TMAO Impairs Mouse Aortic Vasodilation by Inhibiting TRPV4 Channels in Endothelial Cells.

Publisher: Springer Country of Publication: United States NLM ID: 101468585 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1937-5395 (Electronic) Linking ISSN: 19375387 NLM ISO Abbreviation: J Cardiovasc Transl Res Subsets: MEDLINE

Original Publication: New York, NY : Springer

TRPV Cation Channels*/metabolism ; Vasodilation*/drug effects ; Methylamines*/metabolism ; Methylamines*/pharmacology ; Endothelial Cells*/metabolism ; Endothelial Cells*/drug effects ; Endothelial Cells*/pathology ; Mice, Inbred C57BL* ; Aorta*/metabolism ; Aorta*/drug effects ; Aorta*/physiopathology ; Calcium Signaling*/drug effects; Animals ; Male ; Signal Transduction ; Cells, Cultured ; Membrane Potentials ; Mice ; Dose-Response Relationship, Drug ; Humans

Trimethylamine oxide (TMAO) is an intestinal flora metabolite associated with risk of cardiovascular diseases. Transient receptor potential vanilloid 4 (TRPV4) is a Ca ²⁺ -permeable ion channel that is essential for vasodilation and endothelial function. Currently, there are few studies on the effect of TMAO on TRPV4 channels. In the present study, Ca ²⁺ imaging of vascular tissue showed that TMAO inhibited TRPV4-mediated Ca ²⁺ influx into aortic endothelial cells in a dose-dependent manner. Furthermore, a whole-cell patch clamp assay showed that TMAO blocked TRPV4-mediated cation currents. Notably, results of aortic vascular tension measurement showed that TMAO impaired endothelium-dependent vasodilation in mouse aortic vessels through the TRPV4-NO pathway. Our results indicated that TMAO inhibited Ca ²⁺ entry in endothelial cells and impaired vasodilation through the TRPV4-NO pathway in mice. These results provide scientific evidence for novel pathogenic mechanisms underlying the role of TMAO in cardiovascular disease.
Competing Interests: Declarations. Human and Animal Rights: All of the animal experiments were approved by Jiangnan University's Animal Experiment Ethics Committee (Approval number: JN. No20220615c0601230[296]).No human studies were carried out by the authors for this article. Competing Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Zeisel SH, Warrier M. Trimethylamine N-Oxide, the microbiome, and heart and kidney disease. Annu Rev Nutr. 2017;37:157–81. (PMID: 2871599110.1146/annurev-nutr-071816-064732)
Bu J, Wang Z. Cross-talk between gut microbiota and heart via the routes of metabolite and immunity. Gastroenterol Res Pract. 2018;2018:6458094. (PMID: 29967639600874510.1155/2018/6458094)
Kaysen GA, et al. Associations of trimethylamine N-Oxide with nutritional and inflammatory biomarkers and cardiovascular outcomes in patients new to dialysis. J Ren Nutr. 2015;25(4):351–6. (PMID: 25802017446954710.1053/j.jrn.2015.02.006)
Tang WH, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368(17):1575–84. (PMID: 23614584370194510.1056/NEJMoa1109400)
Lever M, et al. Betaine and trimethylamine-N-Oxide as Predictors of cardiovascular outcomes show different patterns in diabetes mellitus: an observational Study. PLoS ONE. 2014;9(12):e114969. (PMID: 25493436426244510.1371/journal.pone.0114969)
Heianza Y, et al. Gut microbiota metabolites and risk of major adverse cardiovascular disease events and death: a systematic review and meta-analysis of prospective studies. J Am Heart Assoc. 2017;6(7):e004947.
Qi J, et al. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. J Cell Mol Med. 2018;22(1):185–94. (PMID: 2878288610.1111/jcmm.13307)
Liu G, et al. Inhibition of microbiota-dependent trimethylamine N-Oxide production ameliorates high salt diet-induced sympathetic excitation and hypertension in rats by attenuating central neuroinflammation and oxidative stress. Front Pharmacol. 2022;13:856914. (PMID: 35359866896132910.3389/fphar.2022.856914)
