Regulation of VCAM-1 and ICAM-1 expression in atherogenesis

单核白细胞粘附分子（例如 VCAM-1 和 ICAM-1）的内皮表达与血液单核细胞和淋巴细胞募集到早期动脉粥样硬化病变的分子机制有关。在晚期病变中，观察到内侧平滑肌细胞向动脉内膜迁移和增殖，并且内皮细胞产生的针对平滑肌细胞的生长因子似乎在这一过程中发挥了作用。我们已经鉴定出溶血磷脂酰胆碱，一种致动脉粥样硬化脂蛋白（如氧化 LDL 和 β-VLDL）的磷脂成分，可作为激活内皮细胞以诱导粘附分子和生长因子（包括 VCAM-、ICAM-1、PDGF-A 和 -B 链以及 HB-EGF）表达的候选物质。在本研究项目中，我们探索了在培养物中溶血 PC 诱导基因表达的信号转导和转录调节机制。血管内皮细胞。我们的研究表明，蛋白激酶 C 的激活似乎并不参与 lyso-PC 诱导的内皮 PDGF 和 ICAM-1 表达；然而，细胞内环AMP水平升高抑制了lyso-PC的作用。我们还发现，某些蛋白质可以响应lyso-PC的激活而快速酪氨酸磷酸化。关于lyso-PC的转录调节，我们的凝胶位移实验表明，lyso-PC不激活NFkappaB，但在一定程度上随时间依赖性地激活AP-1。

Endothelial expression of mononuclear leukocyte adhesion molecules, such as VCAM-1, and ICAM-1, has been implicated in molecular mechanism involved in the recruitment of blood monocytes and lymphocytes into early atherosclerotic lesions. In the advanced lesions, migration and proliferation of medial smooth muscle cells into arterial intima are observed, and endothelial production of growth factors directed to smooth muscle cells appears to play a role in this process. We have identified lysophosphatidylcholine, a phospholipid component of atherogenic lipoproteins, such as oxidized LDL and beta-VLDL, as a candidate to activate endothelium to induce expression of adhesion molecules and growth factors, including VCAM-, ICAM-1, PDGF-A and -B chains and HB-EGF.In this research project, we have explored the signal transduction and transcriptional regulatory mechanisms responsible for lyso-PC-induced gene expression in cultured vascular endothelial cells. Our study revealed that activation of protein kinase C does not appear to be involved in lyso-PC-induced endothelial PDGF and ICAM-1 expression ; however, elevated levels of intracellular cyclic AMP inhibited the effect of lyso-PC.We have also found that certain protein can be rapidly tyrosine phosphorylated in response to activation with lyso-PC.Regarding to the transcriptional regulation by lyso-PC,our gel shift assays showed that lyso-PC did not activate NFkappaB but timedependently activate AP-1 to some extent.