Статья

Interleukin-6 Modulates the Expression of the Bone Morphogenic Protein Receptor Type II Through a Novel STAT3–microRNA Cluster 17/92 Pathway

Matthias BrockFrom the Center for Experimental Rheumatology and Zurich Center for Integrative Human Physiology (M.B., M.T., R.E.G., B.A.M., S.G., L.C.H.), University of Zurich, Switzerland; and Working Group for Pulmonary Hypertension (M.B., M.F., S.U., R.S., L.C.H.), Department for Internal Medicine, University Hospital Zurich, SwitzerlandMichelle TrenkmannFrom the Center for Experimental Rheumatology and Zurich Center for Integrative Human Physiology (M.B., M.T., R.E.G., B.A.M., S.G., L.C.H.), University of Zurich, Switzerland; and Working Group for Pulmonary Hypertension (M.B., M.F., S.U., R.S., L.C.H.), Department for Internal Medicine, University Hospital Zurich, SwitzerlandRenate E. GayFrom the Center for Experimental Rheumatology and Zurich Center for Integrative Human Physiology (M.B., M.T., R.E.G., B.A.M., S.G., L.C.H.), University of Zurich, Switzerland; and Working Group for Pulmonary Hypertension (M.B., M.F., S.U., R.S., L.C.H.), Department for Internal Medicine, University Hospital Zurich, SwitzerlandBeat A. MichelFrom the Center for Experimental Rheumatology and Zurich Center for Integrative Human Physiology (M.B., M.T., R.E.G., B.A.M., S.G., L.C.H.), University of Zurich, Switzerland; and Working Group for Pulmonary Hypertension (M.B., M.F., S.U., R.S., L.C.H.), Department for Internal Medicine, University Hospital Zurich, SwitzerlandSteffen GayFrom the Center for Experimental Rheumatology and Zurich Center for Integrative Human Physiology (M.B., M.T., R.E.G., B.A.M., S.G., L.C.H.), University of Zurich, Switzerland; and Working Group for Pulmonary Hypertension (M.B., M.F., S.U., R.S., L.C.H.), Department for Internal Medicine, University Hospital Zurich, SwitzerlandManuel FischlerFrom the Center for Experimental Rheumatology and Zurich Center for Integrative Human Physiology (M.B., M.T., R.E.G., B.A.M., S.G., L.C.H.), University of Zurich, Switzerland; and Working Group for Pulmonary Hypertension (M.B., M.F., S.U., R.S., L.C.H.), Department for Internal Medicine, University Hospital Zurich, SwitzerlandSilvia UlrichFrom the Center for Experimental Rheumatology and Zurich Center for Integrative Human Physiology (M.B., M.T., R.E.G., B.A.M., S.G., L.C.H.), University of Zurich, Switzerland; and Working Group for Pulmonary Hypertension (M.B., M.F., S.U., R.S., L.C.H.), Department for Internal Medicine, University Hospital Zurich, SwitzerlandRudolf SpeichFrom the Center for Experimental Rheumatology and Zurich Center for Integrative Human Physiology (M.B., M.T., R.E.G., B.A.M., S.G., L.C.H.), University of Zurich, Switzerland; and Working Group for Pulmonary Hypertension (M.B., M.F., S.U., R.S., L.C.H.), Department for Internal Medicine, University Hospital Zurich, SwitzerlandLars C HuberFrom the Center for Experimental Rheumatology and Zurich Center for Integrative Human Physiology (M.B., M.T., R.E.G., B.A.M., S.G., L.C.H.), University of Zurich, Switzerland; and Working Group for Pulmonary Hypertension (M.B., M.F., S.U., R.S., L.C.H.), Department for Internal Medicine, University Hospital Zurich, Switzerland

2009en

ABI

Аннотация

Dysregulated expression of bone morphogenetic protein receptor type II (BMPR2) is a pathogenetic hallmark of pulmonary hypertension. Downregulation of BMPR2 protein but not mRNA has been observed in multiple animal models mimicking the disease, indicating a posttranscriptional mechanism of regulation. Because microRNAs (miRNAs) regulate gene expression mainly through inhibition of target gene translation, we hypothesized that miRNAs may play a role in the modulation of BMPR2. Performing a computational algorithm on the BMPR2 gene, several miRNAs encoded by the miRNA cluster 17/92 (miR-17/92) were retrieved as potential regulators. Ectopic overexpression of miR-17/92 resulted in a strong reduction of the BMPR2 protein, and a reporter gene system showed that BMPR2 is directly targeted by miR-17-5p and miR-20a. By stimulation experiments, we found that the miR-17/92 cluster is modulated by interleukin (IL)-6, a cytokine involved in the pathogenesis of pulmonary hypertension. Because IL-6 signaling is mainly mediated by STAT3 (signal transducer and activator of transcription 3), the expression of STAT3 was knocked down by small interfering RNA, which abolished the IL-6-mediated expression of miR-17/92. Consistent with these data, we found a highly conserved STAT3-binding site in the promoter region of the miR-17/92 gene (C13orf25). Promoter studies confirmed that IL-6 enhances transcription of C13orf25 through this distinct region. Finally, we showed that persistent activation of STAT3 leads to repressed protein expression of BMPR2. Taken together, we describe here a novel STAT3-miR-17/92-BMPR2 pathway, thus providing a mechanistic explanation for the loss of BMPR2 in the development of pulmonary hypertension.

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Идентификаторы

DOI: 10.1161/circresaha.109.197491

Цитирования и источники

Цитирований: 3Использованных источников: 0

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