Intermittent Hypoxia and Hypercapnia Accelerate Atherosclerosis, Partially via Trimethylamine-Oxide
Open accessAbstract
Obstructive sleep apnea (OSA) is a common disorder characterized by intermittent hypoxia and hypercapnia (IHC) during sleep. OSA has been shown to be a risk factor for atherosclerosis, but the relation of IHC to the induction or progression of atherosclerosis is not well understood. To dissect the mechanisms involved, we compared atherosclerotic lesion formation in two mouse models, i.e., apolipoprotein E (ApoE) and low density lipoprotein receptor (Ldlr)–deficient mice, with or without IHC exposure. Ten-week-old ApoE−/− or Ldlr−/− mice were fed a high-fat diet for 4 or 8 weeks while being exposed to IHC for 10 hours/day or room air (RA) for 24 hours/day. En face lesions of the aorta, aortic arch, and pulmonary artery (PA) were examined. Moreover, 3,3-dimethyl-1-butanol (DMB), an inhibitor of microbial trimethylamine (TMA) production, was used to determine the contribution of TMA-oxide (TMAO) to IHC-induced atherosclerosis. Eight weeks of IHC exposure expedited the formation of atherosclerosis in both the PA and aortic arch of ApoE−/− mice, but only in the PA of Ldlr−/− mice (ApoE−/− PA 8 wk, IHC 35.4 ± 1.9% versus RA 8.0 ± 2.8%, P < 0.01). The atherosclerotic lesions evolved faster and to a more severe extent in ApoE−/− mice as compared with Ldlr−/− mice (PA IHC 8 wk, ApoE−/− 35.4 ± 1.9% versus Ldlr−/− 8.2 ± 1.5%, P < 0.01). DMB significantly attenuated but did not totally eliminate IHC-induced PA atherosclerosis. Our findings suggest that IHC, a hallmark of OSA, accelerates the progression of atherosclerosis in the aorta and especially in the PA. This process is partly inhibited by DMB, demonstrating that microbial metabolites may serve as therapeutic targets for OSA-induced atherosclerosis.
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Trimethylamine N-oxide has been shown to enhance atherosclerosis in most, but not all, mechanistic and animal model studies.
“TMAO has been shown to enhance atherosclerosis in most, but not all, mechanistic and animal model studies7, 9, 78–82.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [82]
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NIH Image to ImageJ: 25 years of image analysis
Schneider, C. A., Rasband, W. S., & Eliceiri, K. W. (2012) · Nature Methods · doi:10.1038/nmeth.2089 · Cited by 64,638 · see citing works
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597 · see citing works
Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis
Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., Britt, E. B., Fu, X., Wu, Y., Li, L., et al. (2013) · Nature Medicine · doi:10.1038/nm.3145 · Cited by 4,386 · see citing works
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk
Tang, W. H. W., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., Wu, Y., & Hazen, S. L. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1109400 · Cited by 3,402 · see citing works
Plump, A. S., Smith, J. D., Hayek, T., Aalto-Setälä, K., Walsh, A., Verstuyft, J. G., Rubin, E. M., & Breslow, J. L. (1992) · Cell · doi:10.1016/0092-8674(92)90362-g · Cited by 2,263 · see citing works
Spontaneous Hypercholesterolemia and Arterial Lesions in Mice Lacking Apolipoprotein E
Zhang, S. H., Reddick, R. L., Piedrahita, J. A., & Maeda, N. (1992) · Science · doi:10.1126/science.1411543 · Cited by 2,237 · see citing works
Ishibashi, S., Brown, M. S., Goldstein, J. L., Gerard, R. D., Hammer, R. E., & Herz, J. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116663 · Cited by 1,612 · see citing works
Tabas, I., Williams, K. J., & Borén, J. (2007) · Circulation · doi:10.1161/circulationaha.106.676890 · Cited by 1,399 · see citing works
