2009 The CD36 receptor complex and macrophage drug targets of artherosclerosis 2009

尽管在治疗和预防方面取得了进展，动脉粥样硬化的并发症，包括冠心病和中风，仍然是西方世界死亡的主要原因。动脉粥样硬化现在被广泛认为是血管壁的一种慢性炎症性疾病，由修饰的、通常被氧化的低密度脂蛋白（oxLDL）聚集引起，也被称为“坏胆固醇”。巨噬细胞被认为是动脉粥样硬化发生和发展的关键。当巨噬细胞的表面受体与沉积在内皮下基质上的oxLDL结合时，巨噬细胞产生炎症介质。逐渐地，巨噬细胞吸收和储存过量的胆固醇，成为改变免疫反应的“泡沫细胞”。这些异常导致斑块的形成并最终导致其破裂，从而导致血栓形成，导致梗塞和中风。我们的实验室和其他研究人员最近的结果表明，大颗粒的oxLDL被巨噬细胞缓慢吞噬，这是一个长期的过程，刺激巨噬细胞产生异常的炎症反应。这种异常可能导致局部慢性炎症反应的发展。动脉粥样硬化的发展可以通过减少内皮下炎症和防止巨噬细胞中胆固醇的进一步积累来减轻。理论上，这可以通过中和CD36对oxLDL聚集体的炎症反应来实现，oxLDL聚集体对动脉粥样硬化的发展起着重要作用。然而，在正常情况下，oxLDL的积累和聚集被其活跃的内吞和代谢所阻止，这一过程也由CD36和其他清道夫受体介导。一种合适的策略是使巨噬细胞清除溶解的oxLDL，同时最大限度地减少对动脉内膜中大量oxLDL聚集的炎症反应。这种方法需要能够将发生在纳米颗粒尺度上的正常内吞途径与发生在微颗粒尺度上的清扫剂受体的炎症吞噬功能分离开来。

Despite advances in treatment and prevention, complications of atherosclerosis, including coronary heart disease and stroke, remain the leading cause of mortality in the Western world. Atherosclerosis is now widely regarded as a chronic inflammatory disease of the vascular wall, initiated by the aggregation of modified, usually oxidized, low-density lipoproteins (oxLDL) also called "bad cholesterol". Macrophages are thought to be key to the genesis and progression of atherosclerosis. When their surface receptors engage oxLDL deposited onto the subendothelial matrix, macrophages generate inflammatory mediators. Gradually, the macrophages take up and store inordinate amounts of cholesterol, becoming "foam cells" that have altered immune responsiveness. These abnormalities lead to the formation of plaque and ultimately to its rupture, which causes the thrombosis responsible for infarction and stroke. Recent results from our laboratories and others indicate that large particles of oxLDL are slowly engulfed by macrophages in a protracted process that stimulate macropages into an abnormal inflamatory response. This abnormality could contribute to the development of a localized chronic inflammatory response. The development of atherosclerosis could be lessened by minimizing subendothelial inflammation, and by preventing the further accumulation of cholesterol in macrophages. This can, in theory, be accomplished by neutralizing the inflammatory reaction of CD36 to oxLDL aggregates that contributes prominently to the development of atherosclerosis. However, under normal circumstances, the accumulation and aggregation of oxLDL is prevented by its active endocytosis and metabolism, a process also mediated by CD36 and other scavenger receptors. A suitable strategy would be to enable macrophages to clear dissolved oxLDL, while minimizing the inflammatory response to the large aggregates of oxLDL in the intima of the arteries. This approach requires the ability to separate the normal endocytic pathway that occurs on the nano particle scale from the inflammatory phagocytic functions of scavenger receptors that occurs on the micro particle scale.