Reversal of MicroRNA Dysregulation in an Animal Model of Pulmonary Hypertension
Open Access
- 27 January 2016
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 11 (1), e0147827
- https://doi.org/10.1371/journal.pone.0147827
Abstract
Animals models have played an important role in enhancing our understanding of the pathogenesis of pulmonary arterial hypertension (PAH). Dysregulation of the profile of microRNAs (miRNAs) has been demonstrated in human tissues from PAH patients and in animal models. In this study, we measured miRNA levels in the monocrotaline (MCT) rat model of PAH and examined whether blocking a specific dysregulated miRNA not previously reported in this model, attenuated PAH. We also evaluated changes in miRNA expression in lung specimens from MCT PAH rats overexpressing human prostacyclin synthase, which has been shown to attenuate MCT PAH. Expression levels of a panel of miRNAs were measured in MCT-PAH rats as compared to naïve (saline) control rats. Subsequently, MCT PAH rats were injected with a specific inhibitor (antagomiR) for miR-223 (A223) or a nonspecific control oligonucleotide (A-control) 4 days after MCT administration, then weekly. Three weeks later, RV systolic pressure and RV mass were measured. Total RNA, isolated from the lungs, microdissected pulmonary arteries, and right ventricle, was reverse transcribed and real-time quantitative PCR was performed. MiRNA levels were also measured in RNA isolated from paraffin sections of MCT-PAH rats overexpressing prostacyclin synthase. MiRs 17, 21, and 223 were consistently upregulated, whereas miRs 126, 145, 150, 204, 424, and 503 were downregulated in MCT PAH as compared to vehicle control. A223 significantly reduced levels of miR-223 in PA and lungs of MCT PAH rats as compared to levels measured in A-control or control MCT PAH rats, but A223 did not attenuate MCT PAH. Right ventricular mass and right ventricular systolic pressure in rats treated with A223 were not different from values in A-control or MCT PAH rats. In contrast, analysis of total RNA from lung specimens of MCT PAH rats overexpressing human prostacyclin synthase (hPGIS) demonstrated reversal of MCT-induced upregulation of miRs 17, 21, and 223 and an increase in levels of miR-424 and miR-503. Reduction in bone morphogenetic receptor 2 (BMPR2) messenger (m)RNA expression was not altered by A223, whereas human prostacyclin synthase overexpression restored BMPR2 mRNA to levels in MCT PAH to levels measured in naive controls. Inhibition of miR-223 did not attenuate MCT PAH, whereas human prostacyclin synthase overexpression restored miRNA levels in MCT PAH to levels detected in naïve rats. These data may establish a paradigm linking attenuation of PAH to restoration of BMPR2 signaling.Keywords
This publication has 49 references indexed in Scilit:
- Circulating miRNAs as Potential Marker for Pulmonary HypertensionPLOS ONE, 2013
- MicroRNA-21 Integrates Pathogenic Signaling to Control Pulmonary Hypertension: Results of a Network Bioinformatics ApproachCirculation, 2012
- miR-21 regulates chronic hypoxia-induced pulmonary vascular remodelingAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2012
- Role for miR-204 in human pulmonary arterial hypertensionThe Journal of Experimental Medicine, 2011
- MicroRNA-21 plays a role in hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migrationAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2010
- Dynamic Changes in Lung MicroRNA Profiles During the Development of Pulmonary Hypertension due to Chronic Hypoxia and MonocrotalineArteriosclerosis, Thrombosis, and Vascular Biology, 2010
- The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human diseaseCell Death & Differentiation, 2009
- MicroRNA-145, a Novel Smooth Muscle Cell Phenotypic Marker and Modulator, Controls Vascular Neointimal Lesion FormationCirculation Research, 2009
- Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosisProceedings of the National Academy of Sciences of the United States of America, 2008
- The evolution of gene regulation by transcription factors and microRNAsNature Reviews Genetics, 2007