Short-term Exposure to Intermittent Hypoxia Leads to Changes in Gene Expression Seen in Chronic Pulmonary Disease

Overview

Journal Elife

Specialty Biology

Date 2021 Feb 18

PMID 33599610

Citations 19

Authors

Gang Wu

Yin Yeng Lee

Evelyn M Gulla

Andrew Potter

Joseph Kitzmiller

Marc D Ruben

Nathan Salomonis

Jeffery A Whitsett

Lauren J Francey

John B Hogenesch

David F Smith

Affiliations

Soon will be listed here.

Abstract

Obstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia (IH) and is associated with a host of health complications. Although the lung is the first organ to sense changes in oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor-responsive pathways. We hypothesized that exposure to IH would lead to cell-specific up- and downregulation of diverse expression pathways. We identified changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells showed the most prominent transcriptional changes. Upregulated genes in myofibroblast cells were enriched for genes associated with pulmonary hypertension and included targets of several drugs currently used to treat chronic pulmonary diseases. A better understanding of the pathophysiologic mechanisms underlying diseases associated with OSA could improve our therapeutic approaches, directing therapies to the most relevant cells and molecular pathways.

Citing Articles

Identification of prognostic indicator based on hypoxia-related lncRNAs analysis in lung adenocarcinoma.

Zhang J, Kondowe B, Zhang H, Xie X, Song Q, Guo B Malawi Med J. 2025; 36(3):170-178.

PMID: 40018402 PMC: 11862855. DOI: 10.4314/mmj.v36i3.3.

Elucidating the Interplay of Hypoxia-Inducible Factor and Circadian Clock Signaling in Obstructive Sleep Apnea Patients.

Gabryelska A, Turkiewicz S, Gajewski A, Bialasiewicz P, Strzelecki D, Ditmer M Int J Mol Sci. 2025; 26(3).

PMID: 39940739 PMC: 11817652. DOI: 10.3390/ijms26030971.

Advancements in the Application of scRNA-Seq in Breast Research: A Review.

Zhang Z, Ma X, La Y, Guo X, Chu M, Bao P Int J Mol Sci. 2025; 25(24.

PMID: 39769466 PMC: 11677372. DOI: 10.3390/ijms252413706.

Mendelian randomization study on causal association of TEF and circadian rhythm with pulmonary arterial hypertension.

Chen D, Jin Q, Yang L, Zhang X, Li M, Zhang L Respir Res. 2024; 25(1):301.

PMID: 39113039 PMC: 11308427. DOI: 10.1186/s12931-024-02934-8.

SinglePointRNA, an user-friendly application implementing single cell RNA-seq analysis software.

Puente-Santamaria L, Del Peso L PLoS One. 2024; 19(6):e0300567.

PMID: 38889133 PMC: 11185446. DOI: 10.1371/journal.pone.0300567.

References

Chaouat A, Weitzenblum E, Krieger J, Oswald M, Kessler R . Pulmonary hemodynamics in the obstructive sleep apnea syndrome. Results in 220 consecutive patients. Chest. 1996; 109(2):380-6. DOI: 10.1378/chest.109.2.380. View

Chin K, Shimizu K, Mishima M, Nakamura T, Miyasaka M, Ohi M . Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med. 2000; 109(7):562-7. DOI: 10.1016/s0002-9343(00)00580-5. View

Reinke C, Bevans-Fonti S, Grigoryev D, Drager L, Myers A, Wise R . Chronic intermittent hypoxia induces lung growth in adult mice. Am J Physiol Lung Cell Mol Physiol. 2010; 300(2):L266-73. PMC: 3043819. DOI: 10.1152/ajplung.00239.2010. View

Butler M, Smales C, Wu H, Hussain M, Mohamed Y, Morimoto M . The Circadian System Contributes to Apnea Lengthening across the Night in Obstructive Sleep Apnea. Sleep. 2015; 38(11):1793-801. PMC: 4813360. DOI: 10.5665/sleep.5166. View

