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

低密度脂蛋白(LDL)可为细胞提供胆固醇，而高密度脂蛋白(HDL)可去除动脉壁中多余的胆固醇。另一方面，尽管脂蛋白已知胆固醇代谢以外的其他作用，但脂蛋白中的哪个分子起作用仍不是很清楚。脂蛋白携带多种生物活性物质。我们发现脂蛋白中存在鞘氨醇1-磷酸(S1P)和溶血磷脂酸(LPA)。我们还发现LPA刺激血管平滑肌细胞(VSMCs)的迁移反应，而S1P抑制VSMCs的反应。这些动作模仿低密度脂蛋白和高密度脂蛋白的动作。鉴于VSMCs的迁移是动脉粥样硬化发病机制的标志，我们提出脂蛋白中的LPA参与动脉粥样硬化的促进作用，脂蛋白中的S1P参与抗动脉粥样硬化作用的假说。事实上，LPA1受体活性的抑制显著抑制了低密度脂蛋白诱导的冠状动脉平滑肌细胞(CASMCs)的迁移。相反，高密度脂蛋白对LPA和PDGF诱导的迁移的抑制作用被S1P2受体活性抑制。测定低密度脂蛋白和高密度脂蛋白中S1P的含量。高密度脂蛋白中S1P的含量大约是低密度脂蛋白的4倍，这支持了这一假说。此外，低密度脂蛋白的LPA组分的降解或LPA受体的拮抗可使低密度脂蛋白抑制PDGF诱导的迁移。低密度脂蛋白的抑制作用可通过抑制S1P2受体活性来实现。总之，LPA/LPA1受体和S1P/S1P2受体分别介导对低密度脂蛋白和高密度脂蛋白的刺激和抑制迁移反应。脂蛋白中LPA和S1P的含量以及LPA1和S1P2受体之间的信号活性的平衡可能是决定脂蛋白是CASMC迁移的正调控因子还是负调控因子的关键。

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.