Role of lipoprotein-associated lysophospholipids in migratory activity of coronary artery smooth muscle cells
Role of lipoprotein-associated lysophospholipids in migratory activity of coronary artery smooth muscle cells
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DOI：
10.1152/ajpheart.00865.2006
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发表时间：
2007-05-01
影响因子：
4.8
通讯作者：
Okajima, Fumikazu
中科院分区：
文献类型：
--
作者：
Damirin, Alatangaole;Tomura, Hideaki;Okajima, Fumikazu
血管平滑肌细胞（SMCs）的迁移是血管成形术后动脉粥样硬化和再狭窄发病机制的一个标志。血浆低密度脂蛋白（LDL）而非高密度脂蛋白（HDL）诱导人冠状动脉SMCs （CASMCs）迁移。在假定存在于LDL中的生物活性脂质中，溶血磷脂酸（LPA）明显地模仿LDL的作用。事实上，低密度脂蛋白诱导的迁移被百日咳毒素、LPA受体拮抗剂Ki-16425和靶向LPA1受体的小干扰RNA （siRNA）显著抑制。此外，LDL比HDL含有更多的LPA。高密度脂蛋白显著抑制LPA-和血小板衍生生长因子（PDGF）诱导的迁移，而高密度脂蛋白中鞘氨醇1-磷酸（S1P）的含量是低密度脂蛋白的四倍，模仿了高密度脂蛋白的作用。S1P2受体特异性siRNA可抑制HDL和S1P的抑制作用。另一方面，单甘油酯脂肪酶降解LDL的LPA成分或Ki-16425对LPA受体的拮抗作用使LDL能够抑制pdgf诱导的迁移。低密度脂蛋白的抑制作用再次被S1P(2)受体特异性siRNA抑制。综上所述，LPA/ LPA(1)受体和S1P/S1P(2)受体分别介导对LDL和HDL的刺激和抑制迁移反应。脂蛋白中LPA和S1P含量的平衡，以及细胞中LPA1和S1P(2)受体之间的信号活性的平衡，可能是决定脂蛋白是CASMC迁移的正调节因子还是负调节因子的关键。
The migration of vascular smooth muscle cells (SMCs) is a hallmark of the pathogenesis of atherosclerosis and restenosis after angioplasty. Plasma low-density lipoprotein (LDL), but not high-density lipoprotein (HDL), induced the migration of human coronary artery SMCs (CASMCs). Among bioactive lipids postulated to be present in LDL, lysophosphatidic acid (LPA) appreciably mimicked the LDL action. In fact, the LDL-induced migration was markedly inhibited by pertussis toxin, an LPA receptor antagonist Ki-16425, and a small interfering RNA (siRNA) targeted for LPA1 receptors. Moreover, LDL contains a higher amount of LPA than HDL does. HDL markedly inhibited LPA- and platelet-derived growth factor (PDGF)-induced migration, and sphingosine 1-phosphate (S1P), the content of which is about fourfold higher in HDL than in LDL, mimicked the HDL action. The inhibitory actions of HDL and S1P were suppressed by S1P2 receptor-specific siRNA. On the other hand, the degradation of the LPA component of LDL by monoglyceride lipase or the antagonism of LPA receptors by Ki-16425 allowed LDL to inhibit the PDGF-induced migration. The inhibitory effect of LDL was again Suppressed by S1P(2) receptor-specific siRNA. In conclusion, LPA/ LPA(1) receptors and S1P/S1P(2) receptors mediate the stimulatory and inhibitory migration response to LDL and HDL, respectively. The balance of not only the content of LPA and S1P in lipoproteins but also the signaling activity between LPA1 and S1P(2) receptors in the cells may be critical in determining whether the lipoprotein is a positive or negative regulator of CASMC migration.