LOW- AND HIGH-DENSITY-LIPOPROTEINS AS MITOGENIC FACTORS FOR VASCULAR SMOOTH-MUSCLE CELLS - INDIVIDUAL, ADDITIVE AND SYNERGISTIC EFFECTS

The mitogenic activities of low (LDL)- and high (HDL)-density lipoprot eins have been examined in cultures of human vascular smooth muscle ce lls (VSMC). LDL and HDL(3) dose-dependently (EC(50) values similar to 50 mu g/ml) stimulated DNA and protein synthesis ([H-3]-thymidine and [H-3]-leucine incorporation, respectively) in the absence of exogenous ly added mitogens. The synthetic responses of VSMC to combinations of LDL and HDL(3) were additive, indicating that each lipoprotein mediate s discrete effects. LDL or HDL(3) promoted VSMC proliferation under st rict mitogen-free conditions, but this growth response was not sustain ed. VSMC exposed to combinations of lipoproteins (either LDL or HDL(3) ) and growth factors (either PDGF-BB, EGF, bFGF or IGF) exhibited syne rgistic DNA synthesis responses. In the combined presence of PDGF-BB a nd either LDL or HDL(3), VSMC proliferation was sustained. Anionized l ipoprotein preparations (oxidized, acetylated, carbamylated or malonim ylated) also stimulated DNA and protein synthesis. Since the antioxida nt beta-hydroxylated toluene did not block the effect of native LDL on DNA synthesis, and fucoidin, a specific competitor for the 'scavenger ' receptor, did not inhibit. oxidized LDL-induced DNA synthesis, activ ation of mitogenic signals by lipoproteins does not depend on lipid pe roxidation. Rather, the apparent intrinsic mitogenic potential of lipo proteins may depend upon their direct activation of replication-couple d signal transduction systems.