• Lin Deng, Francisco J Blanco, Hannah Stevens, Ruifang Lu, Axelle Caudrillier, Martin McBride, John D McClure, Jenny Grant, Matthew Thomas, Maria Frid, Kurt Stenmark, Kevin White, Anita G Seto, Nicholas W Morrell, Angela C Bradshaw, Margaret R MacLean, and Andrew H Baker.
• From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (L.D., F.J.B., H.S., A.C., M.M., J.D.M., J.G., K.W., A.C.B., M.R.M., A.H.B.); Novartis Institutes for BioMedical Research, Horsham, United Kingdom (M.T.); Division of Critical Care Medicine/Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics and Medicine, University of Colorado Denver, Aurora (M.F., K.S.); MiRagen Therapeutics, Inc, Boulder, CO (A.G.S.); Division of Respiratory Medicine, Department of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom (N.W.M.); King's British Heart Foundation Centre, King's College London, London, United Kingdom (R.L.); AstraZeneca R&D Mölndal, R&D Respiratory, Inflammation and Autoimmunity (RIA) Innovative Medicines, Mölndal, Sweden (M.T.); and Novartis Institutes for BioMedical Research, Inc, Cambridge, MA (K.W.).
• Circ. Res. 2015 Oct 23;117(10):870-83.

RationaleThe pathogenesis of pulmonary arterial hypertension (PAH) remains unclear. The 4 microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered.ObjectiveTo elucidate the transcriptional regulation of the miR-143/145 cluster and the role of miR-143 in PAH.Methods And ResultsWe identified the promoter region that regulates miR-143/145 microRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signaling pathways, including estrogen receptor, liver X factor/retinoic X receptor, transforming growth factor-β (Smads), and hypoxia (hypoxia response element), that regulated levels of all pri-miR stem loop transcription and resulting microRNA expression. We observed that miR-143-3p is selectively upregulated compared with miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMC-derived exosomes. Using assays with pulmonary arterial endothelial cells, we demonstrated a paracrine promigratory and proangiogenic effect of miR-143-3p-enriched exosomes from PASMC. Quantitative polymerase chain reaction and in situ hybridization showed elevated expression of miR-143 in calf models of PAH and in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role of miR-143 in experimental pulmonary hypertension in vivo in miR-143-/- and anti-miR-143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings.ConclusionsMiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, whereas inhibition of miR-143-3p blocked experimental pulmonary hypertension. Taken together, these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology.© 2015 American Heart Association, Inc.

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