Proliferative effect of lipoprotein lipase on human vascular smooth musclecells

Vascular smooth muscle cell (VSMC) proliferation is a key event in the deve lopment and progression of atherosclerotic lesions. Accumulating evidence s uggests that lipoprotein lipase (LPL) produced in the vascular wall may exe rt proatherogenic effects. The aim of the present study was to examine the effect of LPL on VSMC proliferation. Incubation of growth-arrested human VS MCs with purified endotoxin-free bovine LPL for 48 and 72 hours, in the abs ence of any added exogenous lipoproteins. resulted in a dose-dependent incr ease in VSMC growth. Addition of VLDLs to the culture media did not further enhance the LPL effect. Treatment of growth-arrested VSMCs with purified h uman or murine LPL (1 mug/mL) led to a similar increase in cell proliferati on. Neutralization of bovine LPL by the monoclonal 5D2 antibody, irreversib le inhibition, or heat inactivation of the lipase suppressed the LPL stimul atory effect on VSMC growth. Moreover, preincubation of VSMCs with the spec ific protein kinase C inhibitors calphostin C and chelerythrine totally abo lished LPL-induced VSMC proliferation. In LPL-treated VSMCs, a significant increase in protein kinase C activity was observed. Treatment of VSMCs with heparinase III. (1 U/mL) totally inhibited LPL-induced human VSMC prolifer ation. Taken together, these data indicate that LPL stimulates VSMC prolife ration, LPL enzymatic activity, protein kinase C activation, and LPL bindin g to heparan sulfate proteoglycans expressed on VSMC surfaces are required for this effect. The stimulatory effect of LPL on VSMC proliferation may re present an additional mechanism through which the enzyme contributes to the progression of atherosclerosis.