24 September 2008
The mitogenic activities of low (LDL)- and high (HDL)-density lipoproteins have been examined in cultures of human vascular smooth muscle cells (VSMC). LDL and HDL<sub>3</sub> dose-dependently (EC50 values ∼50 µg/ml) stimulated DNA and protein synthesis ([<sup>3</sup>H]-thymidine and [<sup>3</sup>H]-leucine incorporation, respectively) in the absence of exogenously added mitogens. The synthetic responses of VSMC to combinations of LDL and HDL<sub>3</sub> were additive, indicating that each lipoprotein mediates discrete effects. LDL or HDL<sub>3</sub> promoted VSMC proliferation under strict mitogen-free conditions, but this growth response was not sustained. VSMC exposed to combinations of lipoproteins (either LDL or HDL<sub>3</sub>) and growth factors (either PDGF-BB, EGF, bFGF or IGF) exhibited synergistic DNA synthesis responses. In the combined presence of PDGF-BB and either LDL or HDL<sub>3</sub>, VSMC proliferation was sustained. Anionized lipoprotein preparations (oxidized, acetylated, carbamylated or malonimylated) also stimulated DNA and protein synthesis. Since the antioxidant β-ydroxylated 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, activation of mitogenic signals by lipoproteins does not depend on lipid peroxidation. Rather, the apparent intrinsic mitogenic potential of lipoproteins may depend upon their direct activation of replication-coupled signal transduction systems.