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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 缺乏作为特发性心肌病新病因的病理生理学分析；

基本信息

批准号：
10671070
负责人：
YAMASHITA Shizuya
金额：
$ 2.37万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

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.

CD 36是一种88 kDa的膜糖蛋白，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，CD 36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。我们发现了CD 36缺乏症患者，并报告了3个CD 36基因的新突变。我们还发现，CD 36是氧化LDL的受体，使用来自CD 36缺陷受试者的单核细胞衍生的巨噬细胞，并且CD 36在人动脉粥样硬化主动脉和冠状动脉中的泡沫巨噬细胞上表达。我们还发现CD 36在心肌细胞上表达。CD 36缺陷的受试者缺乏心肌细胞上的CD 36，并且其中一些发展为特发性心肌病。到目前为止，我们确定了26名CD 36缺陷的受试者，他们都表现出心肌对长链脂肪酸类似物-β-D1123-β-D1 I-BMIPP摄取的完全缺乏。6例受试者伴有肥厚型或扩张型心肌病。FDG-PET分析表明，与对照受试者相比，CD 36缺陷受试者心肌对葡萄糖的吸收相当加速。因此，受损的蛋黄酱摄取的长链脂肪酸可能会导致能量转换从长链脂肪酸的葡萄糖在CD 36缺乏症。为了进一步研究CD 36缺陷在心肌病发病机制中的作用，我们试图通过基因工程技术建立CD 36基因敲除小鼠。我们计划在该动物模型中评估是否存在心脏功能受损、心脏肥大或扩张型心肌病，以确定CD 36缺乏在心肌病发病机制中的意义。