AIMS: CD36-mediated uptake of oxidized low-density lipoprotein (oxLDL) plays a pivotal role in macrophage foam-cell formation and atherogenesis. Previously we reported on intermedin (IMD), a novel member of the calcitonin gene-related peptide family, in atherosclerotic plaque reducing atherogenesis in apolipoprotein E-deficient (apoE(-/-)) mice. Here, we studied the role of IMD in CD36-mediated macrophage foam-cell formation.METHODS AND RESULTS: In apoE(-/-) mice, 6-week IMD infusion reduced oxLDL uptake, intracellular cholesterol content, and foam-cell formation in peritoneal macrophages and reduced protein and mRNA levels of CD36. These in vivo results agreed with in vitro observations in primary peritoneal macrophages. Reduced CD36 protein and mRNA levels were due to an IMD-accelerated decay of CD36 mRNA. Tristetraprolin (TTP), which binds to AU-rich elements in the 3' untranslated regions (UTRs) of mRNA and promotes its degradation, mediated CD36 mRNA destabilization. TTP knockdown by short-hairpin RNA increased and TTP overexpression reduced CD36 expression, and TTP knockdown rescued IMD-reduced CD36 expression. Moreover, IMD repressed TTP phosphorylation, thereby activating TTP, for increased TTP binding to the 3'-UTR of CD36 mRNA.CONCLUSION: Thus, IMD attenuates macrophage foam-cell formation via TTP-mediated degradation of CD36 mRNA. Our findings reveal a new mechanism of the anti-atherogenic role of IMD and a novel pattern for regulation of CD36 expression in macrophages.
3' Untranslated Regions Animals