Studies on the initiation and regression of atherosclerosis

采用一种新的内源性高胆固醇血症动物模型--Watanabe遗传性高脂血症兔，观察了动脉粥样硬化病变分别用抗VCAM-1抗体、巨噬细胞抗体和T淋巴细胞抗体覆盖血管内皮细胞前后血管内皮细胞、巨噬细胞和T淋巴细胞的顺序性表达。由于我们的实验目的是连续分析WHHL-兔动脉壁上发生了什么，所以我们选择了检测VCAM-1、巨噬细胞和T淋巴细胞表达和存在的地方，即肋间动脉第一支的开口。1月龄WHHL兔肋间动脉开口处可见VCAM-1分子表达，2月龄时VCAM-1分子覆盖于管壁周围。此外，此时单核细胞开始在动脉壁内积聚，称为内膜军团。三到四周后的…在同一内膜间隙内可见更多的T淋巴细胞。1987年，我们报道了抗氧化剂普罗布考抑制WHHL兔动脉粥样硬化军团的进展。1991年，我们报道普罗布考治疗组动脉粥样硬化斑块中巨噬细胞来源的泡沫细胞比未治疗组少。为了解释这些现象，我们正在考虑普罗布考以某种方式抑制血管内皮细胞VCAM-1表达的可能性，目前这种可能性正在研究中。此外，我们还在体外研究了WHHL兔血管内皮细胞表面VCAM-1的诱导机制以及另一种单核细胞黏附分子ICAM-1。溶血磷脂酰胆碱(Lyso-PC)是动脉粥样硬化病变中产生的一种血管内皮细胞黏附分子-1和细胞间黏附分子-1的表达上调因子。在ICAM-1中，这种分子的诱导不依赖于PMA可调节的PKC的激活，而被细胞内循环AMP水平的升高所抑制。因此，我们与Chait博士和Gimbrone博士合作，重点研究了Lyso-PC对ICAM-1和VCAM-1表达的信号转导系统。较少

Using a new animal model for endogenous hypercholesterolemia, named Watanabe-heritable-hyperlipidemic rabbit, which has a severe fulminant atherosclerosis, we have investigated the sequential expression of monocyteadhesion molecule (VCAM-1), macrophages and T lymphocytes in and on the endothelial monolinear before and after the atherosclerotic lesions covered the space by anti-VCAM-1, macrophage and T lymphocyte antibody respectively. Because our experimental purpose is sequential analysis what is going on the arterial wall in WHHL-rabbit, we chose the place where we examined the expression and existence VCAM-1, macrophage and T lymphocyte, that is the orifice of first branch of intercostal artery. At one month of age WHHL-rabbit, expression of VCAM-1 molecules is observed at the orifice of intercostal artery and covered around the wall at 2 month of age. In addition, at that time, monocytes started to accumulate in the arterial wall, named intimal legion. Three to four weeks later of … More this phenomenon T lymphocytes are observed in the same intimal space. In 1987, we reported that antioxidant, probucol, suppressed the progression of atherosclerotic legions in WHHL-rabbit. In 1991, we reported that in the atherosclerotic legions in probucol treated group there were few macrophage derived foam cells than untreated group. to explain these phenomenon we are thinking the possibility which probucol somehow inhibits the expression of VCAM-1 expression in the endothelial cells and this possibility is now under examined. The mechanism why VCAM-1 is induced on the endothelial cell in WHHL rabbit is under investigated in vitro and ICAM-1, another monocyte adhesion molecule, is also examined. Lysophosphatidylcholine (Lyso-PC) which generated in atherosclerotic lesions, has been shown to differentially up regulate VCAM-1 and ICAM-1 expression in various cultured endothelial cells. In case of ICAM-1, induction of this molecules is independent of PMA-regulatable PKC activation but suppressed by increased level of intracellular cyclic AMP.Therefore we focus and put forward on the signal transduction system of Lyso-PC on the expression of ICAM-1 and VCAM-1 collaboration with both Drs. Chait and Gimbrone. Less