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30.06.2023 | Sleep Breathing Physiology and Disorders • Original Article

The immune response to arterial damage in a mouse model of intermittent hypoxia: a transcriptomics analysis

verfasst von: Chong Xu, Xiangyu Cheng, Xiaoting Wang, Weijun Huang, Yupu Liu, Haibo Ye, Jian Guan, Jinhong Shen, Hongliang Yi

Erschienen in: Sleep and Breathing | Ausgabe 6/2023

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Abstract

Purpose

Mice can develop arterial damage and even atherosclerosis under intermittent hypoxia (IH); however, the specific mechanism of arterial damage induced by IH remains unclear. Hence, this research aimed to illustrate the underlying mechanism linking IH to arterial injury.

Materials and methods

The differential gene expression of the thoracic aorta under normoxia or IH mice was analyzed utilizing RNA sequencing. Furthermore, GO, KEGG pathway, and CIBERSORT analyses were carried out. For verification of the expression of candidate genes affected by IH, quantitative RT-qPCR (qRT-PCR) was conducted. Immunohistochemical (IHC) staining revealed immune cell infiltration in the thoracic aorta.

Results

The thickness of the intima-media of the mouse aorta was increased, and the fiber structure was disordered under IH. Transcriptomics analysis showed that in the aorta, 1137 upregulated genes and 707 downregulated genes were affected by IH, significantly related to the activation of the immune system and cell adhesion. Furthermore, B cell infiltration around the aorta was observed under IH.

Conclusions

IH might lead to structural changes in the aorta by activating the immune response and enhancing cell adhesion.

Jordan AS, McSharry DG, Malhotra A (2014) Adult obstructive sleep apnoea. Lancet 383:736–747. https://doi.org/10.1016/s0140-6736(13)60734-5CrossRefPubMed

Lévy P, Kohler M, McNicholas WT, Barbé F, McEvoy RD, Somers VK, Lavie L, Pépin JL (2015) Obstructive sleep apnoea syndrome. Nat Rev Dis Primers 1:15015. https://doi.org/10.1038/nrdp.2015.15CrossRefPubMed

Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, Floras JS, Hunt CE, Olson LJ, Pickering TG, Russell R, Woo M, Young T (2008) Sleep apnea and cardiovascular disease: an American Heart Association/american College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council On Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 118:1080–1111. https://doi.org/10.1161/circulationaha.107.189375CrossRefPubMed

Bradley TD, Floras JS (2009) Obstructive sleep apnoea and its cardiovascular consequences. Lancet 373:82–93. https://doi.org/10.1016/s0140-6736(08)61622-0CrossRefPubMed

Ma L, Zhang J, Liu Y (2016) Roles and Mechanisms of Obstructive Sleep Apnea-Hypopnea Syndrome and Chronic Intermittent Hypoxia in Atherosclerosis: Evidence and Prospective. Oxid Med Cell Longev 2016:8215082. https://doi.org/10.1155/2016/8215082CrossRefPubMedPubMedCentral

Song D, Fang G, Greenberg H, Liu SF (2015) Chronic intermittent hypoxia exposure-induced atherosclerosis: a brief review. Immunol Res 63:121–130. https://doi.org/10.1007/s12026-015-8703-8CrossRefPubMed

Song F, Zou J, Song Z, Xu H, Qian Y, Zhu H, Liu S, Guan J, Chen J, Yi H (2020) Association of Adipocytokines With Carotid Intima -Media Thickness and Arterial Stiffness in Obstructive Sleep Apnea Patients. Front Endocrinol (Lausanne) 11:177. https://doi.org/10.3389/fendo.2020.00177CrossRefPubMed

Ryan S, Taylor CT, McNicholas WT (2005) Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 112:2660–2667. https://doi.org/10.1161/circulationaha.105.556746CrossRefPubMed

Kylintireas I, Craig S, Nethononda R, Kohler M, Francis J, Choudhury R, Stradling J, Neubauer S (2012) Atherosclerosis and arterial stiffness in obstructive sleep apnea–a cardiovascular magnetic resonance study. Atherosclerosis 222:483–489. https://doi.org/10.1016/j.atherosclerosis.2012.03.036CrossRefPubMedPubMedCentral

10.