Zhang X, et al. 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. Arterioscler Thromb Vasc Biol. 2020;40(3):751–65. (PMID: 3194138210.1161/ATVBAHA.119.313414)
Organ CL, et al. Choline diet and Its gut MICROBE-derived metabolite, trimethylamine N-Oxide, exacerbate pressure overload-induced heart failure. Circ Heart Fail. 2016;9(1):e002314. (PMID: 2669938810.1161/CIRCHEARTFAILURE.115.002314)
Brunt VE, et al. Trimethylamine-N-Oxide promotes age-related vascular oxidative stress and endothelial dysfunction in mice and healthy humans. Hypertension. 2020;76(1):101–12. (PMID: 3252061910.1161/HYPERTENSIONAHA.120.14759)
Querio G, et al. Trimethylamine N-Oxide (TMAO) Impairs purinergic induced intracellular calcium increase and nitric oxide release in endothelial cells. Int J Mol Sci. 2022;23(7):3982.
Peixoto-Neves D, et al. Eugenol dilates mesenteric arteries and reduces systemic BP by activating endothelial cell TRPV4 channels. Br J Pharmacol. 2015;172(14):3484–94. (PMID: 25832173450715410.1111/bph.13156)
Watanabe H, et al. Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J Biol Chem. 2002;277(16):13569–77. (PMID: 1182797510.1074/jbc.M200062200)
Liedtke W, et al. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell. 2000;103(3):525–35. (PMID: 11081638221152810.1016/S0092-8674(00)00143-4)
Grace MS, et al. Modulation of the TRPV4 ion channel as a therapeutic target for disease. Pharmacol Ther. 2017;177:9–22. (PMID: 2820236610.1016/j.pharmthera.2017.02.019)
Kwan HY, Huang Y, Yao X. TRP channels in endothelial function and dysfunction. Biochim Biophys Acta. 2007;1772(8):907–14. (PMID: 1743429410.1016/j.bbadis.2007.02.013)
Zhu Z, Gao P, Huang Y. Turning dilatation to constriction: endothelial TRPV4 (transient receptor potential vanilloid 4) matters. Hypertension. 2018;71(1):56–8. (PMID: 2910919210.1161/HYPERTENSIONAHA.117.09848)
Wolfe MM. Future trends in the development of safer nonsteroidal anti-inflammatory drugs. Am J Med. 1998;105(5a):44s–52s. (PMID: 985517610.1016/S0002-9343(98)00281-2)
Nazıroğlu M. A novel antagonist of TRPM2 and TRPV4 channels: carvacrol. Metab Brain Dis. 2022;37(3):711–28. (PMID: 34989943873297310.1007/s11011-021-00887-1)
Ma X, et al. Functional role of TRPV4-KCa2.3 signaling in vascular endothelial cells in normal and streptozotocin-induced diabetic rats. Hypertension. 2013;62(1):134–9. (PMID: 2364870610.1161/HYPERTENSIONAHA.113.01500)
Gao M, et al. Blocking endothelial TRPV4-Nox2 interaction helps reduce ROS production and inflammation, and improves vascular function in obese mice. J Mol Cell Cardiol. 2021;157:66–76. (PMID: 3393246410.1016/j.yjmcc.2021.04.008)
Shao J, et al. Curcumin Induces Endothelium-Dependent Relaxation by Activating Endothelial TRPV4 Channels. J Cardiovasc Transl Res. 2019;12(6):600–7. (PMID: 3166461510.1007/s12265-019-09928-8)
Zhou T, et al. Puerarin induces mouse mesenteric vasodilation and ameliorates hypertension involving endothelial TRPV4 channels. Food Funct. 2020;11(11):10137–48. (PMID: 3315559910.1039/D0FO02356F)
Han J, et al. Total flavone of rhododendron improves cerebral ischemia injury by activating vascular TRPV4 to induce endothelium-derived hyperpolarizing factor-mediated responses. Evid Based Complement Alternat Med. 2018;2018:8919867. (PMID: 30405745620148910.1155/2018/8919867)
Ma X, et al. Apigenin, a plant-derived flavone, activates transient receptor potential vanilloid 4 cation channel. Br J Pharmacol. 2012;166(1):349–58. (PMID: 22049911341565910.1111/j.1476-5381.2011.01767.x)
Jiang S, et al. Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin II-induced hypertension. Redox Biol. 2021;46:102115. (PMID: 34474396840863210.1016/j.redox.2021.102115)
Ma SR, et al. Berberine treats atherosclerosis via a vitamine-like effect down-regulating Choline-TMA-TMAO production pathway in gut microbiota. Signal Transduct Target Ther. 2022;7(1):207. (PMID: 35794102925958810.1038/s41392-022-01027-6)
