US EPA

3472110 

Journal Article 

MicroRNA-338-5p modulates pulmonary hypertension-like injuries caused by SO2, NO2 and PM2.5 co-exposure through targeting the HIF-1 alpha/Fhl-1 pathway 

Ji, X; Zhang, Y; Ku, T; Yun, Y; Li, G; Sang, N 

2016 

Yes 

Toxicology Research
ISSN: 2045-452X
EISSN: 2045-4538 

5 

6 

1548-1560 

English 

30090456 

10.1039/c6tx00257a 

WOS:000387013300006 

The role of ambient air pollution is considered to be important in the development of chronic obstructive pulmonary disease (COPD), and pulmonary hypertension (PH) is a common clinical manifestation of COPD. However, many studies have mainly focused on the adverse health effects of a single air pollutant, ignoring the combined toxicity of multiple pollutants. In the present study, we co-exposed mice to coal-burning air pollutants (SO2, NO2 and PM2.5), and confirmed PH-like injury occurrence by airflow limitation, marked abnormal endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) expression, and histopathological and ultrastructural alteration. Global microRNA (miRNA) arrays identified three significantly changed miRNAs homologous with humans (miR-338-5p, miR-450b-3p and miR-142-5p), and we targeted miR-338-5p based on real-time reverse transcription-PCR (RT-PCR) validation. Furthermore, bioinformatic and dual-luciferase reporter gene analyses indicated that miR-338-5p bound to 3'-UTR of hypoxia-inducible factor 1 alpha(HIF-1 alpha) mRNA and down-regulation of miR-338-5p led to the increased expression of HIF-1 alpha and its related gene four-and-a-half LIM (Lin-11, Isl-1 and Mec-3) domain 1 (Fhl-1) and contributed to PH. This study provides evidence for the role of miRNAs in PH through targeting HIF-1 alpha/Fhl-1 pathway after air pollutants co-exposure and implies new insights into the molecular markers for COPD caused by air pollution.