Transcriptomics

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A critical role of microRNAs in human pulmonary arterial hypertension. miR-204: a novel therapeutic target (gene expression)


ABSTRACT: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. Downregulation of the BMPR2 gene along with activation of the transcription factor NFAT have been implicated in the maintenance of pro-proliferative and anti-apoptotic stages of cells. Since an increasing number of microRNAs have been implicated in the regulation of genes specifically important for cell proliferation and apoptosis, we hypothesized that microRNAs might be associated with these cellular features in the etiology of PAH. We demonstrate that downregulation of one such microRNA (miR-204) in human PAH-PASMC promotes the activation of an Src/STAT3/NFAT axis that increases PAH-PASMC proliferation and their resistance to apoptosis. Stimulation experiments using the pro-PAH factors (PDGF, endothelin-1 and angiotensin II) and time course analysis in experimental PAH show that STAT3 activation leads to miR-204 downregulation, thereby activating an Src-dependent positive feedback loop sustaining STAT3 and activating NFAT. More importantly, restoring miR-204 expression decreases proliferation and resistance to apoptosis in human and in an experimental PAH model. Taken together, our study uncovers a new STAT3-miR-204-Src/STAT3/NFAT axis that links the STAT3-dependent downregulation of BMPR2 with the NFAT-mediated pro-proliferative and anti-apoptotic phenotype observed in PAH. Our data point toward a novel potential strategy for treating patients with PAH. Comparative expression profiling of PAH versus healthy patients to evaluate the modulated genes in the disease. Following the demonstration of the downregulation of miR-204 in PAH we want to investigate the effect of the inhibition (using antagomir) of miR-204 expression in PASMC cells.

ORGANISM(S): Homo sapiens  

SUBMITTER: Nellie J Giguère   Sébastien Bonnet  Martin J Simard  Jacques Côté  Audrey Courboulin  Roxane Paulin  Eric R Paquet  Nehmé Saksouk 

PROVIDER: E-GEOD-21280 | ArrayExpress | 2010-12-16

SECONDARY ACCESSION(S): GSE21280PRJNA129437

REPOSITORIES: GEO, ArrayExpress

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