Synergistic interaction between thromboxane A(2) and mildly oxidized low density lipoproteins on vascular smooth muscle cell proliferation

Low density lipoprotein (LDL) and mildly oxidized low density lipoprotein ( mox-LDL) are known mitogens for vascular smooth muscle cell (VSMC). Since a ggregating platelets at sites of atherosclerotic injury release thromboxane A(2) (TXA(2)), a known mitogen for VSMC, we examined whether TXA(2) can ac t synergistically with mox-LDL or its oxidative components in inducing VSMC proliferation. Growth arrested primary aortic rabbit VSMCs in 1st or 2nd p assage were incubated with different concentrations of LDL or mox-LDL or ly sophosphatidylcholine (LPC) or H2O2 or 4-hydroxy-2-nonenel (HNE) for 24 h f ollowed by incubation with TXA(2) mimetic U46619 for another 24 h. The amou nt of (3)[H]-thymidine incorporated into the DNA was measured. Both LDL and mox-LDL at a concentration of 120 mug/ml induced proliferation of VSMC (16 8% or 184% respectively) when compared to the control. U46619 induced VSMC proliferation was observed at a concentration of 5 mum/L. As compared to na tive LDL, the mitogenic effect of mox-LDL on VSMC proliferation was markedl y potentiated by U46619 to 301% or 316% at 0.5 or 5 mum/LU46619 respectivel y. LPC, H2O2 and HNE induced DNA synthesis was also marked by enhanced by U 46619. These results suggest that even low concentration of TXA2 released f rom aggregating platelets may potentiate the mitogenic effect of mox-LDL at sites of vascular damage. The mitogenic effect of mox-LDL may be mediated via its oxidation products LPC, H2O2 (reactive oxygen species donor), and H NE. (C) 2000 Harcourt Publishers Ltd.