Abstract
We have previously shown that oxidized low density lipoprotein (LDL) but not native LDL stimulated DNA synthesis in cultured smooth muscle cells (SMC) and that alpha-tocopherol (vitamin E) inhibited this proliferative response (Lafont, A., Chai, Y. C., Cornhill, J. F. , Whitlow, P. L., Howe, P. H., and Chisolm, G. M.(1995) J. Clin. Invest. 95, 1018-1025). The moiety of oxidized LDL that stimulates DNA synthesis and the cellular mechanism for this potentially mitogenic effect are not known. We now report that lipid fractions containing lysophospholipids from oxidized LDL or phospholipase A2-treated native LDL stimulated SMC DNA synthesis as did palmitoyl lysophosphatidylcholine (lysoPC). Protein kinase C inhibitors and down-regulation of protein kinase C activity by phorbol ester inhibited oxidized LDL- and lysoPC-induced DNA synthesis. A neutralizing monoclonal antibody against fibroblast growth factor-2 significantly inhibited oxidized LDL and lysoPC-induced DNA synthesis in SMC; irrelevant antibodies were ineffective. Vitamin E inhibited the DNA synthesis stimulated by lysoPC, an observation that distinguished this effect from DNA synthesis induced by another detergent, digitonin. These results suggest that oxidized LDL and its lysoPC moiety stimulate SMC to enter the cell cycle via an oxidative mechanism that causes the release of fibroblast growth factor-2 and a subsequent autocrine or paracrine response.
Highlights
This effect from DNA synthesis induced by another de- In the present studies we sought to elucidate further the tergent, digitonin
This assertion was strengthened by the fact that vitamin E blunted the enhanced DNA synthesis caused by lysoPC, as shown in Fig. 2B, at vitamin E concentrations shown previously to blunt this effect by oxidized low density lipoprotein (LDL) [25]
Our results indicate that enhanced DNA synthesis by oxidized LDL is linked to cell cycle entry, that one of the oxidized LDL components that can induce this response is lysoPC, and that the mechanism, at least in part, involves an autocrine or paracrine action of the oxidized LDL- or lysoPC-induced release of FGF-2
Summary
This effect from DNA synthesis induced by another de- In the present studies we sought to elucidate further the tergent, digitonin. We have previously shown that oxidized LDL increased [3H]thymidine incorporation into DNA in quiescent smooth muscle cells and that vitamin E blunted this response but not the response to serum [25].
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