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Dipyridamole Alters Cardiac Substrate Preference by Inducing Translocation of FAT/CD36, but Not That of GLUT4

Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (J.J.F.P.L., S.L.M.C., J.W., W.A.C., J.F.C.G.); and Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada (A.R.)

In cardiac myocytes, uptake rates of glucose and long-chain fatty acids (FA) are regulated by translocation of GLUT4 and FA translocase (FAT)/CD36, respectively, from intracellular stores to the sarcolemma. Insulin and contractions are two major physiological stimuli able to induce translocation of both transporters and therefore enhance the uptake of both substrates. Interestingly, the cardiovascular drug dipyridamole was able to enhance FA uptake but had no effect on glucose uptake. The selective stimulatory effect of dipyridamole on FA uptake was unrelated to its effects on phosphodiesterase inhibition and on nucleoside transport inhibition. However, dipyridamole-stimulated FA uptake was abolished in the presence of sulfo-N-succinimidylpalmitate, which indicated that FAT/CD36 is involved in the uptake process. Furthermore, the effect was additive to that of insulin but not to that of the AMP-elevating agent oligomycin, indicating that dipyridamole stimulates FAT/CD36-mediated FA uptake by activating the AMP-activated protein kinase (AMPK) signaling pathway. Dipyridamole, however, neither influenced the intracellular AMP content nor induced activation of AMPK. Finally, dipyridamole was able to induce FAT/CD36 translocation from intracellular storage sites to the sarcolemma but had no effect on the subcellular distribution of GLUT4. It is concluded that beyond AMP-activated protein kinase the contraction-induced and AMPK-mediated signal branches off into separate mobilization of GLUT4 and of FAT/CD36, and that dipyridamole activates a yet unidentified target in the FAT/CD36 mobilizing branch.

Address correspondence to: Dr. Joost J. F. P. Luiken, Department of Molecular Genetics, CARIM, Maastricht University, P.O. Box 616, NL-6200 MD Maastricht. E-mail: j.luiken{at}gen.unimaas.nl

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