microRNA-34a and microRNA 199a-5p in COPD and their control of HIF-1α expression in pulmonary vasucular endothelial cells

Rationale: MicroRNAs (miRNA) are small noncording RNAs that silence target gene expression post-transcriptionally, and their impact on gene expression has been reported in various diseases. In the lungs from COPD patients, increased expression of tumor suppressor p53 and decreased expression of HIF-1α have been reported. However, the regulatory roles of these miRNAs in COPD lungs have not been evaluated. Objective: To assess the expression of miRNAs known to be associated with p53 and HIF-1α expression in lung tissues from patients with COPD/emphysema. Methods: Lung tissue samples from 55 patients were included in this study. Total RNA and miRNA extracted from lung tissues were used for RT-PCR analysis focused on miR-20b, miR-34a, miR-107, miR-199a-5p and miR-210. HIF-1α and p53 protein expression, AKT phosphorylation was measured by Western blot analysis. Gene silencing of HIF-1α and transfection of miR34a and miR-199a-5p precursor RNAs were performed in cultured human pulmonary microvascular endothelial cells (HPMVEC). Measurements and main results: miR-34a and miR-199a-5p expression was increased and the phosphorylation of AKT was decreased in COPD lungs. Transfection of the miR34a precursor decreased the phosphorylation of AKT, and transfection of the miR-199a-5p precursor decreased HIF-1α and VEGF protein expression in HPMVEC. Conclusions: These data indicate that miR-34a and miR-199a-5p contribute to the pathogenesis of emphysema, via decreasing the expression of HIF-1α and increasing the expression of p53 in the lung and thereby affecting the HIF-1a/VEGF-dependent lung structure maintenance program.