MiR-339 inhibits proliferation of pulmonary artery smooth muscle cell by targeting FGF signaling

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.

Targeting Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension (BPD-PH): Potential Role of the FGF Signaling Pathway in the Development of the Pulmonary Vascular System

“…Furthermore, there is evidence that miRs target FGF signaling to regulate proliferation. In the study by Chen et al, the authors showed that miR-339 inhibited the proliferation of pulmonary artery smooth muscle cells (PASMCs) by targeting FGF signals [ 97 ]. By using EdU incorporation assay, they showed that miR-339 inhibited the proliferation of PASMC.…”

Identification of a Plasma Microrna Signature as Biomarker of Subaneurysmal Aortic Dilation in Patients with High Cardiovascular Risk

“…No studies have previously associated miR-339-3p with AAA. MiR-339 is highly expressed in the cardiovascular system and an important regulator of VSMC proliferation in pulmonary arteries [ 40 ]. Predicted genes targeted by miR-339-3p have been involved in adipocytokine, NOD-like receptor, chemokine, insulin, and MAPK signaling pathways and in apoptosis, all of them implicated in AAA pathology [ 41 , 42 ].…”

Diagnostic value of microRNA-27 and -339 in heart transplant recipients with myocardial fibrosis

“…При ишемической болезни сердца miR-339 способна увеличивать оксидативный стресс за счет подавления Nrf2/FOXO3 сигнального пути через специфический белок Sirt2 [24]. В исследовании J. Chen et al показано, что miR-339 подавляет пролиферацию гладкомышечных клеток легочной артерии через ингибирование FGF сигнального пути [25]. Результаты нашего исследования демонстрируют наличие значимо более высоких уровней экспрессии miR-27 и -339 у реципиентов сердца с развитием фибротических процессов в миокарде.…”