Fang G, Song D, Ye X, Mao SZ, Liu G, Liu SF (2012) Chronic intermittent hypoxia exposure induces atherosclerosis in ApoE knockout mice: role of NF-κB p50. Am J Pathol 181:1530–1539. https://doi.org/10.1016/j.ajpath.2012.07.024CrossRefPubMed

11.

Jun J, Reinke C, Bedja D, Berkowitz D, Bevans-Fonti S, Li J, Barouch LA, Gabrielson K, Polotsky VY (2010) Effect of intermittent hypoxia on atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 209:381–386. https://doi.org/10.1016/j.atherosclerosis.2009.10.017CrossRefPubMed

12.

Dematteis M, Godin-Ribuot D, Arnaud C, Ribuot C, Stanke-Labesque F, Pépin JL, Lévy P (2009) Cardiovascular consequences of sleep-disordered breathing: contribution of animal models to understanding the human disease. Ilar j 50:262–281. https://doi.org/10.1093/ilar.50.3.262CrossRefPubMed

13.

Dematteis M, Julien C, Guillermet C, Sturm N, Lantuejoul S, Mallaret M, Lévy P, Gozal E (2008) Intermittent hypoxia induces early functional cardiovascular remodeling in mice. Am J Respir Crit Care Med 177:227–235. https://doi.org/10.1164/rccm.200702-238OCCrossRefPubMed

14.

Savransky V, Nanayakkara A, Li J, Bevans S, Smith PL, Rodriguez A, Polotsky VY (2007) Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med 175:1290–1297. https://doi.org/10.1164/rccm.200612-1771OCCrossRefPubMedPubMedCentral

15.

Arnaud C, Beguin PC, Lantuejoul S, Pepin JL, Guillermet C, Pelli G, Burger F, Buatois V, Ribuot C, Baguet JP, Mach F, Levy P, Dematteis M (2011) The inflammatory pre atherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition. Am J Respir Crit Care Med 184:724–731. https://doi.org/10.1164/rccm.201012-2033OCCrossRefPubMed

16.

Drager LF, Yao Q, Hernandez KL, Shin MK, Bevans-Fonti S, Gay J, Sussan TE, Jun JC, Myers AC, Olivecrona G, Schwartz AR, Halberg N, Scherer PE, Semenza GL, Powell DR, Polotsky VY (2013) Chronic intermittent hypoxia induces atherosclerosis via activation of adipose angiopoietin-like 4. Am J Respir Crit Care Med 188:240–248. https://doi.org/10.1164/rccm.201209-1688OCCrossRefPubMedPubMedCentral

17.

Arnaud C, Poulain L, Lévy P, Dematteis M (2011) Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice. Atherosclerosis 219:425–431. https://doi.org/10.1016/j.atherosclerosis.2011.07.122CrossRefPubMed

18.

Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH (2007) Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol 49:2379–2393. https://doi.org/10.1016/j.jacc.2007.02.059CrossRefPubMed

19.

Hu JJ, Ambrus A, Fossum TW, Miller MW, Humphrey JD, Wilson E (2008) Time courses of growth and remodeling of porcine aortic media during hypertension: a quantitative immunohistochemical examination. J Histochem Cytochem 56:359–370. https://doi.org/10.1369/jhc.7A7324.2007CrossRefPubMedPubMedCentral

20.

Burrows N, Bashford-Rogers RJM, Bhute VJ, Peñalver A, Ferdinand JR, Stewart BJ, Smith JEG, Deobagkar-Lele M, Giudice G, Connor TM, Inaba A, Bergamaschi L, Smith S, Tran MGB, Petsalaki E, Lyons PA, Espeli M, Huntly BJP, Smith KGC, Cornall RJ, Clatworthy MR, Maxwell PH (2020) Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development. Nat Immunol 21:1408–1420. https://doi.org/10.1038/s41590-020-0772-8CrossRefPubMedPubMedCentral

21.

