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Current Vascular Pharmacology

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ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

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Pathogenic Mechanisms of Trimethylamine N-Oxide-induced Atherosclerosis and Cardiomyopathy

Author(s): Youjing Zheng and Jia-Qiang He*

Volume 20, Issue 1, 2022

Published on: 12 August, 2021

Page: [29 - 36] Pages: 8

DOI: 10.2174/1570161119666210812152802

Abstract

Trimethylamine N-oxide (TMAO) is a gut microbiota metabolite derived from trimethylamine- containing nutrient precursors such as choline, L-carnitine, and betaine, which are rich in many vegetables, fruits, nuts, dairy products, and meats. An increasing number of clinical studies have demonstrated a strong relationship between elevated plasma TMAO levels and adverse cardiovascular events. It is commonly agreed that TMAO acts as an independent risk factor and a prognostic index for patients with cardiovascular disease. Although most animal (mainly rodent) data support the clinical findings, the mechanisms by which TMAO modulates the cardiovascular system are still not well understood. In this context, we provide an overview of the potential mechanisms underlying TMAO-induced cardiovascular diseases at the cellular and molecular levels, with a focus on atherosclerosis. We also address the direct effects of TMAO on cardiomyocytes (a new and under-researched area) and finally propose TMAO as a potential biomarker and/or therapeutic target for diagnosis and treatment of patients with cardiovascular disease.

Keywords: Metabolites, trimethylamine N-oxide, atherosclerosis, cardiomyopathy, cardiomyocytes, signalling pathway, mechanism.

