title: RAGE-dependent activation of the oncoprotein Pim1 plays a critical role in systemic vascular remodeling processes.
abstract: OBJECTIVE
  Vascular remodeling diseases (VRD) are mainly characterized by inflammation and a vascular smooth muscle cells (VSMCs) proproliferative and anti-apoptotic phenotype. Recently, the activation of the advanced glycation endproducts receptor (RAGE) has been shown to promote VSMC proliferation and resistance to apoptosis in VRD in a signal transducer and activator of transcription (STAT)3-dependant manner. Interestingly, we previously described in both cancer and VRD that the sustainability of this proproliferative and antiapoptotic phenotype requires activation of the transcription factor NFAT (nuclear factor of activated T-cells). In cancer, NFAT activation is dependent of the oncoprotein provirus integration site for Moloney murine leukemia virus (Pim1), which is regulated by STAT3 and activated in VRD. Therefore, we hypothesized that RAGE/STAT3 activation in VSMC activates Pim1, promoting NFAT and thus VSMC proliferation and resistance to apoptosis. Methods/Results- In vitro, freshly isolated human carotid VSMCs exposed to RAGE activator Nε-(carboxymethyl)lysine (CML) for 48 hours had (1) activated STAT3 (increased P-STAT3/STAT3 ratio and P-STAT3 nuclear translocation); (2) increased STAT3-dependent Pim1 expression resulting in NFATc1 activation; and (3) increased Pim1/NFAT-dependent VSMC proliferation (PCNA, Ki67) and resistance to mitochondrial-dependent apoptosis (TMRM, Annexin V, TUNEL). Similarly to RAGE inhibition (small interfering RNA [siRNA]), Pim1, STAT3 and NFATc1 inhibition (siRNA) reversed these abnormalities in human carotid VSMC. Moreover, carotid artery VSMCs isolated from Pim1 knockout mice were resistant to CML-induced VSMC proliferation and resistance to apoptosis. In vivo, RAGE inhibition decreases STAT3/Pim1/NFAT activation, reversing vascular remodeling in the rat carotid artery-injured model.
  
  
  CONCLUSIONS
  RAGE activation accounts for many features of VRD including VSMC proliferation and resistance to apoptosis by the activation of STAT3/Pim1/NFAT axis. Molecules aimed to inhibit RAGE could be of a great therapeutic interest for the treatment of VRD.
authors.affiliation: Department of Medicine, Université Laval, Québec City, Canada.
authors.forename: Jolyane
authors.initials: J
authors.lastname: Meloche
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.forename: Audrey
authors.initials: A
authors.lastname: Courboulin
authors.forename: Caroline
authors.initials: C
authors.lastname: Lambert
authors.forename: Marjorie
authors.initials: M
authors.lastname: Barrier
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonnet
authors.forename: Malik
authors.initials: M
authors.lastname: Bisserier
authors.forename: Mélanie
authors.initials: M
authors.lastname: Roy
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
authors.forename: Mohsen
authors.initials: M
authors.lastname: Agharazii
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000502:physiology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D050778:NFATC Transcription Factors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D050796:STAT3 Transcription Factor; C048496:N(6)-carboxymethyllysine; C496634:PIM1 protein, human; C496636:Pim1 protein, mouse; C496637:Pim1 protein, rat; D051573:Proto-Oncogene Proteins c-pim-1; D008239:Lysine; D002118:Calcium