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

CD36is an88 kDa membrane glycoprotein and is expressed on platelets，monocytes，monocyte-derived macrophages and adipose tissues.CD36was reported to be a receptor for collagen and thrombospondin as well as a transporter of long-chain fatty acids.We have identified patients with CD36deficiency and reported3novel mutations in the CD36gene.We also found that CD36is a receptor for oxidized LDL，using monocyte-derived macrophages from CD36-deficient subjects and that CD36is expressed on foamed macrophages in the human atherosclerotic aorta and coronary arterise.We also found that CD36is expressed on the cardiac myocytes.CD36-deficient subjects lack CD36on 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 y D1123 I-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 CD36deficiency to the pathogenesis of cardiomyopathy，we are trying to establish CD36knockout 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 CD36deficiency in the pathogenesis of cardiomyopathy.

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.