Role of miR-21-5p/FilGAP axis in estradiol alleviating the progression of monocrotaline-induced pulmonary hypertension

Abstract

Background: Aberrant expression of microRNAs (miRNAs) has been associated with the pathogenesis of pulmonary hypertension (PH). It is, however, not clear whether miRNAs are involved in estrogen rescue of PH. Methods: Fresh plasma samples were prepared from 12 idiopathic pulmonary arterial hypertension (IPAH) patients and 12 healthy controls undergoing right heart catheterization in Shanghai Pulmonary Hospital. From each sample, 5 μg of total RNA was tagged and hybridized on microRNA microarray chips. Monocrotaline-induced PH (MCT-PH) male rats were treated with 17β-estradiol (E2) or vehicle. Subgroups were cotreated with estrogen receptor (ER) antagonist or with antagonist of miRNA. Results: Many circulating miRNAs, including miR-21-5p and miR-574-5p, were markedly expressed in patients and of interest in predicting mean pulmonary arterial pressure elevation in patients. The expression of miR-21-5p in the lungs was significantly upregulated in MCT-PH rats compared with the controls. However, miR-574-5p showed no difference in the lungs of MCT-PH rats and controls. miR-21-5p was selected for further analysis in rats as E2 strongly regulated it. E2 decreased miR-21-5p expression in the lungs of MCT-PH rats by ERβ. E2 reversed miR-21-5p target gene FilGAP downregulation in the lungs of MCT-PH rats. The abnormal expression of RhoA, ROCK2, Rac1 and c-Jun in the lungs of MCT-PH rats was inhibited by E2 and miR-21-5p antagonist. Conclusions: miR-21-5p level was remarkably associated with PH severity in patients. Moreover, the miR-21-5p/FilGAP signaling pathway modulated the protective effect of E2 on MCT-PH through ERβ.