CELLULAR MECHANISM FOR LDL RETENTION BY THE ARTERY WALL

动脉壁保留低密度脂蛋白的细胞机制

• 批准号: 6564896
• 负责人: THOMAS L. INNERARITY
• 金额: $ 23.92万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564896
• 关键词: antiatherogenic agent; apolipoprotein B; atherosclerosis; atherosclerotic plaque; disease /disorder model; gene expression; genetically modified animals; laboratory mouse; lipoprotein lipase; low density lipoprotein; low density lipoprotein receptor; molecular pathology; pathologic process; protein binding; protein structure function; receptor binding; tissue /cell culture; vascular endothelium

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.

尽管有充分证据表明，血浆中 含有apo-B的脂蛋白会导致过早动脉粥样硬化，确切地说 机制尚不清楚。保留反应假说成立 低密度脂蛋白 (LDL) 和其他含有致动脉粥样硬化的 apo-B 脂蛋白通过相互作用被保留或捕获在内皮下层 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基因改变 致动脉粥样硬化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显着 脂蛋白内皮下保留的成分，这些改变 因此脂蛋白不应保留在内皮下。 此外，如果与蛋白聚糖的结合是第一步或重要的一步 在动脉粥样硬化形成中，然后高水平的基因改变 改变有缺陷的蛋白聚糖结合 LDL 将大大降低动脉粥样硬化的发生率 高于正常 LDL 的同等水平。使用转基因小鼠模型，我们 首先确定蛋白聚糖缺陷结合 LDL 是否会导致较少 喂食高胆固醇饮食的低密度脂蛋白动物的动脉粥样硬化程度高于正常动物。如果 小鼠动脉粥样硬化研究表明蛋白聚糖结合缺陷的低密度脂蛋白 动脉粥样硬化性较小，我们将推测其机制 蛋白聚糖结合的低密度脂蛋白不易导致动脉粥样硬化，我们将进行研究 假设蛋白聚糖缺陷结合 LDL 的机制 在内皮下层的保留较差。利用基因靶向技术， 我们将生成蛋白聚糖缺陷结合 apo-B48 以确定是否 含 B48 脂蛋白引起的动脉粥样硬化是由于其 与蛋白聚糖结合。最后，我们将确定脂蛋白脂肪酶是否 通过增强动脉粥样硬化的直接桥接作用 LDL 与蛋白聚糖的结合。这些研究应该有助于阐明如何 LDL 和其他含 apo-B 的脂蛋白会导致动脉粥样硬化。 此外，如果抑制 LDL 与蛋白聚糖的结合是抗- 致动脉粥样硬化，然后使用小分子抑制 LDL 结合 蛋白多糖可能具有减少或预防的治疗潜力 动脉粥样硬化。