Editors' ChoiceLUNG PHYSIOLOGY

Pulmonary Hypertension’s Appealing News

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Science Translational Medicine  23 Jan 2013:
Vol. 5, Issue 169, pp. 169ec15
DOI: 10.1126/scitranslmed.3005692

The complex human cardiovascular system is composed of a systemic and a pulmonary circulation, each of which has its own personality. The former is a high-pressure system that carries oxygenated blood from the lungs to the periphery, whereas in the latter, blood vessels carry deoxygenated blood from the heart to the lungs in a low-pressure system. Whereas arterial hypertension is mostly synonymous with an increase in systemic blood pressure, more and more patients are being diagnosed with an increased blood pressure in pulmonary vessels. Research over the past decades has revealed pathophysiological differences between systemic and pulmonary arterial hypertension (PAH). Now, work by Kim and colleagues on the role of the peptide apelin in PAH adds new intrigue to this fascinating field of research.

Patients suffering from PAH display decreased expression of apelin (a peptide encoded by the APLN gene) on endothelial cells; increased expression of fibroblast growth factor 2 (FGF-2); and enhanced signaling through the FGF pathway—which is involved in cell proliferation and differentiation. Kim et al. combined these previous findings and linked them in a pathophysiological sequence that cumulates in aberrant proliferation of pulmonary artery endothelial cells (PAECs) and smooth muscle cells (PASMCs). The authors found an opposed expression of apelin and FGF-2 and FGF signaling in PAECs and PASMCs isolated from explanted normal donor lungs (up-regulated apelin, down-regulated FGF-2) and lungs of subjects with idiopathic or familial PAH (down-regulated apelin, up-regulated FGF-2).

Experiments with mouse models in which APLN was knocked down and gene expression microarray analyses revealed that FGF-2 is modulated by two microRNAs (miRNAs) whose synthesis was shown to be regulated downstream of apelin. miRNAs affect the stability of messenger RNA. Real-time polymerase chain reaction experiments showed that miR-424 and miR-503 expression was significantly down-regulated by knockdown of APLN. The importance of both miRNAs in the regulation of FGF-2 expression and function was demonstrated in apelin-null mice and in PAECs by blocking miRNA activity and FGF-2 expression. Accordingly, Kim and colleagues demonstrated reduced expression of apelin, miR-424, and miR-503 but increased expression of FGF-2 in PAECs from patients with PAH when compared with PAECs isolated from healthy lungs. As proof of concept, the authors also showed that intranasal delivery of lentiviral-encoded miR-424 and miR-503 down-regulated FGF-2 expression, ameliorating PAH in two experimental rat models of the disease.

The new work offers new insights into the underlying pathophysiology of PAH by identifying an apelin-dependent miRNA-FGF signaling pathway that is important for maintenance of pulmonary vascular homeostasis. These findings might reveal new therapeutic targets for the treatment of PAH and spur further research to identify other targets, beyond FGF signaling, that lie downstream of APLN or are regulated by miR-424 and miR-503.

J. Kim et al., An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat. Med. 19, 74–82 (2013). [PubMed]

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