Abstract
Pulmonary artery hypertension (PAH) is a fatal disorder. Recent studies suggest that microRNA (miRNA) plays an important role in regulating proliferation of pulmonary artery smooth muscle cells (PASMC), which underlies the pathology of PAH. However, the exact mechanism of action of miRNAs remains elusive. In this study, we found that miR‐339 was highly expressed in the cardiovascular system and was downregulated by a group of cytokines and growth factors, especially PDGF‐BB and FGF2. Functional analyses revealed that miR‐339 can inhibit proliferation of PASMC. Also, miR‐339 inhibited FGF2‐induced proliferation, but had no effect on proliferation induced by PDGF‐BB. The fibroblast growth factor receptor substrate 2 (FRS2) was identified as a potential direct target of miR‐339. Consistent with the actions of miR‐339, knockdown of FRS2 only inhibited FGF2‐ but not PDGF‐BB‐induced proliferation of PASMC. In addition, our results showed that inhibition of ERK and PI3K abrogated the downregulation of miR‐339 induced by PDGF‐BB. Finally, miR‐339 expression was found to be decreased in the pulmonary arteries of rats with MCT‐induced PAH. Our study is the first report on the biological role of miR‐339 in regulating proliferation of PASMC by targeting FGF signaling, providing new mechanistic insights into PASMC proliferation and pathogenesis of PAH.
Highlights
Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vascular system, primarily affecting small pulmonary arterioles (Lai et al 2014)
We found that miR-339, one of the miRNAs regulated by plateletderived growth factor BB (PDGF-BB) identified in our earlier study, was highly expressed in cardiovascular system, which implicated a potential role for miR-339 in cardiovascular diseases
We found that miR-339 could be downregulated by many cytokines and growth factors, and that it inhibited the proliferation of pulmonary artery smooth muscle cell (PASMC) by targeting factor receptor substrate 2 (FRS2), a critical adaptor protein in the FGF signaling pathway (Chen et al 2009)
Summary
Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vascular system, primarily affecting small pulmonary arterioles (Lai et al 2014). PAH is a fast progressing vascular disease characterized by uncontrolled cell proliferation, migration, and reduced apoptosis of pulmonary artery smooth muscle cell (PASMC), leading to a progressive increase in pulmonary vascular resistance, right ventricular failure, and death (Stenmark et al 2006; Lai et al 2014). Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society
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