Identification of a biologically active component in minimally oxidized low density lipoprotein (MM-LDL) responsible for aortic smooth muscle cell proliferation

Although low concentrations (10 mug/ml) of oxidized LDL density lipoproteins (Ox-LDL) and minimally modified LDL (MM-LDL) can stimulate the proliferation of aortic smooth muscle cells the biologically active component responsible for this phenomena has not been identified. Here we report that the 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-4-phosphocholine (m/e594.3) (POVPC) present in MM-LDL but not 1-palmitoyl-2-glutaryl-sn-glycero-3-phophochline (m/e610.2)(PGPC) can stimulate the activity of UDP-galactose:glucosylceramide (beta 1-->4) galactosyltransferase (GalT-2) and produce lactosyceramide (LacCer). LacCer, in turn, generated superoxide radicals (O-2(.-)). This is accompanied by the phosphorylation/activation of a cytosolic transcriptional factor p(44) MAPK and the subsequent proliferation of human aortic smooth muscle cells. D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of GalT-2, impaired the induction of GalT-2 activity, O-2(.-) generation, and cell proliferation. Thus POVPC may serve as a surrogate in MM-LDL mediated induction of aortic smooth muscle cells (A-SMC) proliferation via GalT-2 activation. The LacCer produced as a consequence of GalT-2 activation may serve as a lipid second messenger in the activation of an oxidant sensitive transcriptional pahtway that ultimately leads to cell proliferation and may contribute to the pathophysiology of atherosclerosis.