title: Krüppel-like factor 5 contributes to pulmonary artery smooth muscle proliferation and resistance to apoptosis in human pulmonary arterial hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation of pulmonary artery smooth muscle cell (PASMC) and suppressed apoptosis. This phenotype has been associated with the upregulation of the oncoprotein survivin promoting mitochondrial membrane potential hyperpolarization (decreasing apoptosis) and the upregulation of growth factor and cytokines like PDGF, IL-6 and vasoactive agent like endothelin-1 (ET-1) promoting PASMC proliferation. Krüppel-like factor 5 (KLF5), is a zinc-finger-type transcription factor implicated in the regulation of cell differentiation, proliferation, migration and apoptosis. Recent studies have demonstrated the implication of KLF5 in tissue remodeling in cardiovascular diseases, such as atherosclerosis, restenosis, and cardiac hypertrophy. Nonetheless, the implication of KLF5 in pulmonary arterial hypertension (PAH) remains unknown. We hypothesized that KLF5 up-regulation in PAH triggers PASMC proliferation and resistance to apoptosis.
  
  
  RESULTS
  We showed that KFL5 is upregulated in both human lung biopsies and cultured human PASMC isolated from distal pulmonary arteries from PAH patients compared to controls. Using stimulation experiments, we demonstrated that PDGF, ET-1 and IL-6 trigger KLF-5 activation in control PASMC to a level similar to the one seen in PAH-PASMC. Inhibition of the STAT3 pathway abrogates KLF5 activation in PAH-PASMC. Once activated, KLF5 promotes cyclin B1 upregulation and promotes PASMC proliferation and triggers survivin expression hyperpolarizing mitochondria membrane potential decreasing PASMC ability to undergo apoptosis.
  
  
  CONCLUSIONS
  We demonstrated for the first time that KLF5 is activated in human PAH and implicated in the pro-proliferative and anti-apoptotic phenotype that characterize PAH-PASMC. We believe that our findings will open new avenues of investigation on the role of KLF5 in PAH and might lead to the identification of new therapeutic targets.
authors.affiliation: Department of Medicine, Faculty of Medicine, Laval University, Quebec QC, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Courboulin
authors.forename: Véronique L
authors.initials: VL
authors.lastname: Tremblay
authors.forename: Marjorie
authors.initials: M
authors.lastname: Barrier
authors.forename: Jolyane
authors.initials: J
authors.lastname: Meloche
authors.forename: Maria Helena
authors.initials: MH
authors.lastname: Jacob
authors.forename: Mathilde
authors.initials: M
authors.lastname: Chapolard
authors.forename: Malik
authors.initials: M
authors.lastname: Bisserier
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.forename: Caroline
authors.initials: C
authors.lastname: Lambert
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology*; D016130:Immunophenotyping; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors