OXIDIZED LOW-DENSITY-LIPOPROTEIN AND LYSOPHOSPHATIDYLCHOLINE STIMULATE CELL-CYCLE ENTRY IN VASCULAR SMOOTH-MUSCLE CELLS - EVIDENCE FOR RELEASE OF FIBROBLAST GROWTH-FACTOR-2

We have previously shown that oxidized low density lipoprotein (LDL) b ut not native LDL stimulated DNA synthesis in cultured smooth muscle c ells (SMC) and that alpha-tocopherol (vitamin E) inhibited this prolif erative response (Lafont, A., Chai, Y. C., Cornhill, J, F., Whitlow, P . L., Howe, P. H., and Chisolm, G. M. (1995) J. Chin, Invest. 95, 1018 -1025). The moiety of oxidized LDL that stimulates DNA synthesis and t he cellular mechanism for this potentially mitogenic effect are not kn own. We now report that lipid fractions containing lysophospholipids f rom oxidized LDL or phospholipase A(2)-treated native LDL stimulated S MC DNA synthesis as did palmitoyl lysophosphatidylcholine (lysoPC). Pr otein kinase C inhibitors and down regulation of protein kinase C acti vity by phorbol ester inhibited oxidized LDL- and lysoPC-induced DNA s ynthesis. A neutralizing monoclonal antibody against fibroblast growth factor-a significantly inhibited oxidized LDL and lysoPC-induced DNA synthesis in SMC; irrelevant antibodies were ineffective. Vitamin E in hibited the DNA synthesis stimulated by lysoPC, an observation that di stinguished this effect from DNA synthesis induced by another detergen t, digitonin, These results suggest that oxidized LDL and its lysoPC m oiety stimulate SMC to enter the cell cycle via an oxidative mechanism that causes the release of fibroblast growth factor-2 and a subsequen t autocrine or paracrine response.