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Theaflavin indicates protection on vascular endothelium via hydrogen sulfide production

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Molecular & Cellular Toxicology Aims and scope Submit manuscript

Abstract

Background

Tea polyphenols have different beneficial effects on vascular endothelium through the controlled production of nitric oxide (NO), regulation of cell proliferation, and antioxidant system. Recently, hydrogen sulfide (H2S) has been proposed as the gaseous signaling molecule in the vascular endothelium. In this study, we investigated the differences in biological functions with tea polyphenols through NO and H2S production in vascular endothelium.

Objective

Providing high potential therapeutic effect on vascular endothelium with theaflavin.

Results

Theaflavin significantly stimulated H2S production in vascular endothelial cells (VECs) by 1.51-fold compared to the control, while EGCG showed no effect. Both EGCG and theaflavin increased NO production (1.63 and 2.16-fold vs control), eNOS (1.45- and 1.74-fold vs control), p-eNOS (1.41-, 2.01-fold vs control), wound healing (1.30- and 1.75-fold vs control), and oxidative stress-induced reduction of cell viability (89.0 and 94.0% vs control). The potency of theaflavin was found to be higher than that of EGCG. Upon treatment with 100 μM DL-propargylglycine (PPG) to inhibit cystathionine-γ-lyase activity, all cell responses were suppressed in both EGCG and theaflavin treatments, and the reduction rate in the theaflavin treatment was higher than that of the control and EGCG treatments in all responses.

Conclusion

These results indicate that the protective effect of VECs is dependent on NO production and that both EGCG and theaflavin have therapeutic potential for VECs. Theaflavin has a relatively higher therapeutic potential than EGCG due to its ability to increase H2S production, which in turn affects NO production and biological activity.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author, S.Y., on reasonable request.

References

  • Antoniades C et al (2007) Altered plasma versus vascular biopterins in human atherosclerosis reveal relationships between endothelial nitric oxide synthase coupling, endothelial function, and inflammation. Circulation 116:2851–2859

    Article  CAS  PubMed  Google Scholar 

  • Cao X et al (2019) A review of hydrogen sulfide synthesis, metabolism, and measurement: is modulation of hydrogen sulfide a novel therapeutic for cancer? Antioxid Redox Signal 31:1–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ceriello A, Motz E (2004) Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol 24:816–823

    Article  CAS  PubMed  Google Scholar 

  • Chen Y et al (2021) Molecular mechanisms and applications of tea polyphenols: a narrative review. J Food Biochem 45:e13910

    Article  CAS  PubMed  Google Scholar 

  • Cirino G, Vellecco V, Bucci M (2017) Nitric oxide and hydrogen sulfide: the gasotransmitter paradigm of the vascular system. British J Pharmacol 174:4021–4031

    Article  CAS  Google Scholar 

  • Fang J et al (2019) Trends of tea in cardiovascular health and disease: a critical review. Trends Food Sci Technol 88:385–396

    Article  CAS  Google Scholar 

  • Fogo JK, Popowsky M (1949) Spectrophotometric determination of hydrogen sulfide. Anal Chem 21:732–734

    Article  CAS  Google Scholar 

  • Förstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33:829–837

    Article  PubMed  Google Scholar 

  • Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376

    Article  CAS  PubMed  Google Scholar 

  • Grove KA, Lambert JD (2010) Laboratory, epidemiological, and human intervention studies show that tea (Camellia sinensis) may be useful in the prevention of obesity. J Nutr 140:446–453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hine C, Mitchell JR (2017) Endpoint or kinetic measurement of hydrogen sulfide production capacity in tissue extracts. Bio-Protoc 7:e2382–e2382

    Article  PubMed  PubMed Central  Google Scholar 

  • Ignarro LJ (1999) Nitric oxide: a unique endogenous signaling molecule in vascular biology (Nobel lecture). Angew Chem Int Ed 38(13–14):1882–1892

    Article  CAS  Google Scholar 

  • Jarosz AP, Yep T, Mutus B (2013) Microplate-based colorimetric detection of free hydrogen sulfide. Anal Chem 85:3638–3643

    Article  CAS  PubMed  Google Scholar 

  • Katsouda A, Bibli SI, Pyriochou A, Szabo C, Papapetropoulos A (2016) Regulation and role of endogenously produced hydrogen sulfide in angiogenesis. Pharmacol Res 113:175–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim HS, Quon MJ, Kim JA (2014) New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate. Redox Biol 2:187–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JA et al (2007) Epigallocatechin gallate, a green tea polyphenol, mediates NO-dependent vasodilation using signaling pathways in vascular endothelium requiring reactive oxygen species and Fyn. J Biol Chem 282:13736–13745

