Oxidized low density lipoprotein stimulates aortic smooth muscle cell proliferation

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Abstract
We have investigated the effects of oxidized low density lipoproteins (Ox-LDL) on aortic smooth muscle cell (SMC) proliferation and the biosynthesis of glycosphingo-lipids. We found that Ox-LDL exerted a concentration, time, and temperature dependent alteration of cell proliferation and the biosynthesis of lactosylceramide. At low concentrations (5–10 μg/ml medium) Ox-LDL stimulated cell proliferation measured by an increase in the incorporation of 3H-thymidine in cells and the synthesis of lactosylceramide, but not glucosylceramide synthesis. Oxidized LDL exerted a threefold increase in the incorporation of [3H]-galactose and [3H]-serine in lactosylceramide. The activity of lactosylceramide synthetase; UDP-galactose glucosylceramide β1 → 4 galactosyltransferase (GaTT-2), but not glucosylceramide synthetase (GlcT-1) was stimulated by Ox-LDL. On the other hand, LDL suppressed the activity of GaIT-2 in these cells. When cells were preincubated with antibody against Ox-LDL or GaIT-2 it compromised the Ox-LDL mediated stimulation in cell proliferation and GaIT-2 activity. Similarly, D-PDMP an inhibitor of GaIT-2 compromised the Ox-LDL mediated effects in cells. In contrast, L-PDMP further stimulated the Ox-LDL mediated cell proliferation and GaIT-2 activity. However, preincubation of cells with preimmune rabbit serum IgG failed to abrogate Ox-LDL mediated stimulation in cell proliferation and GaIT-2 activity. In sum, we found that Ox-LDL stimulated aortic smooth muscle cell proliferation in culture. This effect resulted from Ox-LDL mediated activation of GaIT-2 that produced lactosylceramide. Lactosylceramide in turn, contributed to cell proliferation. Such correlations are supportive of the notion that GaIT-2 action mediates the signal transduction of Ox-LDL contributing to cell proliferation.

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