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[1]
Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics-2019 update: A report from the american heart association. Circulation 2019; 139(10): e56-e528.
[http://dx.doi.org/10.1161/CIR.0000000000000659] [PMID: 30700139]
[2]
Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: A policy statement from the American Heart Association. Circulation 2011; 123(8): 933-44.
[http://dx.doi.org/10.1161/CIR.0b013e31820a55f5] [PMID: 21262990]
[3]
Dumas ME, Kinross J, Nicholson JK. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology 2014; 146(1): 46-62.
[http://dx.doi.org/10.1053/j.gastro.2013.11.001] [PMID: 24211299]
[4]
Zeisel SH, Warrier M. Trimethylamine N-oxide, the microbiome, and heart and kidney disease. Annu Rev Nutr 2017; 37: 157-81.
[http://dx.doi.org/10.1146/annurev-nutr-071816-064732] [PMID: 28715991]
[5]
Anbazhagan AN, Priyamvada S, Priyadarshini M. Gut microbiota in vascular disease: Therapeutic target? Curr Vasc Pharmacol 2017; 15(4): 291-5.
[http://dx.doi.org/10.2174/1570161115666170105095834] [PMID: 28056754]
[6]
Nam HS. Gut microbiota and ischemic stroke: The role of trimethylamine N-oxide. J Stroke 2019; 21(2): 151-9.
[http://dx.doi.org/10.5853/jos.2019.00472] [PMID: 31161760]
[7]
Hosseinkhani F, Heinken A, Thiele I, Lindenburg PW, Harms AC, Hankemeier T. The contribution of gut bacterial metabolites in the human immune signaling pathway of non-communicable diseases. Gut Microbes 2021; 13(1): 1-22.
[http://dx.doi.org/10.1080/19490976.2021.1882927] [PMID: 33590776]
[8]
Ussher JR, Lopaschuk GD, Arduini A. Gut microbiota metabolism of L-carnitine and cardiovascular risk. Atherosclerosis 2013; 231(2): 456-61.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.10.013] [PMID: 24267266]
[9]
Battson ML, Lee DM, Weir TL, Gentile CL. The gut microbiota as a novel regulator of cardiovascular function and disease. J Nutr Biochem 2018; 56: 1-15.
[http://dx.doi.org/10.1016/j.jnutbio.2017.12.010] [PMID: 29427903]
[10]
Burcelin R, Serino M, Chabo C, Blasco-Baque V, Amar J. Gut microbiota and diabetes: From pathogenesis to therapeutic perspective. Acta Diabetol 2011; 48(4): 257-73.
[http://dx.doi.org/10.1007/s00592-011-0333-6] [PMID: 21964884]
[11]
Zhou W, Cheng Y, Zhu P, Nasser MI, Zhang X, Zhao M. Implication of gut microbiota in cardiovascular diseases. Oxid Med Cell Longev 2020; 2020: 5394096.
[http://dx.doi.org/10.1155/2020/5394096] [PMID: 33062141]
[12]
Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472(7341): 57-63.
[http://dx.doi.org/10.1038/nature09922] [PMID: 21475195]
[13]
Borges NA, Stenvinkel P, Bergman P, et al. Effects of probiotic supplementation on trimethylamine-N-oxide plasma levels in hemodialysis patients: A pilot study. Probiotics Antimicrob Proteins 2019; 11(2): 648-54.
[http://dx.doi.org/10.1007/s12602-018-9411-1] [PMID: 29651635]
[14]
Jin M, Qian Z, Yin J, Xu W, Zhou X. The role of intestinal microbiota in cardiovascular disease. J Cell Mol Med 2019; 23(4): 2343-50.
[http://dx.doi.org/10.1111/jcmm.14195] [PMID: 30712327]
[15]
Zhao X, Oduro PK, Tong W, Wang Y, Gao X, Wang Q. Therapeutic potential of natural products against atherosclerosis: Targeting on gut microbiota. Pharmacol Res 2021; 163: 105362.
[http://dx.doi.org/10.1016/j.phrs.2020.105362] [PMID: 33285231]
[16]
Thomas MS, Fernandez ML. Trimethylamine N-oxide (TMAO), diet and cardiovascular disease. Curr Atheroscler Rep 2021; 23(4): 12.
[http://dx.doi.org/10.1007/s11883-021-00910-x] [PMID: 33594574]
[17]
Gatarek P, Kaluzna-Czaplinska J. Trimethylamine N-oxide (TMAO) in human health. EXCLI J 2021; 20: 301-19.
[PMID: 33746664]
[18]
Papandreou C, Moré M, Bellamine A. Trimethylamine N-oxide in relation to cardiometabolic health-cause or effect? Nutrients 2020; 12(5): 12.
[http://dx.doi.org/10.3390/nu12051330] [PMID: 32392758]
[19]
