Chest
Volume 142, Issue 3, September 2012, Pages 663-672
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Original Research
COPD
MicroRNA-199a-5p Is Associated With Hypoxia-Inducible Factor-1α Expression in Lungs From Patients With COPD

https://doi.org/10.1378/chest.11-2746Get rights and content

Background

MicroRNAs (miRNAs) are small noncoding RNAs that silence target gene expression posttranscriptionally, and their impact on gene expression has been reported in various diseases. It has been reported that the expression of the hypoxia-inducible factor-1α (HIF-1α) is reduced and that of p53 is increased in lungs from patients with COPD. However, the role of miRNAs associated with these genes in lungs from patients with COPD is unknown.

Methods

Lung tissue samples from 55 patients were included in this study. Total RNA, miRNA, and protein were extracted from lung tissues and used for reverse transcriptase polymerase chain reaction and Western blot analysis. Cell culture experiments were performed using cultured human pulmonary microvascular endothelial cells (HPMVECs).

Results

miR-34a and miR-199a-5p expressions were increased, and the phosphorylation of AKT was decreased in the lung tissue samples of patients with COPD. The miR-199a-5p expression was correlated with HIF-1α protein expression in the lungs of patients with COPD. Transfection of HPMVECs with the miR-199a-5p precursor gene decreased HIF-1α protein expression, and transfection with the miR-34a precursor gene increased miR-199a-5p expression.

Conclusions

These data suggest that miR-34a and miR-199a-5p contribute to the pathogenesis of COPD, and these miRNAs may also affect the HIF-1α-dependent lung structure maintenance program.

Section snippets

Lung Tissue Samples

Lung tissue samples from 55 patients were included in this study. We divided the patients into four groups according to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) classification. Ten samples were from patients with normal lung function (no COPD); the remainder of the samples were from patients with mild (n = 13; stage I, GOLD classification), moderate (n = 17; stage II, GOLD classification), and severe (n = 15; stage III and IV, GOLD classification) COPD. Table 1

Patient Characteristics

The data and characteristics describing the patients from which the lung tissue samples (LTRC) have been derived are displayed in Table 1. The lung samples from never smokers with normal lung function were all from female patients. Although a histopathologic diagnosis of lung cancer had been made in 24 of 55 patients, the tissue samples investigated were all histologically cancer-free and represented tissue highly remote from any tumor. The LTRC data set did not provide blood gas information

Discussion

The destruction of lung tissue in patients with COPD and emphysema has been well characterized by histologic studies and inflammatory and per se noninflammatory pathomechanisms have been proposed and discussed,24 also in the context of a homeostatic adult lung structure maintenance program.25 We have reported a decreased expression of HIF-1α protein in lungs from patients with COPD and varying degrees of lung function impairment.14 Here, to our knowledge, we report for the first time the

Acknowledgments

Author contributions: Dr Mizuno: contributed to designing and organizing the experiments, carrying out the data analysis, and writing of the manuscript.

Dr Bogaard: contributed to the design of the study and revising the manuscript.

Dr Gomez-Arroyo: contributed to laboratory measurements, data analysis, and writing of the manuscript.

Dr Alhussaini: contributed to laboratory measurements, data analysis, and writing of the manuscript.

Dr Kraskauskas: contributed to laboratory measurements, data

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    Funding/Support: This study was supported by the National Institutes of Health [Grant N01-HR-46160-3], and funds from the Victoria Johnson Center for Lung Research of the Virginia Commonwealth University.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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