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

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 (E(2)) 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 E(2) strongly regulated it. E(2) decreased miR‐21‐5p expression in the lungs of MCT‐PH rats by ERβ. E(2) 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 E(2) 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 E(2) on MCT‐PH through ERβ.