Miller NB, Beigelman A, Utterson E, Shinawi M. Transient massive trimethylaminuria associated with food protein-induced enterocolitis syndrome. JIMD Rep 2014; 12: 11-5.
[http://dx.doi.org/10.1007/8904_2013_238] [PMID: 23821320]
[20]
Brugère JF, Borrel G, Gaci N, Tottey W, O’Toole PW, Malpuech-Brugère C. Archaebiotics: Proposed therapeutic use of archaea to prevent trimethylaminuria and cardiovascular disease. Gut Microbes 2014; 5(1): 5-10.
[http://dx.doi.org/10.4161/gmic.26749] [PMID: 24247281]
[21]
Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology 2011; 140(3): 976-86.
[http://dx.doi.org/10.1053/j.gastro.2010.11.049] [PMID: 21129376]
[22]
Krueger SK, Williams DE. Mammalian flavin-containing monooxygenases: Structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther 2005; 106(3): 357-87.
[http://dx.doi.org/10.1016/j.pharmthera.2005.01.001] [PMID: 15922018]
[23]
Fennema D, Phillips IR, Shephard EA. Trimethylamine and trimethylamine N-oxide, a flavin-containing monooxygenase 3 (FMO3)-mediated host-microbiome metabolic axis implicated in health and disease. Drug Metab Dispos 2016; 44(11): 1839-50.
[http://dx.doi.org/10.1124/dmd.116.070615] [PMID: 27190056]
[24]
Rehman HU. Fish odor syndrome. Postgrad Med J 1999; 75(886): 451-2.
[http://dx.doi.org/10.1136/pgmj.75.886.451] [PMID: 10646019]
[25]
Tang WH, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013; 368(17): 1575-84.
[http://dx.doi.org/10.1056/NEJMoa1109400] [PMID: 23614584]
[26]
Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest 2014; 124(10): 4204-11.
[http://dx.doi.org/10.1172/JCI72331] [PMID: 25271725]
[27]
Trøseid M, Ueland T, Hov JR, et al. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med 2015; 277(6): 717-26.
[http://dx.doi.org/10.1111/joim.12328] [PMID: 25382824]
[28]
Haissman JM, Knudsen A, Hoel H, et al. Microbiota-dependent marker TMAO is elevated in silent ischemia but is not associated with first-time myocardial infarction in HIV infection. J Acquir Immune Defic Syndr 2016; 71(2): 130-6.
[http://dx.doi.org/10.1097/QAI.0000000000000843] [PMID: 26413854]
[29]
Mafune A, Iwamoto T, Tsutsumi Y, et al. Associations among serum trimethylamine-N-oxide (TMAO) levels, kidney function and infarcted coronary artery number in patients undergoing cardiovascular surgery: A cross-sectional study. Clin Exp Nephrol 2016; 20(5): 731-9.
[http://dx.doi.org/10.1007/s10157-015-1207-y] [PMID: 26676906]
[30]
Suzuki T, Heaney LM, Jones DJ, Ng LL. Trimethylamine N-oxide and risk stratification after acute myocardial infarction. Clin Chem 2017; 63(1): 420-8.
[http://dx.doi.org/10.1373/clinchem.2016.264853] [PMID: 28062632]
[31]
Tabas I, García-Cardeña G, Owens GK. Recent insights into the cellular biology of atherosclerosis. J Cell Biol 2015; 209(1): 13-22.
[http://dx.doi.org/10.1083/jcb.201412052] [PMID: 25869663]
[32]
Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res 2019; 124(2): 315-27.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.313591] [PMID: 30653442]
[33]
Park YM. CD36, a scavenger receptor implicated in atherosclerosis. Exp Mol Med 2014; 46: e99.
[http://dx.doi.org/10.1038/emm.2014.38] [PMID: 24903227]
[34]
Febbraio M, Podrez EA, Smith JD, et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest 2000; 105(8): 1049-56.
[http://dx.doi.org/10.1172/JCI9259] [PMID: 10772649]
[35]
Mohammadi A, Vahabzadeh Z, Jamalzadeh S, Khalili T. Trimethylamine-N-oxide, as a risk factor for atherosclerosis, induces stress in J774A.1 murine macrophages. Adv Med Sci 2018; 63(1): 57-63.
[http://dx.doi.org/10.1016/j.advms.2017.06.006] [PMID: 28822264]
[36]
Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19(5): 576-85.
[http://dx.doi.org/10.1038/nm.3145] [PMID: 23563705]
[37]
Ohashi R, Mu H, Wang X, Yao Q, Chen C. Reverse cholesterol transport and cholesterol efflux in atherosclerosis. QJM 2005; 98(12): 845-56.
