title: microRNA-122 down-regulation may play a role in severe myocardial fibrosis in human aortic stenosis through TGF-β1 up-regulation.
abstract: miRNAs (microRNAs) have been shown to play a role in myocardial fibrosis. The present study was designed to analyse whether alterations in miRNA expression contribute to the progression of myocardial fibrosis in AS (aortic valve stenosis) patients through up-regulation of the pro-fibrotic factor TGF-β1 (transforming growth factor-β type 1). Endomyocardial biopsies were obtained from 28 patients with severe AS, and from the necropsies of 10 control subjects. AS patients presented increased myocardial CVF (collagen volume fraction) and TGF-β1 compared with the controls, these parameters being correlated in all patients. Patients were divided into two groups by cluster analysis according to their CVF: SF (severe fibrosis; CVF >15%; n=15) and non-SF (CVF ≤15%; n=13). TGF-β1 was increased in patients with SF compared with those with non-SF. To analyse the involvement of miRNAs in SF, the miRNA expression profile of 10 patients (four with non-SF and six with SF) was analysed showing that 99 miRNAs were down-regulated and 19 up-regulated in the SF patients compared with the non-SF patients. Those miRNAs potentially targeting TGF-β1 were validated by real-time RT (reverse transcription)-PCR in the whole test population, corroborating that miR-122 and miR-18b were down-regulated in patients with SF compared with those with non-SF and the control subjects. Additionally, miR-122 was inversely correlated with the CVF, TGF-β1 and the TGF-β1-regulated PCPE-1 (procollagen C-terminal proteinase enhancer-1) in all patients. Experiments in human fibroblasts demonstrated that miR-122 targets and inhibits TGF-β1. In conclusion, for the first time we show that myocardial down-regulation of miR-122 might be involved in myocardial fibrosis in AS patients, probably through TGF-β1 up-regulation.
authors.affiliation: *Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Beaumont
authors.affiliation: *Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.affiliation: *Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Hermida
authors.affiliation: †Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER Maastricht, The Netherlands.
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
authors.affiliation: *Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Gorka
authors.initials: G
authors.lastname: San José
authors.affiliation: †Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER Maastricht, The Netherlands.
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.affiliation: ‡Division of Cardiology, Virgen de la Victoria University Hospital, 29010 Málaga, Spain.
authors.forename: Félix
authors.initials: F
authors.lastname: Valencia
authors.affiliation: ‡Division of Cardiology, Virgen de la Victoria University Hospital, 29010 Málaga, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Gómez-Doblas
authors.affiliation: ‡Division of Cardiology, Virgen de la Victoria University Hospital, 29010 Málaga, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: De Teresa
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
authors.affiliation: *Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Arantxa
authors.initials: A
authors.lastname: González
mesh_terms: D000368:Aged; D001024:Aortic Valve Stenosis / Q000503:physiopathology*; D015536:Down-Regulation; D005260:Female; D005355:Fibrosis / Q000503:physiopathology*; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1