    Article  CAS  PubMed  Google Scholar 

  • Kolluru GK, Shen X, Bir SC, Kevil CG (2013) Hydrogen sulfide chemical biology: pathophysiological roles and detection. Nitric Oxide 35:5–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kolluru GK, Yuan S, Shen X, Kevil CG (2015) H2S regulation of nitric oxide metabolism. Methods Enzymol 554:271–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuhlencordt PJ et al (2001) Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice. Circulation 104:448–454

    Article  CAS  PubMed  Google Scholar 

  • Kumar R, Banerjee R (2021) Regulation of the redox metabolome and thiol proteome by hydrogen sulfide. Crit Rev Biochem Mol Biol 56:221–235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li H, Horke S, Forstermann U (2013) Oxidative stress in vascular disease and its pharmacological prevention. Trends Pharmacol Sci 34:313–319

    Article  PubMed  Google Scholar 

  • Mani S, Untereiner A, Wu L, Wang R (2014) Hydrogen sulfide and the pathogenesis of atherosclerosis. Antioxid Redox Signal 20:805–817

    Article  CAS  PubMed  Google Scholar 

  • Módis K, Coletta C, Erdélyi K, Papapetropoulos A, Szabo C (2013) Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics. FASEB J 27:601–611

    Article  PubMed  Google Scholar 

  • Ota H et al (2010) Induction of endothelial nitric oxide synthase, SIRT1, and catalase by statins inhibits endothelial senescence through the Akt pathway. Arterioscler Thromb Vasc Biol 30:2205–2211

    Article  CAS  PubMed  Google Scholar 

  • Shen X, Kolluru GK, Yuan S, Kevil CG (2015) Measurement of H2S in vivo and in vitro by the monobromobimane method. Methods Enzymol 554:31–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szabo C (2007) Hydrogen sulphide and its therapeutic potential. Nature Rev Drug Discov 6:917–935

    Article  CAS  Google Scholar 

  • Szabo C (2010) Gaseotransmitters: new frontiers for translational science. Sci Transl Med 2:59ps54-59ps54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takano Y, Shimamoto K, Hanaoka K (2016) Chemical tools for the study of hydrogen sulfide (H2S) and sulfane sulfur and their applications to biological studies. J Clin Biochem Nutr 58:15–91

    Article  Google Scholar 

  • Wang MJ et al (2010) The hydrogen sulfide donor NaHS promotes angiogenesis in a rat model of hind limb ischemia. Antioxid Redox Signal 12:1065–1077

    Article  CAS  PubMed  Google Scholar 

  • Wu YY, Li W, Xu Y, Jin EH, Tu YY (2011) Evaluation of the antioxidant effects of four main theaflavin derivatives through chemiluminescence and DNA damage analyses. J Zhejiang Univ Sci B 12:744–751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamada H, Watanabe H (2007) Tea polyphenols in preventing cardiovascular diseases. Cardiovasc Res 73:439–440

    Article  CAS  PubMed  Google Scholar 

  • Yang G et al (2008a) H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase. Science 322:587–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Z et al (2008b) Radical-scavenging abilities and antioxidant properties of theaflavins and their gallate esters in H2O2-mediated oxidative damage system in the HPF-1 cells. Toxicol in Vitro 22:1250–1256

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Qi R, Mine Y (2019) The impact of oolong and black tea polyphenols on human health. Food Biosci 29:55–61

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank the Tsukuba-Plant Innovation Research Center (T-PIRC) of the University of Tsukuba for the use of a CO2 incubator and microplate reader for cell culture and fluorescence analysis of the VECs. We would like to thank Editage (www.editage.co.kr) for English language editing.

Funding

Not applicable.

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Authors and Affiliations

Authors

Contributions

WJL performed the entire experiment and wrote the manuscript. TT, WQJ, and YQZ performed part of the experiment and analyzed the data. HM and SY provided valuable advice and revised the manuscript. SY organized the whole study. All authors provided appropriate comments on the manuscript.

Corresponding author

Correspondence to Shigeki Yoshida.

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Conflict of interest

WonJune Lee declares that he has no conflicts of interest in this study. Tomoko Terada declares that she has no conflicts of interest in this study. WenQian Jiang declares that she has no conflicts of interest in this study. YiQian Zhang declares that he has no conflicts of interest in this study. Hitoshi Miyazaki declares that he has no conflicts of interest in this study. Shigeki Yoshida declares that he has no conflicts of interest in this study.

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This article does not contain any studies with humans and animals. This study was performed following institutional and national guidelines.

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Lee, W., Terada, T., Jiang, W. et al. Theaflavin indicates protection on vascular endothelium via hydrogen sulfide production. Mol. Cell. Toxicol. (2023). https://doi.org/10.1007/s13273-023-00365-y

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