title: Intermedin inhibits macrophage foam-cell formation via tristetraprolin-mediated decay of CD36 mRNA.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, P. R. China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Dai
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.forename: Weiliang
authors.initials: W
authors.lastname: Sun
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Ding
authors.forename: Wengong
authors.initials: W
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.forename: Chaoshu
authors.initials: C
authors.lastname: Tang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ming-Jiang
authors.initials: MJ
authors.lastname: Xu
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001057:Apolipoproteins E; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001665:Binding Sites; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D001057:Apolipoproteins E; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D009479:Neuropeptides; D012333:RNA, Messenger; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse; C514552:intermedin protein, mouse; C099252:oxidized low density lipoprotein; D002784:Cholesterol
keywords: Atherosclerosis; Macrophage; Peptide; Scavenger receptor; mRNA degradation