Wang, Z., Roberts, A. B., Buffa, J. A., Levison, B. S., Zhu, W., Org, E., Gu, X., Huang, Y., Zamanian-Daryoush, M., Culley, M. K., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.055 · Cited by 1,317 · see citing works
Piedrahita, J. A., Zhang, S. H., Hagaman, J. R., Oliver, P. M., & Maeda, N. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.10.4471 · Cited by 944 · see citing works
McNicholas, W. T., Bonsignore, M. R., & the Management Committee of EU COST ACTION B26 (2007) · European Respiratory Journal · doi:10.1183/09031936.00027406 · Cited by 911 · see citing works
Tang, W. H. W., Wang, Z., Fan, Y., Levison, B., Hazen, J. E., Donahue, L. M., Wu, Y., & Hazen, S. L. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.02.617 · Cited by 681 · see citing works
Early Signs of Atherosclerosis in Obstructive Sleep Apnea
Drager, L. F., Bortolotto, L. A., Lorenzi, M. C., Figueiredo, A. C., Krieger, E. M., & Lorenzi‐Filho, G. (2005) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200503-340oc · Cited by 596 · see citing works
Epidemiology of obstructive sleep apnea: a population-based perspective
Lee, W. J., Nagubadi, S., Kryger, M. H., & Mokhlesi, B. (2008) · Expert Review of Respiratory Medicine · doi:10.1586/17476348.2.3.349 · Cited by 517 · see citing works
Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation
Gregory, J. C., Buffa, J. A., Org, E., Wang, Z., Levison, B. S., Zhu, W., Wagner, M. A., Bennett, B. J., Li, L., DiDonato, J. A., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.618249 · Cited by 486 · see citing works
An independent association between obstructive sleep apnoea and coronary artery disease
Peker, Y., Kraiczi, H., Hedner, J. A., Löth, S., Johansson, A., & Bende, M. (1999) · European Respiratory Journal · doi:10.1034/j.1399-3003.1999.14a30.x · Cited by 476 · see citing works
Trøseid, M., Ueland, T., Hov, J. R., Svardal, A., Gregersen, I., Dahl, C. P., Aakhus, S., Gude, E., Bjørndal, B., Halvorsen, B., et al. (2015) · Journal of Internal Medicine · doi:10.1111/joim.12328 · Cited by 464 · see citing works
Chronic Intermittent Hypoxia Induces Atherosclerosis
Savransky, V., Nanayakkara, A., Li, J., Bevans‐Fonti, S., Smith, P. L., Rodríguez, A., & Polotsky, V. Y. (2007) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200612-1771oc · Cited by 389 · see citing works
Evidence for Lipid Peroxidation in Obstructive Sleep Apnea
Lavie, L., Vishnevsky, A., & Lavie, P. (2004) · SLEEP · doi:10.1093/sleep/27.1.123 · Cited by 385 · see citing works
Apolipoprotein E Induces Antiinflammatory Phenotype in Macrophages
Baitsch, D., Bock, H. H., Engel, T., Telgmann, R., Müller‐Tidow, C., Varga, G., Bot, M., Herz, J., Robenek, H., von Eckardstein, A., et al. (2011) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.111.222745 · Cited by 361 · see citing works
Robinson, G. V. (2004) · Thorax · doi:10.1136/thx.2003.018739 · Cited by 318 · see citing works
Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea
Moreno‐Indias, I., Torres, M., Montserrat, J. M., Sánchez‐Alcoholado, L., Cardona, F., Tinahones, F. J., Gozal, D., Poroyko, V. A., Navajas, D., Queipo‐Ortuño, M. I., et al. (2014) · European Respiratory Journal · doi:10.1183/09031936.00184314 · Cited by 277 · see citing works
Metabolic Risk Factors for Vascular Disease in Obstructive Sleep Apnea
McArdle, N., Hillman, D. R., Beilin, L. J., & Watts, G. F. (2006) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200602-270oc · Cited by 242 · see citing works
Senthong, V., Li, X. S., Hudec, T., Coughlin, J., Wu, Y., Levison, B., Wang, Z., Hazen, S. L., & Tang, W. H. W. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.03.546 · Cited by 242 · see citing works
Getz, G. S., & Reardon, C. A. (2016) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.116.306874 · Cited by 198 · see citing works
