Pathophysiological Analysis of CD36 Deficiency As a Novel Cause of Idiopathic Cardiomyopathy; Role of Long-chain Fatty Acid Transporter, CD36, in Myocardial Energy Metabolism

CD36 是一种 88 kDa 膜糖蛋白，在血小板、单核细胞、单核细胞衍生的巨噬细胞和脂肪组织上表达。据报道，CD36 是胶原蛋白和血小板反应蛋白的受体以及长链脂肪酸的转运蛋白。我们已经确定了 CD36 缺乏症患者，并报告了 CD36 基因的 3 个新突变。我们还发现 CD36 是氧化 LDL 的受体，利用来自 CD36 缺陷受试者的单核细胞衍生的巨噬细胞，并且 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。我们还发现 CD36 在心肌细胞上表达。 CD36 缺陷受试者的心肌细胞上缺乏 CD36，其中一些人会患上特发性心肌病。到目前为止，我们鉴定了 26 名 CD36 缺陷受试者，所有受试者都表现出心肌摄取完全缺乏。FDG-PET 分析表明，与对照组相比，CD36 缺陷受试者的心肌葡萄糖摄取速度相当快。因此，在 CD36 缺乏的情况下，心肌对长链脂肪酸的摄取受损可能导致能量从长链脂肪酸转换为葡萄糖。为了进一步探讨CD36缺陷在心肌病发病中的可能作用，我们正在尝试通过基因工程技术建立CD36敲除小鼠。我们计划评估该动物模型中是否存在心功能受损、心脏肥大或扩张型心肌病，以确定 CD36 缺乏在心肌病发病机制中的重要性。

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 arterise. We also found that CD36 is expressed on the cardiac myocytes. CD36-deficient subjects lack CD36 on the cardiomyocytes and some of them develop idiopathic cardiomyopathy. So far, we identified 26 CD36-deficient subjects, all of whom showed a complete deficiency of myocardial uptake of ィイD1123ィエD1I-BMIPP, a long-chain fatty acid analogue. Six subjects were accompanied by hypertrophic or dilated cardiomyopathy. FDG-PET anlysis demonstrated that glucose uptake by the heart muscle was rather accelerated in the CD36-deficient subjects compared with conmtrol subjects. Thus, the impaired mayocardial uptake of long-chain fatty acids may lead to an energy switching from long-chain fatty acids to glucose in CD36 deficiency. To further examine the possible contribution of CD36 deficiency to the pathogenesis of cardiomyopathy, we are trying to establish CD36 knockout mice by genetic engineering technique. We are planning to evaluate the presence or absence of impaired cardiac function, cardiac hypertrophy or dilated cardiomyopathy in this animal model to establish the significance of CD36 deficiency in the pathogenesis of cardiomyopathy.