title: Role for miR-204 in human pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR-204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down-regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease.
authors.affiliation: Département de médecine, Faculté de médecine, Hôtel-Dieude Québec, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Courboulin
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.forename: Nellie J
authors.initials: NJ
authors.lastname: Giguère
authors.forename: Nehmé
authors.initials: N
authors.lastname: Saksouk
authors.forename: Tanya
authors.initials: T
authors.lastname: Perreault
authors.forename: Jolyane
authors.initials: J
authors.lastname: Meloche
authors.forename: Eric R
authors.initials: ER
authors.lastname: Paquet
authors.forename: Sabrina
authors.initials: S
authors.lastname: Biardel
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
authors.forename: Jacques
authors.initials: J
authors.lastname: Côté
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Simard
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D065627:Familial Primary Pulmonary Hypertension; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000235:genetics / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology
chemical_list: D005819:Genetic Markers; C549404:MIRN204 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019061:src-Family Kinases