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Implication of the transcription Factor FOXM1 in pulmonary arterial hypertension
Author(s) -
BOUCHERAT Olivier,
TRINH Isabelle,
LAMBERT Caroline,
POTUS François,
BREUILSBONNET Sandra,
NADEAU Valérie,
PAULIN Roxanne,
PROVENCHER Steeve,
BONNET Sébastien
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1073.12
Subject(s) - foxm1 , cancer research , apoptosis , thiostrepton , protein kinase b , transcription factor , dna damage , cell cycle , cell growth , medicine , biology , dna , ribosome , rna , biochemistry , genetics , gene
RATIONALE Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary vasculature, defined by an elevated pulmonary vascular resistance, leading to right heart failure and premature death. PAH is characterized by enhanced pulmonary artery smooth muscle (PASMC) proliferation and suppressed apoptosis within pulmonary artery (PA) wall. Targeting the cancer‐like of PASMCs represents an attractive therapeutic avenue to tackle PAH. Overexpression of the transcription factor FOXM1 has been shown to be a key driver of cancer progression through the stimulation of DNA repair, cell proliferation and cell survival. OBJECTIVE Using a multidisciplinary and translational approach we aimed to demonstrate that up‐regulation of FOXM1 in PAH‐PASMCs triggers proliferation and resistance to apoptosis. METHODS AND RESULTS FOXM1 is significantly increased (immunoblot and immunofluorescence) in lungs, distal PAs, and isolated PASMCs from PAH patients as well as in the monocrotaline (MCT)‐induced PAH model compared to controls. We demonstrated that, in response to growth factors like PDGF and IGF1, Akt is activated (increased P‐Akt), phosphorylates FOXO3a and inhibits it, allowing the up‐regulation of FOXM1. Moreover, we found that inhibition of FOXM1 in PAH‐PASMCs increases DNA damage (gH2AX) and reduces expression of NBS1 and PLK1 (immunoblot), two factors up‐regulated in PAH‐PASMCs (immunoblot and immunofluorescence) and involved in DNA repair and cell cycle progression. Consistently, pharmacological inhibition of FOXM1 using Thiostrepton dose‐dependently reduces PAH‐PASMC proliferation (Ki67 labeling) and resistance to apoptosis (Annexin V assay) in vitro . Inhibition of FOXM1 with Thiostrepton improves established PAH (right heart catheterization) in the MCT model. CONCLUSION We showed for the first time that FOXM1 is overexpressed in human PAH and implicated in the pro‐proliferative and anti‐apoptotic phenotype of PAH‐PASMCs. Support or Funding Information None