Chronic intermittent hypoxia and obstructive sleep apnea: an experimental and clinical approach
Sforza, E. A., & Roche, F. (2016) · Hypoxia · doi:10.2147/hp.s103091 · Cited by 184 · see citing works
Vadász, I., Dada, L. A., Briva, A., Bittar, H. E. T., Welch, L. C., Chen, J., Tóth, P. T., Lecuona, E., Witters, L. A., Schumacker, P. T., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci29723 · Cited by 167 · see citing works
Effect of intermittent hypoxia on atherosclerosis in apolipoprotein E-deficient mice
Jun, J. C., Reinke, C., Bedja, D., Berkowitz, D. E., Bevans‐Fonti, S., Li, J., Barouch, L. A., Gabrielson, K., & Polotsky, V. Y. (2009) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2009.10.017 · Cited by 146 · see citing works
Mente, A., Chalcraft, K., Ak, H., Davis, A. D., Lonn, E., Miller, R., Potter, M. A., Yusuf, S., Anand, S. S., & McQueen, M. J. (2015) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2015.06.016 · Cited by 128 · see citing works
Tauman, R., O'Brien, L. M., & Gozal, D. (2006) · Sleep And Breathing · doi:10.1007/s11325-006-0085-7 · Cited by 121 · see citing works
Inflammatory Aspects of Sleep Apnea and Their Cardiovascular Consequences
Kasasbeh, E. S., Chi, D. S., & Krishnaswamy, G. A. (2006) · Southern Medical Journal · doi:10.1097/01.smj.0000197705.99639.50 · Cited by 120 · see citing works
Reduction of Isoprostanes and Regression of Advanced Atherosclerosis by Apolipoprotein E
Tangirala, R. K., Praticò, D., FitzGerald, G. A., Chun, S. H., Tsukamoto, K., Maugeais, C., Usher, D. C., Puré, E., & Rader, D. J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m003324200 · Cited by 112 · see citing works
Hypercapnia induces injury to alveolar epithelial cells via a nitric oxide-dependent pathway
Lang, J. D., Chumley, P. H., Eiserich, J. P., Estévez, Á. G., Bamberg, T. V., Adhami, A., Crow, J. P., & Freeman, B. Α. (2000) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2000.279.5.l994 · Cited by 109 · see citing works
Role of gut microbiota in the modulation of atherosclerosis-associated immune response
Chistiakov, D. A., Bobryshev, Y. V., Kozarov, E. V., Sobenin, I. A., & Orekhov, A. N. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.00671 · Cited by 101 · see citing works
The role of carbon dioxide in free radical reactions in organism
Veselá, A., & Wilhelm, J. (2002) · Physiological Research · doi:10.33549/physiolres.930206 · Cited by 87 · see citing works
Arnaud, C., Poulain, L., Levy, P. A., & Demattéis, M. (2011) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2011.07.122 · Cited by 87 · see citing works
Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat
Kantores, C., McNamara, P. J., Teixeira, L. S., et al. (2006) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00480.2005 · Cited by 86 · see citing works
Leukotriene B4 Receptor-1 Mediates Intermittent Hypoxia-induced Atherogenesis
Li, R. C., Haribabu, B., Mathis, S., Kim, J., & Gozal, D. (2011) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201012-2039oc · Cited by 79 · see citing works
Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling
Ooi, H., Cadogan, E. B., Sweeney, M., et al. (2000) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2000.278.2.h331 · Cited by 79 · see citing works
Cardiovascular Morbidity and Mortality in Obstructive Sleep Apnea
Lavie, P., & Lavie, L. (2008) · Current Pharmaceutical Design · doi:10.2174/138161208786549317 · Cited by 73 · see citing works
Langheinrich, A. C., Michniewicz, A., Bohle, R. M., & Ritman, E. L. (2006) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2006.05.021 · Cited by 72 · see citing works
Central Pulmonary Artery Lesions in Chronic Obstructive Pulmonary Disease
Russo, A., Luca, M. D., Vigna, C., et al. (1999) · Circulation · doi:10.1161/01.cir.100.17.1808 · Cited by 69 · see citing works
Obstructive Sleep Apnea Is Associated With Future Subclinical Carotid Artery Disease
Gunnarsson, S. I., Peppard, P. E., Korcarz, C. E., Barnet, J. H., Aeschlimann, S. E., Hagen, E. W., Young, T. B., Hla, K. M., & Stein, J. H. (2014) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.114.303965 · Cited by 63 · see citing works
Moore, G. W., Smith, R. R., & Hutchins, G. M. (1982) · PubMed · Cited by 47 · see citing works
Douglas, R. M., Xue, J., Chen, J. Y., et al. (2003) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01089.2002 · Cited by 44 · see citing works
Self-citationThe physiological and molecular effects of elevated CO2levels
Azzam, Z. S., Sharabi, K., Guetta, J., et al. (2010) · Cell Cycle · doi:10.4161/cc.9.8.11196 · Cited by 24 · see citing works
Douglas, R. M., Bowden, K., Pattison, J., Peterson, A. B., Juliano, J., Dalton, N. D., Gu, Y., Alvarez, E. A., Imamura, T., Peterson, K. L., et al. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00442.2013 · Cited by 14 · see citing works
Self-citation
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Research works printed but not linked: 2
- [24]National Heart, Blood, and Lung Institute Health information for the publicWhat is sleep apnea? [Accessed 2017 Jun 1]. Available from: https://www.nhlbi.nih.gov/health/health-topics/topics/sleepapnea/ [Google Scholar]
- [44]Tripathi A, Meehan MJ, Humphrey G, Zhou D, Xue J, Poulsen O, Sanders J, Haddad GG, Dorrestein PC, Knight R.Atherosclerosis, sleep apnea and obesity: evidence of a microbiome connectionPresented at the Fifth Annual Winter Q-Bio Meeting. February 21–24, 2017, Koloa (Kauai), Hawaiip. 131 [Google Scholar]
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Witkowski, M., Weeks, T. L., & Hazen, S. L. (2020) · Circulation Research · doi:10.1161/circresaha.120.316242 · Cited by 1,051 · see citing works
Metrics of sleep apnea severity: beyond the apnea-hypopnea index
Malhotra, A., Ayappa, I., Ayas, N., Collop, N., Kirsch, D., Mcardle, N., Mehra, R., Pack, A. I., Punjabi, N., White, D. P., et al. (2021) · SLEEP · doi:10.1093/sleep/zsab030 · Cited by 489 · see citing works
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- Authors
- Xue, J., Zhou, D., Poulsen, O., Imamura, T., Hsiao, Y.-H., Smith, T. H., Malhotra, A., Dorrestein, P., Knight, R., & Haddad, G. G.
- Affiliations
- Departments of Pediatrics
- Internal Medicine, and
- University of California San Diego (US)
- Corresponding author
- Haddad, Gabriel G.
- Venue
- American Journal of Respiratory Cell and Molecular Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-11-01
- Volume
- 57
- Issue
- 5
- Pages
- 581-588
- ISSN
- 1044-1549 (ISSN-L)
- 1535-4989
- PMC
- PMC5705907
- OpenAlex
- W2729454705
- Cited by
- 77
- References
- 47
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 5 · 2023: 9 · 2022: 16 · 2021: 12 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 4
- FWCI
- 5.26
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Respiratory Cell and Molecular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- University of California, San Diego
- National Heart, Lung, and Blood Institute (T32HL134632, R01HL085188, K24HL132105)
- Topics
- Health Sciences › Medicine › Physiology › Obstructive Sleep Apnea Research
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- obstructive sleep apnea, atherosclerosis, trimethylamine N-oxide, trimethylamine, 3,3-dimethyl-1-butanol, ApoE-deficient mice, Ldlr-deficient mice, aortic arch atherosclerosis, high-fat diet, microbial metabolites, atherosclerotic lesion formation
- MeSH terms
- Animals, Hypoxia, Disease Models, Animal, Hypercapnia, Methylamines, Mice, Inbred C57BL, Oxides, Pulmonary Artery, Receptors, LDL, Mice, Knockout, Atherosclerosis
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