Gene engineering, cell biological aproaches to the mechanisms for early stage of atherosclerosis

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Vascular endothelial cells, at early stage of atherosclerosis, plays a pivotal role, expressing endothelial leukocytes adhesion molecules (ICAM-1, VCAM-1) , growth factors (HB-EGF,PDGF-A,B chain) and cytokines in response to various pathophysiological stimuli. We have found that lysophosphatidyl-choline (Lyso-PC) , a prominent phospholipid component of atherogenic lipoproteins, such as oxidized LDL,upregulated differentially VCAM-1 and ICAM-1 expression in various cultured endothelial cells. In addition Lyso-PC has been demonstrated to induce gene expression of potent smooth muscle growth factors such as PDGF-A and B chain, and HB-EGF in cultured human endothelial cells. We are now trying to identify some proteins which are phosphorylated by the stimulation of Lyso-PC and verify the signal transduction pathway for Lyso-PC reactions in vascular endothelial cells. We also examined the expression of adhesion molecules and blood cells (such as monocyte-macrophages, T lymphocytes) in the atherosclerotic lesions in vivo, using WHHL-rabbits and cholesterol fed rabbits by immunological methods. At very early stage, around one P selectin molecules are expressed. At 3 week, we found that activated macrophages and after one more week T lymphocytes are identified at same lesions as adhesion molecules are expressed. Finally we found Lyso-PC could induce some growth factors and cytokines in T lymphocytes. We are now studying the molecular mechanisms of Lyso-PC actions to endothelial cells and T-lymphocytes.