An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension
- Authors
- Kim, Jongmin; Kang, Yujung; Kojima, Yoko; Lighthouse, Janet K; Hu, Xiaoyue; Aldred, Micheala A; McLean, Danielle L; Park, Hyekyung; Comhair, Suzy A; Greif, Daniel M; Erzurum, Serpil C; Chun, Hyung J
- Issue Date
- Jan-2013
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- NATURE MEDICINE, v.19, no.1, pp 74 - 82
- Pages
- 9
- Journal Title
- NATURE MEDICINE
- Volume
- 19
- Number
- 1
- Start Page
- 74
- End Page
- 82
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/147505
- DOI
- 10.1038/nm.3040
- ISSN
- 1078-8956
1546-170X
- Abstract
- Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling associated with obliteration of pulmonary arterioles and formation of plexiform lesions composed of hyperproliferative endothelial and vascular smooth-muscle cells. Here we describe a microRNA (miRNA)-dependent association between apelin (APLN) and fibroblast growth factor 2 (FGF2) signaling in pulmonary artery endothelial cells (PAECs). APLN deficiency in these cells led to increased expression of FGF2 and its receptor FGFR1 as a consequence of decreased expression of miR-424 and miR-503, which directly target FGF2 and FGFR1. miR-424 and miR-503 were downregulated in PAH, exerted antiproliferative effects in PAECs and inhibited the capacity of PAEC-conditioned medium to induce the proliferation of pulmonary artery smooth-muscle cells. Reconstitution of miR-424 and miR-503 in vivo ameliorated pulmonary hypertension in experimental models. These studies identify an APLN-dependent miRNA-FGF signaling axis needed for the maintenance of pulmonary vascular homeostasis.
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