title: Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis.
abstract: BACKGROUND
  The mammalian target of rapamycin complex 1 inhibitor, rapamycin, has been shown to decrease atherosclerosis, even while increasing plasma low-density lipoprotein levels. This suggests an antiatherogenic effect possibly mediated by the modulation of inflammatory responses in atherosclerotic plaques.
  
  
  OBJECTIVE
  Our aim was to assess the role of macrophage mammalian target of rapamycin complex 1 in atherogenesis.
  
  
  RESULTS
  We transplanted bone marrow from mice in which a key mammalian target of rapamycin complex 1 adaptor, regulatory-associated protein of mTOR, was deleted in macrophages by Cre/loxP recombination (Mac-Rap(KO) mice) into Ldlr(-/-) mice and then fed them the Western-type diet. Atherosclerotic lesions from Mac-Rap(KO) mice showed decreased infiltration of macrophages, lesion size, and chemokine gene expression compared with control mice. Treatment of macrophages with minimally modified low-density lipoprotein resulted in increased levels of chemokine mRNAs and signal transducer and activator of transcription (STAT) 3 phosphorylation; these effects were reduced in Mac-Rap(KO) macrophages. Although wild-type and Mac-Rap(KO) macrophages showed similar STAT3 phosphorylation on Tyr705, Mac-Rap(KO) macrophages showed decreased STAT3Ser727 phosphorylation in response to minimally modified low-density lipoprotein treatment and decreased Ccl2 promoter binding of STAT3.
  
  
  CONCLUSIONS
  The results demonstrate cross-talk between nutritionally induced mammalian target of rapamycin complex 1 signaling and minimally modified low-density lipoprotein-mediated inflammatory signaling via combinatorial phosphorylation of STAT3 in macrophages, leading to increased STAT3 activity on the chemokine (C-C motif) ligand 2 (monocyte chemoattractant protein 1) promoter with proatherogenic consequences.
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (D.A., H.J., M. Westerterp, A.J.M., M. Wang, A.G., S.A., C.W., A.R.T.); Department of Physiology, Tianjin Medical University, Tianjin, China (D.A., Y.Z.); Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M. Westerterp); and Department of Medicine, University of California at San Diego, CA (F.A., Y.I.M.).
authors.forename: Ding
authors.initials: D
authors.lastname: Ai
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Jiang
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Mi
authors.initials: M
authors.lastname: Wang
authors.forename: Anjali
authors.initials: A
authors.lastname: Ganda
authors.forename: Sandra
authors.initials: S
authors.lastname: Abramowicz
authors.forename: Carrie
authors.initials: C
authors.lastname: Welch
authors.forename: Felicidad
authors.initials: F
authors.lastname: Almazan
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yury I
authors.initials: YI
authors.lastname: Miller
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D004041:Dietary Fats / Q000009:adverse effects; D005786:Gene Expression Regulation; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D018925:Chemokines; D004041:Dietary Fats; D046912:Multiprotein Complexes; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: atherosclerosis; macrophages; mammalian target of rapamycin complex 1