Gatarek P, Kaluzna-Czaplinska J. Trimethylamine N-oxide (TMAO) in human health. Excli j. 2021;20:301–19. (PMID: 337466647975634)
Liu S, et al. Targeting gut microbiota in aging-related cardiovascular dysfunction: focus on the mechanisms. Gut Microbes. 2023;15(2):2290331. (PMID: 380730961073015110.1080/19490976.2023.2290331)
Zhou S, et al. Gut-flora-dependent metabolite trimethylamine-N-Oxide promotes atherosclerosis-associated inflammation responses by indirect ros stimulation and signaling involving AMPK and SIRT1. Nutrients. 2022;14(16):3338.
Brunt VE, et al. Suppression of the gut microbiome ameliorates age-related arterial dysfunction and oxidative stress in mice. J Physiol. 2019;597(9):2361–78. (PMID: 30714619648793510.1113/JP277336)
Hakhamaneshi MS, et al. Toll-Like Receptor 4: A Macrophage Cell Surface Receptor Is Activated By Trimethylamine-N-Oxide. Cell J. 2021;23(5):516–22. (PMID: 348376788588815)
Chen ML, et al. 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):e006347.
Malekmohammad K, Bezsonov EE, Rafieian-Kopaei M. Role of lipid accumulation and inflammation in atherosclerosis: focus on molecular and cellular mechanisms. Front Cardiovasc Med. 2021;8:707529. (PMID: 34552965845035610.3389/fcvm.2021.707529)
Tian C, et al. Transient receptor potential ankyrin 1 contributes to the lysophosphatidylcholine-induced oxidative stress and cytotoxicity in OLN-93 oligodendrocyte. Cell Stress Chaperones. 2020;25(6):955–68. (PMID: 32572784759168410.1007/s12192-020-01131-y)
Everaerts W, Nilius B, Owsianik G. The vanilloid transient receptor potential channel TRPV4: from structure to disease. Prog Biophys Mol Biol. 2010;103(1):2–17. (PMID: 1983590810.1016/j.pbiomolbio.2009.10.002)
Randhawa PK, Jaggi AS. TRPV4 channels: physiological and pathological role in cardiovascular system. Basic Res Cardiol. 2015;110(6):54. (PMID: 2641588110.1007/s00395-015-0512-7)
Sonkusare SK, et al. Elementary Ca ²⁺ signals through endothelial TRPV4 channels regulate vascular function. Science. 2012;336(6081):597–601. (PMID: 22556255371599310.1126/science.1216283)
Yao X, Kwan HY, Huang Y. A mechanosensitive cation channel in endothelial cells. J Card Surg. 2002;17(4):340–1. (PMID: 1254608310.1111/j.1540-8191.2001.tb01154.x)
Huang Y, et al. Urocortin-induced endothelium-dependent relaxation of rat coronary artery: role of nitric oxide and K+ channels. Br J Pharmacol. 2002;135(6):1467–76. (PMID: 11906960157325210.1038/sj.bjp.0704587)
Chan HY, et al. Isoproterenol amplifies 17 beta-estradiol-mediated vasorelaxation: role of endothelium/nitric oxide and cyclic AMP. Cardiovasc Res. 2002;53(3):627–33. (PMID: 1186103310.1016/S0008-6363(01)00498-9)
Shimokawa H, Godo S. Diverse functions of endothelial NO synthases system: NO and EDH. J Cardiovasc Pharmacol. 2016;67(5):361–6. (PMID: 2664711910.1097/FJC.0000000000000348)
Bagher P, et al. Low intravascular pressure activates endothelial cell TRPV4 channels, local Ca2+ events, and IKCa channels, reducing arteriolar tone. Proc Natl Acad Sci U S A. 2012;109(44):18174–9. (PMID: 23071308349774510.1073/pnas.1211946109)
He D, et al. Treatment of hypertension by increasing impaired endothelial TRPV4-KCa2.3 interaction. EMBO Mol Med. 2017;9(11):1491–503. (PMID: 28899928566631610.15252/emmm.201707725)

JUSRP12047 Fundamental Research Funds for the Central Universities; 81800430 National Natural Science Foundation of China; 82200463 National Natural Science Foundation of China

Keywords: Endothelial cell; TRPV4; Trimethylamine oxide; Vasodilatation

0 (TRPV Cation Channels)
FLD0K1SJ1A (trimethyloxamine)
0 (Methylamines)
0 (Trpv4 protein, mouse)

Date Created: 20240709 Date Completed: 20241211 Latest Revision: 20241211

20241212

10.1007/s12265-024-10543-5

38980653