Establishment of A New Strategy for the Treatment of Atherosclerosis by Inhibition of an Oxidized LDL Receptor, CD36

CD36是一种88 kDa的膜糖蛋白，在血小板、单核细胞、单核细胞源性巨噬细胞和脂肪组织中表达。据报道，CD36是胶原蛋白和血小板反应蛋白的受体，也是长链脂肪酸的转运蛋白。我们已经确定了CD36缺乏症患者，并报道了CD36基因的3个新突变。我们还发现CD36是氧化LDL的受体，使用来自CD36缺陷受试者的单核细胞来源的巨噬细胞，CD36在人动脉粥样硬化主动脉和冠状动脉的泡沫巨噬细胞上表达。在目前的研究中，我们试图建立阻断CD36的多克隆抗体，并通过基因工程技术开发CD36敲除小鼠。我们已经通过同源重组获得了ES细胞，目前正在尝试通过显微注射获得嵌合体小鼠，以研究CD36敲除对载脂蛋白E或LDL受体敲除小鼠动脉粥样硬化发展的影响。到目前为止，我们已经确定了26名cd36缺陷的受试者，他们都表现出心肌摄取^<123 b> I-BMIPP（一种长链脂肪酸类似物）完全缺乏。值得注意的是，cd36缺陷患者伴有高脂血症（特别是高甘油三酯血症），残余脂蛋白增加和血压轻微升高。这些受试者还伴有胰岛素抵抗和多种危险因素。因此，CD36缺乏可能是多种危险因素综合征的遗传原因之一，可能与胰岛素抵抗有关。CD36缺乏患者胰岛素抵抗的机制目前正在研究中。

CD36 is an 88 kDa membrane glycoprotein and is expressed on platelets, monocytes, monocyte-derived macrophages and adipose tissues. CD36 was reported to be a receptor for collagen and thrombospondin as well as a transporter of long-chain fatty acids. We have identified patients with CD36 deficiency and reported 3 novel mutations in the CD36 gene. We also found that CD36 is a receptor for oxidized LDL, using monocyte-derived macrophages from CD36-deficient subjects and that CD36 is expressed on foamed macrophages in the human atherosclerotic aorta and coronary arteries. In the current study, we tried to establish polyclonal antibodies that block CD36 and also to develop CD36 knockout mice by genetic engineering technique. We have obtained ES cells with a homologous recombination and are currently trying to obtain chimera mice by microinjection to examine the effect of CD36 knockout on the development of atherosclerosis in apo E or LDL receptor knockout mice. We have so far identified 26 CD36-deficient subjects, all of whom showed a complete deficiency of myocardial uptake of ^<123>I-BMIPP, a long-chain fatty acid analogue. It is noteworthy that the CD36-deficient patients were accompanied by hyperlipidemia (especially hypertriglyceridemia), an increase in remnant lipoproteins and a slight elevation of blood pressure. These subjects were also accompanied by insulin resistance and multiple risk factors. Thus, deficiency of CD36 may be one of the genetic causes of multiple risk factor syndrome possibly through insulin resistance. The mechanism for the insulin resistance in patients with CD36 deficency is currently underway.