Role of lipoprotein-associated lysophospholipids in cellular activities of vascular smooth muscle cells

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Low-density lipoprotein (LDL) and provides cholesterol to cells, while high-density lipoprotein (HDL) removes excess cholesterol from artery walls. On the other hand, which molecule in the lipoprotein plays the role is not understood still well, although actions other than the cholesterol metabolism are known to the lipoprotein. Lipoproteins carry a variety of bioactive substances. We showed sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) were present in the lipoproteins. We also showed that LPA stimulates migratory response and S1P inhibits the response of vascular smooth muscle cells (VSMCs). These actions mimicked the LDL and HDL actions. Since migration of VSMCs is a hallmark of the pathogenesis of atherosclerosis, we set up the hypothesis that LPA in the lipoprotein took part in the atherosclerosis promotion and S1P in the lipoprotein in the anti-atherosclerosis action. In fact, the LDL-induced migration of coronary artery smooth muscle cells (CASMCs) was markedly inhibited by the suppression of LPA1 receptor-activity. On the contrary, HDL-induced inhibition of LPA- and PDGF-induced migration was suppressed by the S1P2-receptor-activity. We measured the amount of S1P in LDL and HDL. The content of S1P is about 4-fold higher in HDL than in LDL, which supports the hypothesis. In addition, degradation of LPA component of LDL or antagonism of LPA receptors allowed LDL to inhibit the PDGF-induced migration. The inhibitory effect of LDL was suppressed by the inhibition of S1P2-receptor-activity. In conclusion, LPA/LPA1 receptors and S1P/S1P2 receptors mediate stimulatory and inhibitory migration response to LDL and HDL, respectively. A balance of not only the content of LPA and S1P in lipoproteins but also the signaling activity between LPA1 and S1P2 receptors may be crucial to determine whether the lipoprotein is a positive or negative regulator of CASMC migration.