[http://dx.doi.org/10.1093/qjmed/hci136] [PMID: 16258026]
[38]
Spann NJ, Garmire LX, McDonald JG, et al. Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell 2012; 151(1): 138-52.
[http://dx.doi.org/10.1016/j.cell.2012.06.054] [PMID: 23021221]
[39]
Chen ML, Yi L, Zhang Y, et al. Resveratrol attenuates trimethylamine-N-oxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota. MBio 2016; 7(2): e02210-5.
[http://dx.doi.org/10.1128/mBio.02210-15] [PMID: 27048804]
[40]
Charach G, Rabinovich A, Argov O, Weintraub M, Rabinovich P. The role of bile acid excretion in atherosclerotic coronary artery disease. Int J Vasc Med 2012; 2012: 949672.
[http://dx.doi.org/10.1155/2012/949672] [PMID: 21918722]
[41]
Lu Y, Feskens EJ, Boer JM, Müller M. The potential influence of genetic variants in genes along bile acid and bile metabolic pathway on blood cholesterol levels in the population. Atherosclerosis 2010; 210(1): 14-27.
[http://dx.doi.org/10.1016/j.atherosclerosis.2009.10.035] [PMID: 19932478]
[42]
Miyake JH, Duong-Polk XT, Taylor JM, et al. Transgenic expression of cholesterol-7-alpha-hydroxylase prevents atherosclerosis in C57BL/6J mice. Arterioscler Thromb Vasc Biol 2002; 22(1): 121-6.
[http://dx.doi.org/10.1161/hq0102.102588] [PMID: 11788471]
[43]
Ding L, Chang M, Guo Y, et al. Trimethylamine-N-oxide (TMAO)-induced atherosclerosis is associated with bile acid metabolism. Lipids Health Dis 2018; 17(1): 286-94.
[http://dx.doi.org/10.1186/s12944-018-0939-6] [PMID: 30567573]
[44]
Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004; 109(23)(Suppl. 1): III27-32.
[http://dx.doi.org/10.1161/01.CIR.0000131515.03336.f8] [PMID: 15198963]
[45]
Seldin MM, Meng Y, Qi H, et al. Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-κB. J Am Heart Assoc 2016; 5(2): 1-12.
[http://dx.doi.org/10.1161/JAHA.115.002767] [PMID: 26903003]
[46]
Ma G, Pan B, Chen Y, et al. Trimethylamine N-oxide in atherogenesis: Impairing endothelial self-repair capacity and enhancing monocyte adhesion. Biosci Rep 2017; 37(2): 1-12.
[http://dx.doi.org/10.1042/BSR20160244] [PMID: 28153917]
[47]
Durpès MC, Morin C, Paquin-Veillet J, et al. PKC-β activation inhibits IL-18-binding protein causing endothelial dysfunction and diabetic atherosclerosis. Cardiovasc Res 2015; 106(2): 303-13.
[http://dx.doi.org/10.1093/cvr/cvv107] [PMID: 25808972]
[48]
Zhou X, Chen M, Zeng X, et al. Resveratrol regulates mitochondrial reactive oxygen species homeostasis through Sirt3 signaling pathway in human vascular endothelial cells. Cell Death Dis 2014; 5: e1576.
[http://dx.doi.org/10.1038/cddis.2014.530] [PMID: 25522270]
[49]
Chen ML, Zhu XH, Ran L, Lang HD, Yi L, Mi MT. Trimethylamine-N-oxide induces vascular inflammation by activating the NLRP3 inflammasome through the SIRT3-SOD2-mtROS signaling pathway. J Am Heart Assoc 2017; 6(9): 1-12.
[http://dx.doi.org/10.1161/JAHA.117.006347] [PMID: 28871042]
[50]
Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 2012; 24(5): 981-90.
[http://dx.doi.org/10.1016/j.cellsig.2012.01.008] [PMID: 22286106]
[51]
Sun X, Jiao X, Ma Y, et al. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. Biochem Biophys Res Commun 2016; 481(1-2): 63-70.
[http://dx.doi.org/10.1016/j.bbrc.2016.11.017] [PMID: 27833015]
[52]
Tao R, Coleman MC, Pennington JD, et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 2010; 40(6): 893-904.
[http://dx.doi.org/10.1016/j.molcel.2010.12.013] [PMID: 21172655]
[53]
Li T, Chen Y, Gua C, Li X. Elevated circulating trimethylamine N-oxide levels contribute to endothelial dysfunction in aged rats through vascular inflammation and oxidative stress. Front Physiol 2017; 8: 350.
[http://dx.doi.org/10.3389/fphys.2017.00350] [PMID: 28611682]
[54]
Ke Y, Li D, Zhao M, et al. Gut flora-dependent metabolite trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress. Free Radic Biol Med 2018; 116: 88-100.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.01.007] [PMID: 29325896]