Gillich A, Zhang F, Farmer C, Travaglini K, Tan S, Gu M . Capillary cell-type specialization in the alveolus. Nature. 2020; 586(7831):785-789. PMC: 7721049. DOI: 10.1038/s41586-020-2822-7. View

McIntosh B, Hogenesch J, Bradfield C . Mammalian Per-Arnt-Sim proteins in environmental adaptation. Annu Rev Physiol. 2010; 72:625-45. DOI: 10.1146/annurev-physiol-021909-135922. View

Wu G, Lee Y, Gulla E, Potter A, Kitzmiller J, Ruben M . Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease. Elife. 2021; 10. PMC: 7909952. DOI: 10.7554/eLife.63003. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Zambon A, Gaj S, Ho I, Hanspers K, Vranizan K, Evelo C . GO-Elite: a flexible solution for pathway and ontology over-representation. Bioinformatics. 2012; 28(16):2209-10. PMC: 3413395. DOI: 10.1093/bioinformatics/bts366. View

10.

Gibbs J, Beesley S, Plumb J, Singh D, Farrow S, Ray D . Circadian timing in the lung; a specific role for bronchiolar epithelial cells. Endocrinology. 2008; 150(1):268-76. PMC: 4340583. DOI: 10.1210/en.2008-0638. View

11.

Gallego-Martin T, Farre R, Almendros I, Gonzalez-Obeso E, Obeso A . Chronic intermittent hypoxia mimicking sleep apnoea increases spontaneous tumorigenesis in mice. Eur Respir J. 2017; 49(2). DOI: 10.1183/13993003.02111-2016. View

12.

Travaglini K, Nabhan A, Penland L, Sinha R, Gillich A, Sit R . A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature. 2020; 587(7835):619-625. PMC: 7704697. DOI: 10.1038/s41586-020-2922-4. View

13.

Gu Y, Hogenesch J, Bradfield C . The PAS superfamily: sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol. 2000; 40:519-61. DOI: 10.1146/annurev.pharmtox.40.1.519. View

14.

Osorio R, Gumb T, Pirraglia E, Varga A, Lu S, Lim J . Sleep-disordered breathing advances cognitive decline in the elderly. Neurology. 2015; 84(19):1964-71. PMC: 4433459. DOI: 10.1212/WNL.0000000000001566. View

15.

Li L, Zhang S, Wei L, Wang Z, Ma W, Liu F . FGF2 and FGFR2 in patients with idiopathic pulmonary fibrosis and lung cancer. Oncol Lett. 2018; 16(2):2490-2494. PMC: 6036565. DOI: 10.3892/ol.2018.8903. View

16.

DePasquale E, Schnell D, Dexheimer P, Ferchen K, Hay S, Chetal K . cellHarmony: cell-level matching and holistic comparison of single-cell transcriptomes. Nucleic Acids Res. 2019; 47(21):e138. PMC: 6868361. DOI: 10.1093/nar/gkz789. View

17.

Nisbet R, Graves A, Kleinhenz D, Rupnow H, Reed A, Fan T . The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice. Am J Respir Cell Mol Biol. 2008; 40(5):601-9. PMC: 2677439. DOI: 10.1165/2008-0145OC. View

18.

Guo M, Du Y, Gokey J, Ray S, Bell S, Adam M . Single cell RNA analysis identifies cellular heterogeneity and adaptive responses of the lung at birth. Nat Commun. 2019; 10(1):37. PMC: 6318311. DOI: 10.1038/s41467-018-07770-1. View

19.

Du Y, Kitzmiller J, Sridharan A, Perl A, Bridges J, Misra R . Lung Gene Expression Analysis (LGEA): an integrative web portal for comprehensive gene expression data analysis in lung development. Thorax. 2017; 72(5):481-484. PMC: 5520249. DOI: 10.1136/thoraxjnl-2016-209598. View

20.

Tuder R, Voelkel N . Angiogenesis and pulmonary hypertension: a unique process in a unique disease. Antioxid Redox Signal. 2002; 4(5):833-43. DOI: 10.1089/152308602760598990. View