Unanticipated role of apelin: regulation of miRNA generation.

Recently, a paper by Kim et al. [1] in Nature Medicine magazine in January, 2013 showed that apelin (also known as APLN) inhibits fibroblast growth factor 2 (FGF2) and FGF receptor 1 (FGFR1) expression to ameliorate pulmonary hypertension by regulating the expression of miR-424 and miR-503. This study revealed the molecular mechanism of apelin in inhibiting the process of pulmonary arterial hypertension (PAH) and discovered the role of apelin in regulating miRNA generation for the first time. miRNA functions in the transcriptional regulation of gene expression to control cellular processes. miRNA is a key regulatory factor of protein expression, but the generation and regulation mechanism of miRNA is still unclear. These novel findings bring us inspiration for further research, especially on the mechanism of miRNA generation. Experiments on revealing endogenous active substance, which regulates the generation of miRNAs or revealing miRNAs that regulate the expression of apelin, may bring more breakthroughs in the future. 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. Recent studies have suggested that apelin is a novel PAH endothelial function homeostasis-related factor. Alastalo et al. [2] found that apelin expression is decreased in endothelial cells of the pulmonary hypertension. However, the exact mechanism remains poorly understood. FGF2 is highly expressed in PAH and plays an important role in the progress of PAH by promoting proliferation [3] and inhibiting apoptosis [4] in endothelial cells and smooth muscle cells. miRNA is a fundamental factor of numerous cellular events by regulating RNA modification, transcription, and translation. Current studies of miRNA showed its critical function in the development of PAH. Morphological changes of plexiform vasculopathy in the end-stage PAH lung are reflected by alterations at the miRNA level [5]. Kim et al. [1] integrated these isolated observations into a mechanism and identified the miRNA-FGF signaling axis that is apelin-dependent in the maintenance of pulmonary vascular homeostasis. Previous studies found that hypoxia induces endothelial function injury. Accumulating evidence revealed that hypoxia also induces the expression of apelin [6,7],which is reduced in PAH. Actually, apelin expression and secretion, which are strongly induced under hypoxic conditions, are the early response [7]. Mechanisms that maintain sustained expression of apelin may contribute to preventing injuries caused by hypoxia and restoring the function of endothelial cells in PAH. These findings supported the development of novel therapeutic strategies to augment apelin, as well as to inhibit FGF2 signaling. In portal vein hypertension, another vascular disease, apelin/APJ presents a novel therapeutic target. APJ antagonist F13A effectively decreased the formation of portosystemic collateral vessels [8]. In atherosclerosis (AS), increasing evidence tends to prove that apelin is a novel therapeutic target for AS [9]. Although no effective treatment for PAH is available at present, certain medicines are available to mitigate disease progression. Considering its protective effect on vasodilatory and endothelial cells, apelin may be a more efficacious target for PAH therapy. In past decades, apelin was suggested to involve in numerous physiological processes, including vasodilation, systole, salt and water balance, as well as pathophysiological processes such as high blood pressure, cancer, and so on. There must be many other undiscovered functions of apelin. The findings of the intimate relationship between apelin and miRNA provide much fresh thinking for the study of apelin. The study on miR-424 and miR-503 will help to discover additional features of apelin. Park et al. [10] found that the high expression of miR-424 and miR-503 is significantly implicated in chemoresistance and tumor progression in ovarian cancer, which probably regulates cancer stem cell processes. These results indicated that apelin probably plays a vital role in epithelial mesenchymal transition in cancers. A recent study revealed that miR-503 makes women predispose to lupus [11]. The relationship between apelin and lupus has not been explored. More evidence is required to confirm whether apelin controls the effects of miR-424 and miR-503 in the above process. There are some controversial reports of apelin/APJ effects on AS. Chun et al. [12] found that apelin decreases AS formation by blocking AngII actions in ApoE-KO mice. But Hashimoto et al. [13] Acta Biochim Biophys Sin 2013, 45: 896–898 |a The Author 2013. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. DOI: 10.1093/abbs/gmt090. Advance Access Publication 28 August 2013