[55]
Chou RH, Chen CY, Chen IC, et al. Trimethylamine N-oxide, circulating endothelial progenitor cells, and endothelial function in patients with stable angina. Sci Rep 2019; 9(1): 4249-59.
[http://dx.doi.org/10.1038/s41598-019-40638-y] [PMID: 30862856]
[56]
Toya T, Ozcan I, Corban MT, et al. Compositional change of gut microbiome and osteocalcin expressing endothelial progenitor cells in patients with coronary artery disease. PLoS One 2021; 16(3): e0249187.
[http://dx.doi.org/10.1371/journal.pone.0249187] [PMID: 33765061]
[57]
Michowitz Y, Goldstein E, Wexler D, Sheps D, Keren G, George J. Circulating endothelial progenitor cells and clinical outcome in patients with congestive heart failure. Heart 2007; 93(9): 1046-50.
[http://dx.doi.org/10.1136/hrt.2006.102657] [PMID: 17277352]
[58]
Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003; 108(4): 457-63.
[http://dx.doi.org/10.1161/01.CIR.0000082924.75945.48] [PMID: 12860902]
[59]
Savi M, Bocchi L, Bresciani L, et al. Trimethylamine-N-oxide (TMAO)-induced impairment of cardiomyocyte function and the protective role of urolithin B-glucuronide. Molecules 2018; 23(3): 549-62.
[http://dx.doi.org/10.3390/molecules23030549] [PMID: 29494535]
[60]
Makrecka-Kuka M, Volska K, Antone U, et al. Trimethylamine N-oxide impairs pyruvate and fatty acid oxidation in cardiac mitochondria. Toxicol Lett 2017; 267: 32-8.
[http://dx.doi.org/10.1016/j.toxlet.2016.12.017] [PMID: 28049038]
[61]
Oakley CI, Vallejo JA, Wang D, et al. Trimethylamine-N-oxide acutely increases cardiac muscle contractility. Am J Physiol Heart Circ Physiol 2020; 318(5): H1272-82.
[http://dx.doi.org/10.1152/ajpheart.00507.2019] [PMID: 32243768]
[62]
Li Z, Wu Z, Yan J, et al. Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis. Lab Invest 2019; 99(3): 346-57.
[http://dx.doi.org/10.1038/s41374-018-0091-y] [PMID: 30068915]
[63]
Janeiro MH, Ramírez MJ, Milagro FI, Martínez JA, Solas M. Implication of trimethylamine N-oxide (TMAO) in disease: Potential biomarker or new therapeutic target. Nutrients 2018; 10(10): 10.
[http://dx.doi.org/10.3390/nu10101398] [PMID: 30275434]
[64]
Martínez-González MA, Gea A, Ruiz-Canela M. The mediterranean diet and cardiovascular health. Circ Res 2019; 124(5): 779-98.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.313348] [PMID: 30817261]
[65]
O’Morain VL, Ramji DP. The potential of probiotics in the prevention and treatment of atherosclerosis. Mol Nutr Food Res 2020; 64(4): e1900797.
[http://dx.doi.org/10.1002/mnfr.201900797] [PMID: 31697015]
[66]
Liang X, Zhang Z, Lv Y, et al. Reduction of intestinal trimethylamine by probiotics ameliorated lipid metabolic disorders associated with atherosclerosis. Nutrition 2020; 79-80: 110941.
[http://dx.doi.org/10.1016/j.nut.2020.110941] [PMID: 32858376]
[67]
Chen S, Jiang PP, Yu D, et al. Effects of probiotic supplementation on serum trimethylamine-N-oxide level and gut microbiota composition in young males: A double-blinded randomized controlled trial. Eur J Nutr 2021; 60(2): 747-58.
[http://dx.doi.org/10.1007/s00394-020-02278-1] [PMID: 32440731]
[68]
Wang Z, Roberts AB, Buffa JA, et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 2015; 163(7): 1585-95.
[http://dx.doi.org/10.1016/j.cell.2015.11.055] [PMID: 26687352]
[69]
Bennett BJ, de Aguiar Vallim TQ, Wang Z, et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 2013; 17(1): 49-60.
[http://dx.doi.org/10.1016/j.cmet.2012.12.011] [PMID: 23312283]
[70]
Sethi NJ, Safi S, Korang SK, et al. Antibiotics for secondary prevention of coronary heart disease. Cochrane Database Syst Rev 2021; 2: CD003610.
[http://dx.doi.org/10.1002/14651858.CD003610.pub4] [PMID: 33704780]

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