CELLULAR MECHANISM FOR LDL RETENTION BY THE ARTERY WALL

尽管有充分的证据表明，具有高血浆水平的动物 含有载脂蛋白B的脂蛋白会导致过早的动脉粥样硬化， 机制仍然未知。记忆反应假说成立 低密度脂蛋白（LDL）和其他含有载脂蛋白B的致动脉粥样硬化物质， 脂蛋白通过相互作用被保留或捕获在内皮下 内膜蛋白聚糖引发早期动脉粥样硬化。我们 初步证据显示我们可以设计并从基因上改变 致动脉粥样硬化的脂蛋白，使其不与动脉 壁蛋白聚糖如果与蛋白聚糖的相互作用是显著的， 在脂蛋白的内皮下保留的成分，这些改变 因此，脂蛋白不应保留在内皮下。 此外，如果与蛋白聚糖结合是初始步骤或重要步骤， 在动脉粥样硬化形成过程中， 改变的蛋白聚糖结合缺陷型低密度脂蛋白的致动脉粥样硬化作用将小得多 与正常LDL水平相当。使用转基因小鼠模型， 将首先确定蛋白聚糖缺陷结合低密度脂蛋白是否 动脉粥样硬化的动物比正常的低密度脂蛋白喂养高胆固醇饮食。如果 小鼠动脉粥样硬化研究表明， 较少致动脉粥样硬化，我们将研究其机制与假设 结合蛋白多糖的低密度脂蛋白致动脉粥样硬化性较低，我们将研究 推测蛋白聚糖缺陷结合LDL 在内皮下的保留很差。利用基因靶向技术， 我们将产生蛋白聚糖缺陷结合apo-B48，以确定 由含B48的脂蛋白引起的动脉粥样硬化是由于它们 与蛋白聚糖结合。最后，我们将确定脂蛋白脂酶是否 有助于动脉粥样硬化的直接桥梁作用， LDL与蛋白聚糖的结合。这些研究应该有助于阐明 LDL和其他含载脂蛋白B的脂蛋白导致动脉粥样硬化。 此外，如果LDL与蛋白聚糖结合的抑制是抗- 致动脉粥样硬化，然后使用小分子抑制LDL结合， 蛋白聚糖可能具有治疗潜力， 动脉粥样硬化

Although it is well-documented that animals with high plasma levels of lipoproteins containing apo-B develop premature atherosclerosis, the exact mechanism is still unknown. The response-to-retention hypothesis holds that low density lipoproteins (LDL) and other atherogenic apo-B containing lipoproteins are retained or trapped in the subendothelium by interacting with intimal proteoglycans initiating early atherosclerosis. Our preliminary evidence shows that we can design and genetically alter atherogenic lipoproteins in such a way that they will not bind to artery wall proteoglycans. If the interaction with proteoglycans is a significant component in the subendothelial retention of lipoproteins, these altered lipoproteins therefore should not be retained in the subendothelium. Further, if binding to proteoglycans is the initial or a significant step in atherogenesis, then high levels of genetically altered of genetically altered defective-proteoglycan-binding LDL will be much less atherogenic than equivalent levels of normal LDL. Using transgenic mouse models we will first determine if proteoglycan-defective-binding LDL causes less atherosclerosis than normal LDL animals fed a high cholesterol diet. If mouse atherosclerosis studies indicate defective-proteoglycan-binding LDL are less atherogenic, we will investigate the mechanism with presumption that proteoglycan-binding LDL are less atherogenic, we will investigate the mechanism with the presumption that proteoglycan-defective-binding LDL are poorly retained in the subendothelium. Using gene-targeted technology, we will generate proteoglycan-defective-binding apo-B48 to determine if the atherogenesis causes by B48-containing lipoproteins is due to their binding to proteoglycans. Finally, we will determine if lipoprotein lipase contributes to atherosclerosis in a direct bridging role by enhancing the binding of LDL with proteoglycans. These studies should help clarify how LDL and other apo-B-containing lipoproteins cause atherosclerosis. Moreover, if the inhibition of LDL binding to proteoglycans is anti- atherogenic, then the use of small molecules to inhibit LDL binding to proteoglycans may have therapeutic potential to reduce or prevent atherosclerosis.