Xie H, Yin J, Bai Y, Peng H, Zhou X, Bai J (2019) Differential expression of immune markers in the patients with obstructive sleep apnea/hypopnea syndrome. Eur Arch Otorhinolaryngol 276:735–744. https://doi.org/10.1007/s00405-018-5219-6CrossRefPubMed

22.

Paci P, Fiscon G, Conte F, Licursi V, Morrow J, Hersh C, Cho M, Castaldi P, Glass K, Silverman EK, Farina L (2020) Integrated transcriptomic correlation network analysis identifies COPD molecular determinants. Sci Rep 10:3361. https://doi.org/10.1038/s41598-020-60228-7CrossRefPubMedPubMedCentral

23.

Theodorou E, Nezos A, Antypa E, Ioakeimidis D, Koutsilieris M, Tektonidou M, Moutsopoulos HM, Mavragani CP (2018) B-cell activating factor and related genetic variants in lupus related atherosclerosis. J Autoimmun 92:87–92. https://doi.org/10.1016/j.jaut.2018.05.002CrossRefPubMed

24.

Stanke-Labesque F, Pépin JL, de Jouvencel T, Arnaud C, Baguet JP, Petri MH, Tamisier R, Jourdil JF, Lévy P, Bäck M (2012) Leukotriene B4 pathway activation and atherosclerosis in obstructive sleep apnea. J Lipid Res 53:1944–1951. https://doi.org/10.1194/jlr.P022814CrossRefPubMedPubMedCentral

25.

Dyugovskaya L, Lavie P, Lavie L (2002) Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 165:934–939. https://doi.org/10.1164/ajrccm.165.7.2104126CrossRefPubMed

26.

Ohga E, Tomita T, Wada H, Yamamoto H, Nagase T, Ouchi Y (1985) Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1. J Appl Physiol 94(2003):179–184. https://doi.org/10.1152/japplphysiol.00177.2002CrossRef

27.

Schober A (2008) Chemokines in vascular dysfunction and remodeling. Arterioscler Thromb Vasc Biol 28:1950–1959. https://doi.org/10.1161/atvbaha.107.161224CrossRefPubMed

28.

Krohn R, Raffetseder U, Bot I, Zernecke A, Shagdarsuren E, Liehn EA, van Santbrink PJ, Nelson PJ, Biessen EA, Mertens PR, Weber C (2007) Y-box binding protein-1 controls CC chemokine ligand-5 (CCL5) expression in smooth muscle cells and contributes to neointima formation in atherosclerosis-prone mice. Circulation 116:1812–1820. https://doi.org/10.1161/circulationaha.107.708016CrossRefPubMed

29.

Ise W, Fujii K, Shiroguchi K, Ito A, Kometani K, Takeda K, Kawakami E, Yamashita K, Suzuki K, Okada T, Kurosaki T (2018) T Follicular Helper Cell-Germinal Center B Cell Interaction Strength Regulates Entry into Plasma Cell or Recycling Germinal Center Cell Fate. Immunity 48:702-715.e704. https://doi.org/10.1016/j.immuni.2018.03.027CrossRefPubMed

30.

Erdozain OJ, Pegrum S, Winrow VR, Horrocks M, Stevens CR (2011) Hypoxia in abdominal aortic aneurysm supports a role for HIF-1α and Ets-1 as drivers of matrix metalloproteinase upregulation in human aortic smooth muscle cells. J Vasc Res 48:163–170. https://doi.org/10.1159/000318806CrossRefPubMed

Titel: The immune response to arterial damage in a mouse model of intermittent hypoxia: a transcriptomics analysis
verfasst von: Chong Xu
Xiangyu Cheng
Xiaoting Wang
Weijun Huang
Yupu Liu
Haibo Ye
Jian Guan
Jinhong Shen
Hongliang Yi
Publikationsdatum: 30.06.2023
Verlag: Springer International Publishing
Erschienen in: Sleep and Breathing / Ausgabe 6/2023
Print ISSN: 1520-9512
Elektronische ISSN: 1522-1709
DOI: https://doi.org/10.1007/s11325-023-02866-5

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The immune response to arterial damage in a mouse model of intermittent hypoxia: a transcriptomics analysis