and also stimulated cell growth, in contrast to exo genous phospholipases A2, C, or D. This mitogenic effect was reproduce d by incubating the cells with the cell-permeant ceramides, N-acetyl- and N-hexanoylsphingosines. Altogether, these data strongly suggest fo r the first time that activation of the sphingomyelin-ceramide pathway may play a pivotal role in the oxLDL-induced SMC proliferation and at herogenesis.