Synergistic interaction between thromboxane A2and mildly oxidized low density lipoproteins on vascular smooth muscle cell proliferation

• Published in: Prostaglandins, leukotrienes and essential fatty acids leukotrienes and essential fatty acids, 2000-12, Vol.63 (6), p.329-335
• Main Authors: Koba, S., Pakala, R., Watanabe, T., Katagiri, T., Benedict, C.R.
• Format: Article
• Language: English
• ISSN: 0952-3278; 1532-2823
• DOI: 10.1054/plef.2000.0223

Low density lipoprotein (LDL) and mildly oxidized low density lipoprotein (mox-LDL) are known mitogens for vascular smooth muscle cell (VSMC). Since aggregating platelets at sites of atherosclerotic injury release thromboxane A2(TXA2), a known mitogen for VSMC, we examined whether TXA2can act synergistically with mox-LDL or its oxidative components in inducing VSMC proliferation. Growth arrested primary aortic rabbit VSMCs in 1st or 2nd passage were incubated with different concentrations of LDL or mox-LDL or lysophosphatidylcholine (LPC) or H2O2or 4-hydroxy-2-nonenel (HNE) for 24 h followed by incubation with TXA2mimetic U46619 for another 24 h. The amount of3[H]-thymidine incorporated into the DNA was measured. Both LDL and mox-LDL at a concentration of 120 μg/ml induced proliferation of VSMC (168% or 184% respectively) when compared to the control. U46619 induced VSMC proliferation was observed at a concentration of 5 μm/L. As compared to native LDL, the mitogenic effect of mox-LDL on VSMC proliferation was markedly potentiated by U46619 to 301% or 316% at 0.5 or 5 μm/L U46619 respectively. LPC, H2O2and HNE induced DNA synthesis was also marked by enhanced by U46619. These results suggest that even low concentration of TXA2released from 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 HNE.