CELLULAR MECHANISM FOR LDL RETENTION BY THE ARTERY WALL

尽管有充分的证据表明，血浆中高水平的 含有载脂蛋白B的脂蛋白会导致过早的动脉粥样硬化 机制仍不清楚。保留反应假说成立 低密度脂蛋白(LDL)和其他致动脉粥样硬化的载脂蛋白B 脂蛋白通过相互作用滞留或滞留在内皮下层 血管内膜蛋白多糖引发早期动脉粥样硬化。我们的 初步证据表明，我们可以设计和遗传改变 致动脉粥样硬化的脂蛋白不会与动脉结合 壁蛋白多糖。如果与蛋白多糖的相互作用是显著的 脂蛋白内皮下滞留的成分，这些改变 因此，脂蛋白不应保留在内皮下层。 此外，如果与蛋白多糖结合是第一步或重要的一步 在动脉粥样硬化形成中，然后是高水平的遗传改变 修饰的有缺陷的蛋白多糖结合的低密度脂蛋白将不会导致动脉粥样硬化 比等量的正常低密度脂蛋白水平高。使用转基因小鼠模型 将首先确定结合蛋白多糖缺陷的低密度脂蛋白是否会导致 动脉粥样硬化比正常低密度脂蛋白喂养的动物高胆固醇饮食。如果 小鼠动脉粥样硬化研究表明蛋白多糖结合缺陷低密度脂蛋白 较少导致动脉粥样硬化，我们将推定其机制。 蛋白多糖结合的低密度脂蛋白不会导致动脉粥样硬化，我们将进行调查 推测蛋白多糖缺陷结合低密度脂蛋白的机制 在内皮下层的保留率很低。利用基因靶向技术， 我们将产生与蛋白多糖缺陷结合的apo-B48来确定 含B48的脂蛋白引起的动脉粥样硬化是由于其 结合蛋白多糖。最后，我们将确定脂蛋白脂酶 在动脉粥样硬化中起到直接的桥梁作用 低密度脂蛋白与蛋白多糖的结合。这些研究应该有助于澄清 低密度脂蛋白和其他含载脂蛋白B的脂蛋白会导致动脉粥样硬化。 此外，如果低密度脂蛋白与蛋白多糖结合的抑制是反 致动脉粥样硬化，然后使用小分子抑制低密度脂蛋白结合 蛋白多糖可能有治疗潜力，可以减少或预防 动脉硬化。

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.