title: Adiponectin induces vascular smooth muscle cell differentiation via repression of mammalian target of rapamycin complex 1 and FoxO4.
abstract: OBJECTIVE
  The adipocyte-secreted hormone adiponectin exerts important cardioprotective and antidiabetic effects. Little is known about its effect on vascular smooth muscle cells (VSMC), key cells in restenosis, hypertension, and atherosclerosis.
  
  
  RESULTS
  Using human coronary artery VSMC, we found that recombinant adiponectin in the high-molecular-weight or trimeric forms but not the globular form induced VSMC differentiation through a mechanism similar to the classic feedback signaling used by rapamycin, a drug known to effectively inhibit restenosis on drug-eluting stents. Using a combination of pharmacological agents, small interfering RNA, and overexpression approaches, we demonstrated that adiponectin activated 5'-AMP-activated protein kinase α2 isoform, leading to inhibition of mammalian target of rapamycin complex 1 and S6K1. This in turn stabilized insulin receptor substrate-1, driving Akt2-mediated inhibition of FoxO4 and subsequent contractile protein induction. Although adiponectin and rapamycin have similarly beneficial effects on VSMC phenotype in both cell and organ culture, a direct comparison of the effects of rapamycin versus adiponectin on endothelial cells revealed distinct differences: rapamycin inhibited Akt phosphorylation, whereas adiponectin maintained it. Importantly, Akt activity preserves endothelial function.
  
  
  CONCLUSIONS
  Adiponectin promotes VSMC differentiation and preserves endothelial cell Akt signaling, suggesting that targeting the adiponectin pathway may have advantages over rapamycin in developing new drug-eluting stent therapeutics.
authors: Section of Vascular Surgery, Department of Surgery, Dartmouth Medical School, Lebanon, NH, USA.
authors: Min
authors: M
authors: Ding
authors: Yi
authors: Y
authors: Xie
authors: Robert J
authors: RJ
authors: Wagner
authors: Yu
authors: Y
authors: Jin
authors: Ana Catarina
authors: AC
authors: Carrao
authors: Lucinda S
authors: LS
authors: Liu
authors: Anthony K
authors: AK
authors: Guzman
authors: Richard J
authors: RJ
authors: Powell
authors: John
authors: J
authors: Hwa
authors: Eva M
authors: EM
authors: Rzucidlo
authors: Kathleen A
authors: KA
authors: Martin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D052242:Adiponectin / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects; D051858:Forkhead Transcription Factors; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D052242:Adiponectin; D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D046912:Multiprotein Complexes; D011506:Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; C494921:AKT2 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus