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Trimethylamine-N-Oxide Promotes Vascular Calcification Through Activation of NLRP3 (Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3) Inflammasome and NF-κB (Nuclear Factor κB) Signals
Open accessAbstract
Objectives: Vascular calcification is highly prevalent in patients with chronic kidney disease. Increased plasma trimethylamine N-oxide (TMAO), a gut microbiota-dependent product, concentrations are found in patients undergoing hemodialysis. However, a clear mechanistic link between TMAO and vascular calcification is not yet established. In this study, we investigate whether TMAO participates in the progression of vascular calcification using in vitro, ex vivo, and in vivo models. Approach and Results: Alizarin red staining revealed that TMAO promoted calcium/phosphate-induced calcification of rat and human vascular smooth muscle cells in a dose-dependent manner, and this was confirmed by calcium content assay. Similarly, TMAO upregulated the expression of bone-related molecules including Runx2 (Runt-related transcription factor 2) and BMP2 (bone morphogenetic protein-2), suggesting that TMAO promoted osteogenic differentiation of vascular smooth muscle cells. In addition, ex vivo study also showed the positive regulatory effect of TMAO on vascular calcification. Furthermore, we found that TMAO accelerated vascular calcification in rats with chronic kidney disease, as indicated by Mico-computed tomography analysis, alizarin red staining and calcium content assay. By contrast, reducing TMAO levels by antibiotics attenuated vascular calcification in chronic kidney disease rats. Interestingly, TMAO activated NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome and NF-κB (nuclear factor κB) signals during vascular calcification. Inhibition of NLRP3 inflammasome and NF-κB signals attenuated TMAO-induced vascular smooth muscle cell calcification. Conclusions: This study for the first time demonstrates that TMAO promotes vascular calcification through activation of NLRP3 inflammasome and NF-κB signals, suggesting the potential link between gut microbial metabolism and vascular calcification. Reducing the levels of TMAO could become a potential treatment strategy for vascular calcification in chronic kidney disease.
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“It has also been shown to promote platelet reactivity and thrombosis potential14, 83–85, vascular inflammation and inflammasome activation86–88, heightened heart failure89–91 and CKD92–95 related phenotypes in animal models (Figure 2).”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [88]
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Cites
Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization
Go, A. S., Chertow, G. M., Fan, D., McCulloch, C. E., & Hsu, C.-Y. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa041031 · Cited by 11,369
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
Functional interactions between the gut microbiota and host metabolism
Tremaroli, V., & Bäckhed, F. (2012) · Nature · doi:10.1038/nature11552 · Cited by 4,387
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
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 3,400
Greenland, P. (2004) · JAMA · doi:10.1001/jama.291.2.210 · Cited by 1,825
Assessment of Coronary Artery Disease by Cardiac Computed Tomography
Budoff, M. J., Achenbach, S. S., Blumenthal, R. S., Carr, J. J., Goldin, J. G., Greenland, P., Guerci, A. D., Lima, J. A. C., Rader, D. J., Rubin, G. D., et al. (2006) · Circulation · doi:10.1161/circulationaha.106.178458 · Cited by 1,400
Tang, W. H. W., Wang, Z., Kennedy, D. J., Wu, Y., Buffa, J. A., Agatisa-Boyle, B., Li, X. S., Levison, B. S., & Hazen, S. L. (2015) · Circulation Research · doi:10.1161/circresaha.116.305360 · Cited by 1,223
Durham, A. L., Speer, M. Y., Scatena, M., Giachelli, C. M., & Shanahan, C. M. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy010 · Cited by 1,156
Marques, F. Z., Nelson, E., Chu, P.-Y., Horlock, D., Fiedler, A., Ziemann, M., Tan, J. K., Kuruppu, S., Rajapakse, N. W., El-Osta, A., et al. (2017) · Circulation · doi:10.1161/circulationaha.116.024545 · Cited by 1,065
Bone morphogenetic protein expression in human atherosclerotic lesions.
Boström, K. I., Watson, K. E., Horn, S. E. V., Wortham, C., Herman, I. M., & Demer, L. L. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116391 · Cited by 1,020
NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis
Grebe, A., Hoss, F., & Latz, E. (2018) · Circulation Research · doi:10.1161/circresaha.118.311362 · Cited by 926
Seldin, M. M., Meng, Y., Qi, H., Zhu, W., Wang, Z., Hazen, S. L., Lusis, A. J., & Shih, D. M. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.115.002767 · Cited by 911
Abderrazak, A., Syrovets, T., Couchie, D., Hadri, K. E., Friguet, B., Simmet, T., & Rouis, M. (2015) · Redox Biology · doi:10.1016/j.redox.2015.01.008 · Cited by 749
Abdominal Aortic Calcific Deposits Are an Important Predictor of Vascular Morbidity and Mortality
Wilson, P. W. F., Kauppila, L. I., O’Donnell, C. J., Kiel, D. P., Hannan, M. T., Polak, J. F., & Cupples, L. A. (2001) · Circulation · doi:10.1161/01.cir.103.11.1529 · Cited by 668
The Clinical Epidemiology of Cardiac Disease in Chronic Renal Failure
Parfrey, P. S., & Foley, R. N. (1999) · Journal of the American Society of Nephrology · doi:10.1681/asn.v1071606 · Cited by 652
Chen, M., Zhu, X., Ran, L., Lang, H., Yi, L., & Mi, M. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.117.006347 · Cited by 600
Self-citationTumor Necrosis Factor-α Promotes In Vitro Calcification of Vascular Cells via the cAMP Pathway
Tintut, Y., Patel, J., Parhami, F., & Demer, L. L. (2000) · Circulation · doi:10.1161/01.cir.102.21.2636 · Cited by 528
Sun, X., Jiao, X., Ma, Y., Liu, Y., Zhang, L., He, Y., & Chen, Y. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.11.017 · Cited by 507
Self-citationSerum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden
Stubbs, J. R., House, J. A., Ocque, A. J., Zhang, S., Johnson, C., Kimber, C., Schmidt, K., Gupta, A., Wetmore, J. B., Nolin, T. D., et al. (2016) · Journal of the American Society of Nephrology · doi:10.1681/asn.2014111063 · Cited by 450
Organ, C. L., Otsuka, H., Bhushan, S., Wang, Z., Bradley, J., Trivedi, R., Polhemus, D. J., Tang, W. H. W., Wu, Y., Hazen, S. L., et al. (2016) · Circulation: Heart Failure · doi:10.1161/circheartfailure.115.002314 · Cited by 382
Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair
Tang, T. W. H., Chen, H.-C., Chen, C.-Y., Yen, C. Y. T., Lin, C.-J., Prajnamitra, R. P., Chen, L.-L., Ruan, S.-C., Lin, J.-H., Lin, P.-J., et al. (2019) · Circulation · doi:10.1161/circulationaha.118.035235 · Cited by 348
Smooth Muscle Cell–Specific Runx2 Deficiency Inhibits Vascular Calcification
Sun, Y., Byon, C. H., Yuan, K., Chen, J., Mao, X., Heath, J. M., Javed, A., Zhang, K., Anderson, P. G., & Chen, Y. (2012) · Circulation Research · doi:10.1161/circresaha.112.267237 · Cited by 344
Self-citationMissailidis, C., Hällqvist, J., Qureshi, A. R., Barany, P., Heimbürger, O., Lindholm, B., Stenvinkel, P., & Bergman, P. (2016) · PLOS ONE · doi:10.1371/journal.pone.0141738 · Cited by 338
Wang, Z., Levison, B. S., Hazen, J. E., Donahue, L., Li, X.-M., & Hazen, S. L. (2014) · Analytical Biochemistry · doi:10.1016/j.ab.2014.03.016 · Cited by 320
Bain, M. A., Faull, R., Fornasini, G., Milne, R. W., & Evans, A. M. (2006) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfk056 · Cited by 282
Sun, H., Ren, X., Xiong, X., Chen, Y.-Z., Zhao, M., Wang, J., Zhou, Y., Han, Y., Chen, Q., Li, Y., et al. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.470 · Cited by 244
Self-citationInflammation and the Osteogenic Regulation of Vascular Calcification
Shao, J.-S., Cheng, S., Sadhu, J. S., & Towler, D. A. (2010) · Hypertension · doi:10.1161/hypertensionaha.109.134205 · Cited by 227
Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis
Li, Z., Wu, Z., Yan, J., Liu, H., Liu, Q., Deng, Y., Ou, C., & Chen, M. (2018) · Laboratory Investigation · doi:10.1038/s41374-018-0091-y · Cited by 221
Self-citationZhao, M.-M., Xu, M., Cai, Y., Zhao, G., Guan, Y., Kong, W., Tang, C., & Wang, X. (2011) · Kidney International · doi:10.1038/ki.2011.18 · Cited by 216
Li, T., Chen, Y., Gua, C., & Li, X. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00350 · Cited by 216
Self-citationYamada, S., Tokumoto, M., Tatsumoto, N., Taniguchi, M., Noguchi, H., Nakano, T., Masutani, K., Ooboshi, H., Tsuruya, K., & Kitazono, T. (2014) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00633.2013 · Cited by 182
Brunt, V. E., Gioscia‐Ryan, R. A., Richey, J. J., Zigler, M. C., Cuevas, L. M., Gonzalez, A., Vázquez‐Baeza, Y., Battson, M. L., Smithson, A. T., Gilley, A. D., et al. (2019) · The Journal of Physiology · doi:10.1113/jp277336 · Cited by 182
Agharazii, M., St-Louis, R., Gauthier-Bastien, A., Ung, R., Mokas, S., Larivière, R., & Richard, D. E. (2014) · American Journal of Hypertension · doi:10.1093/ajh/hpu225 · Cited by 180
Interaction between gut microbiome and cardiovascular disease
Peng, J., Xiao, X., Hu, M., & Zhang, X. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.10.063 · Cited by 180
Self-citationMeyer, K. A., Benton, T. Z., Bennett, B. J., Jacobs, D. R., Lloyd‐Jones, D. M., Gross, M. D., Carr, J. J., Gordon‐Larsen, P., & Zeisel, S. H. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.116.003970 · Cited by 168
Kaysen, G. A., Johansen, K. L., Chertow, G. M., Dalrymple, L. S., Kornak, J., Grimes, B., Dwyer, T., Chassy, A. W., & Fiehn, O. (2015) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2015.02.006 · Cited by 164
Zhao, G., Xu, M., Zhao, M., Dai, X.-Y., Kong, W., Wilson, G. M., Guan, Y., Wang, C., & Wang, X. (2012) · Kidney International · doi:10.1038/ki.2012.40 · Cited by 160
Vitamin B6 Prevents IL-1β Protein Production by Inhibiting NLRP3 Inflammasome Activation
Zhang, P., Tsuchiya, K., Kinoshita, T., Kushiyama, H., Suidasari, S., Hatakeyama, M., Imura, H., Katô, N., & Suda, T. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.743815 · Cited by 146
Henley, C. M., Colloton, M., Cattley, R. C., Shatzen, E. M., Towler, D. A., Lacey, D. L., & Martin, D. (2005) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfh834 · Cited by 138
Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β Production
Ceneri, N. M., Zhao, L., Young, B. D., Healy, A. L., Coşkun, S., Vasavada, H. H., Yarovinsky, T. O., Ike, K., Pardi, R., Qin, L., et al. (2016) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.308507 · Cited by 120
Lin, M.-E., Chen, T. M., Wallingford, M. C., Nguyen, N. B., Yamada, S., Sawangmake, C., Zhang, J., Speer, M. Y., & Giachelli, C. M. (2016) · Cardiovascular Research · doi:10.1093/cvr/cvw205 · Cited by 116
Nalp3 inflammasome is activated and required for vascular smooth muscle cell calcification
Wen, C., Yang, X., Yan, Z., Zhao, M., Yue, X., Cheng, X., Zheng, Z., Guan, K., Dou, J., Xu, T., et al. (2013) · International Journal of Cardiology · doi:10.1016/j.ijcard.2013.01.211 · Cited by 110
Mafune, A., Iwamoto, T., Tsutsumi, Y., Nakashima, A., Yamamoto, I., Yokoyama, K., Yokoo, T., & Urashima, M. (2016) · Clinical and Experimental Nephrology · doi:10.1007/s10157-015-1207-y · Cited by 103
Song, Y., Hou, M., Li, Z., Luo, C., Ou, J., Yu, H., Yan, J., & Lu, L. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.11.029 · Cited by 99
Self-citationLencel, P., Delplace, S., Pilet, P., Leterme, D., Miellot, F., Sourice, S., Caudrillier, A., Hardouin, P., Guicheux, J., & Magne, D. (2011) · Laboratory Investigation · doi:10.1038/labinvest.2011.83 · Cited by 86
Chang, J. R., Guo, J. F., Wang, Y., Hou, Y., Lu, W., Zhang, J. S., Yu, Y. R., Xu, M. J., Liu, X., Wang, X. J., et al. (2016) · Kidney International · doi:10.1016/j.kint.2015.12.029 · Cited by 80
Self-citationYan, J., Stringer, S. E., Hamilton, A., Charlton-Menys, V., Götting, C., Muller, B. Z., Aeschlimann, D. P., & Alexander, M. Y. (2011) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.110.220749 · Cited by 79
Self-citationCheng, S.-L., Behrmann, A., Shao, J.-S., Ramachandran, B., Krchma, K., Bello Arredondo, Y., Kovacs, A., Mead, M., Maxson, R., & Towler, D. A. (2014) · Diabetes · doi:10.2337/db14-0326 · Cited by 77
Vascular Calcification in Chronic Kidney Disease: The Role of Inflammation
Benz, K., Hilgers, K., Daniel, C., & Amann, K. (2018) · International Journal of Nephrology · doi:10.1155/2018/4310379 · Cited by 73
Prevention of aortic calcification by etidronate in the renal failure rat model
Tamura, K., Suzuki, Y., Matsushita, M., Fujii, H., Miyaura, C., Aizawa, S., & Kogo, H. (2006) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2006.12.006 · Cited by 55
CDC42 promotes vascular calcification in chronic kidney disease
Li, Z., Ji, W., Zhang, X., Ou, C., Zhong, X., Chen, Y., Lu, L., Liu, H., Li, Y., Liu, X., et al. (2019) · The Journal of Pathology · doi:10.1002/path.5334 · Cited by 53
Self-citationInhibition of Vascular Calcification
Liu, L., Zeng, P., Yang, X., Duan, Y., Zhang, W., Ma, C., Zhang, X., Yang, S., Li, X., Yang, J. A., et al. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.311546 · Cited by 52
Self-citationAwan, Z. A., Denis, M., Roubtsova, A., Essalmani, R., Marcinkiewicz, J., Awan, A., Gram, H., Seidah, N. G., & Genest, J. J. (2015) · Angiology · doi:10.1177/0003319715583205 · Cited by 51
AT2 receptor stimulation inhibits phosphate-induced vascular calcification
Kukida, M., Mogi, M., Kan‐no, H., Tsukuda, K., Bai, H., Shan, B., Yamauchi, T., Higaki, A., Min, L., Iwanami, J., et al. (2018) · Kidney International · doi:10.1016/j.kint.2018.07.028 · Cited by 45
Curcumin attenuates osteogenic differentiation and calcification of rat vascular smooth muscle cells
Hou, M., Song, Y., Li, Z., Luo, C., Ou, J., Yu, H., Yan, J., & Lu, L. (2016) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-016-2778-y · Cited by 41
Self-citationHyaluronan negatively regulates vascular calcification involving BMP2 signaling
Kong, Y., Liang, Q., Chen, Y., Yang, P., Liu, X., Li, Y., Feng, S., Ji, W., Liu, W., Tang, J., et al. (2018) · Laboratory Investigation · doi:10.1038/s41374-018-0076-x · Cited by 38
Self-citationInterleukin-1β Is a Key Biomarker and Mediator of Inflammatory Vascular Calcification
Shobeiri, N., & Bendeck, M. P. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.308724 · Cited by 30
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Anbazhagan, A. N., Priyamvada, S., & Priyadarshini, M. (2017) · Current Vascular Pharmacology · doi:10.2174/1570161115666170105095834 · Cited by 23
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Metadata
- Authors
- Zhang, X., Li, Y., Yang, P., Liu, X., Lu, L., Chen, Y., Zhong, X., Li, Z., Liu, H., Ou, C., Yan, J., & Chen, M.
- Affiliations
- Zhujiang Hospital (CN)
- Sun Yat-sen University (CN)
- Corresponding author
- Zhang, Xiuli
- Li, Yining
- Yang, Pingzhen
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2020-03
- Volume
- 40
- Issue
- 3
- Pages
- 751-765
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2999495572
- Cited by
- 291
- References
- 59
- Citations by year
- 2026: 45 · 2025: 60 · 2024: 53 · 2023: 42 · 2022: 46 · 2021: 32 · 2020: 13
- FWCI
- 20.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81870190, U1501222, 31771060, 81871504, 81770280)
- Science and Technology Planning Project of Guangdong Province (2017A020215184)
- Basic and Applied Basic Research Foundation of Guangdong Province (2019A1515010682)
- Topics
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- trimethylamine N-oxide, vascular calcification, NLRP3 inflammasome, NF-κB signaling, chronic kidney disease, vascular smooth muscle cells, osteogenic differentiation, Runx2, BMP-2, gut microbiota, antibiotics, hemodialysis
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Adult, Aged, Animals, Anti-Bacterial Agents, Aorta, Thoracic, Cells, Cultured, Disease Models, Animal, Female, Humans, Male, Methylamines, Middle Aged, Muscle, Smooth, Vascular, Osteogenesis, Signal Transduction, NF-kappa B, Tibial Arteries, Myocytes, Smooth Muscle, Tissue Culture Techniques, Renal Insufficiency, Chronic, Inflammasomes, Vascular Calcification
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