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

Abstract

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 AMPelevating 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.

AMPK activation is not critical in the regulation of muscle FA uptake and oxidation during low-intensity muscle contraction

“…Our results show that lowintensity muscle contraction increased both glucose and FA uptake without significantly increasing AMPK activity, providing evidence that AMPK activation may not always be necessary to measure contraction-induced increases in FA and glucose uptake. In agreement with other data (8,15,17), our results suggest that AMPK-independent mechanisms may be involved in the regulation of contraction-induced FA and glucose uptake under some conditions. Indeed, in quiescent rat cardiac myocytes, dipyridamole, an inhibitor of nucleoside transport, was shown to induce FAT/CD36 translocation and FA uptake without stimulating AMPK activity (17).…”

“…In agreement with other data (8,15,17), our results suggest that AMPK-independent mechanisms may be involved in the regulation of contraction-induced FA and glucose uptake under some conditions. Indeed, in quiescent rat cardiac myocytes, dipyridamole, an inhibitor of nucleoside transport, was shown to induce FAT/CD36 translocation and FA uptake without stimulating AMPK activity (17). In slow oxidative muscle it has been shown that, although a high precontraction glycogen level prevented the contraction-induced activation of AMPK, it did not reduce the rate of contraction-induced glucose uptake (8).…”

Membrane Fatty Acid Transporters as Regulators of Lipid Metabolism: Implications for Metabolic Disease

“…Recent work in our group and by others has shown that insulin and leptin, as well as the pharmacological agents oligomycin, AICAR, and dipyridamole, induce the translocation of CD36 in skeletal muscle (164,278,305) and heart (73,153,274,281,305,324). Insulin has also been reported to induce FATP1 translocation in adipocytes (399), but this insulin-induced FATP1 translocation in adipocytes was not observed in another study (346), or in the heart (73,152).…”

Regulation of Sarcolemmal Transport of Substrates in the Healthy and Diseased Heart

“…However, recently we have identified pharmacological compounds able to selectively recruit either transporter thereby increasing the rate of uptake of a single type of substrate. The phosphodiesterase inhibitor dipyridamole was found to mobilize CD36 from contraction-inducible storage depots while not affecting GLUT4 mobilization [18]. This stimulatory action of dipyridamole-which is unrelated to its effects on phosphodiesterase inhibition and on nucleoside transport, but likely due to activation of a yet unidentified protein kinase which is situated in the contraction signaling cascade downstream of AMPK-was accompanied by a higher rate of LCFA uptake and a decreased glucose uptake.…”