Skip to main content
Log in

Protective effects of luteolin on the venous endothelium

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Luteolin is a flavonoid with antioxidant properties already demonstrated in studies related to inflammation, tumor, and cardiovascular processes; however, there are no available information regarding its antioxidant effects at the venous endothelial site. We investigated the effects of luteolin (10, 20, and 50 μmol/L) in cultures of rat venous endothelial cells. Nitric oxide (NO) and reactive oxygen species (ROS) were analyzed by fluorimetry; 3-nitrotyrosine (3-NT) residues were evaluated by immunofluorescence, and prostacyclin (PGI2) release was investigated by colorimetry. Intracellular NO levels were significantly enhanced after 10 min of luteolin incubation, with a parallel decrease in ROS generation. These results were accompanied by a significant reduction in the expression of 3-NT residues and enhanced PGI2 rates. Therefore, luteolin is effective in reducing ROS thereby improving NO availability in venous endothelial cells. Besides, luteolin-induced decrease in 3-NT residues may correlate with the enhancement in endothelial PGI2 bioavailability. These findings suggest the future application of this flavonoid as a protective agent by improving endothelial function in several circulatory disorders related to venous insufficiency.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Nabavi SF, Braidy N, Gortzi O et al (2015) Luteolin as an anti-inflammatory and neuroprotective agent: a brief review. Brain Res Bull 119:1–11. https://doi.org/10.1016/j.brainresbull.2015.09.002

    Article  CAS  PubMed  Google Scholar 

  2. Luo Y, Shang P, Li D (2017) Luteolin: a flavonoid that has multiple cardio-protective effects and its molecular mechanisms. Front Pharmacol 8:1–10. https://doi.org/10.3389/fphar.2017.00692

    Article  CAS  Google Scholar 

  3. Cordaro M, Cuzzocrea S, Crupi R (2020) An update of palmitoylethanolamide and luteolin effects in preclinical and clinical studies of neuroinflammatory events. Antioxidants 9:216. https://doi.org/10.3390/antiox9030216

    Article  CAS  PubMed Central  Google Scholar 

  4. Yi L, Chen CY, Jin X et al (2012) Differential suppression of intracellular reactive oxygen species-mediated signaling pathway in vascular endothelial cells by several subclasses of flavonoids. Biochimie 94:2035–2044. https://doi.org/10.1016/j.biochi.2012.05.027

    Article  CAS  PubMed  Google Scholar 

  5. Duarte J, Francisco V, Perez-Vizcaino F (2014) Modulation of nitric oxide by flavonoids. Food Funct 5:1653–1668. https://doi.org/10.1039/c4fo00144c

    Article  CAS  PubMed  Google Scholar 

  6. López-López G, Moreno L, Cogolludo A et al (2004) Nitric oxide (NO) scavenging and NO protecting effects of quercetin and their biological significance in vascular smooth muscle. Mol Pharmacol 65:851–859. https://doi.org/10.1124/mol.65.4.851

    Article  PubMed  Google Scholar 

  7. Versari D, Daghini E, Virdis A et al (2009) Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol 157:527–536. https://doi.org/10.1111/j.1476-5381.2009.00240.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Félétou M, Huang Y, Vanhoutte PM (2011) Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol 164:894–912. https://doi.org/10.1111/j.1476-5381.2011.01276.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vanhoutte PM, Zhao Y, Xu A, Leung SWS (2016) Thirty years of saying NO. Circ Res 119:375–396. https://doi.org/10.1161/CIRCRESAHA.116.306531

    Article  CAS  PubMed  Google Scholar 

  10. Tang EHC, Vanhoutte PM (2008) Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension. Physiol Genomics 32:409–418. https://doi.org/10.1152/physiolgenomics.00136.2007

    Article  CAS  PubMed  Google Scholar 

  11. Feletou M, Tang EHC, Vanhoutte PM (2008) Nitric oxide the gatekeeper of endothelial vasomotor control. Front Biosci 13:4198–4217. https://doi.org/10.2741/3000

    Article  CAS  PubMed  Google Scholar 

  12. Ischiropoulos H (2009) Protein tyrosine nitration—an update. Arch Biochem Biophys 484:117–121. https://doi.org/10.1016/j.abb.2008.10.034

    Article  CAS  PubMed  Google Scholar 

  13. Forman HJ, Ursini F, Maiorino M (2014) An overview of mechanisms of redox signaling. J Mol Cell Cardiol 73:2–9. https://doi.org/10.1016/j.yjmcc.2014.01.018

    Article  CAS  PubMed  Google Scholar 

  14. Rothe CF (1993) Mean circulatory filling pressure: its meaning and measurement. J Appl Physiol 74:499–509. https://doi.org/10.1152/jappl.1993.74.2.499

    Article  CAS  PubMed  Google Scholar 

  15. Ward AO, Caputo M, Angelini GD et al (2017) Activation and inflammation of the venous endothelium in vein graft disease. Atherosclerosis 265:266–274. https://doi.org/10.1016/j.atherosclerosis.2017.08.023

    Article  CAS  PubMed  Google Scholar 

  16. Trindade MR, Assunção HCR, Torres TC et al (2018) Venous endothelium reactivity to angiotensin II: a study in primary endothelial cultures of rat vena cava and portal vein. Exp Cell Res 362:188–194. https://doi.org/10.1016/j.yexcr.2017.11.016

    Article  CAS  PubMed  Google Scholar 

  17. Nakatsubo N, Kojima H, Kikuchi K et al (1998) Direct evidence of nitric oxide production from bovine aortic endothelial cells using new fluorescence indicators: diaminofluoresceins. FEBS Lett 427:263–266. https://doi.org/10.1016/S0014-5793(98)00440-2

    Article  CAS  PubMed  Google Scholar 

  18. Bindokas VP, Jordán J, Lee CC, Miller RJ (1996) Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine. J Neurosci 16:1324–1336. https://doi.org/10.1523/jneurosci.16-04-01324.1996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pueyo ME, Gonzalez W, Nicoletti A et al (2000) Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-κB activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol 20:645–651. https://doi.org/10.1161/01.ATV.20.3.645

    Article  CAS  PubMed  Google Scholar 

  20. Seelinger G, Merfort I, Schempp CM (2008) Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Med 74:1667–1677. https://doi.org/10.1055/s-0028-1088314

    Article  CAS  PubMed  Google Scholar 

  21. Nakayama A, Morita H, Nakao T et al (2015) A food-derived flavonoid luteolin protects against angiotensin II-induced cardiac remodeling. PLoS One 10:1–15. https://doi.org/10.1371/journal.pone.0137106

    Article  CAS  Google Scholar 

  22. Su J, Xu HT, Yu JJ et al (2015) Luteolin ameliorates hypertensive vascular remodeling through inhibiting the proliferation and migration of vascular smooth muscle cells. Evidence-Based Complementary Altern Med 2015:364876. https://doi.org/10.1155/2015/364876

    Article  Google Scholar 

  23. Kamkaew N, Paracha TU, Ingkaninan K et al (2019) Vasodilatory effects and mechanisms of action of bacopa monnieri active compounds on rat mesenteric arteries. Molecules 24:1–11. https://doi.org/10.3390/molecules24122243

    Article  CAS  Google Scholar 

  24. Jiang H, Xia Q, Wang X et al (2005) Luteolin induces vasorelaxion in rat thoracic aorta via calcium and potassium channels. Pharmazie 60:444–447

    CAS  PubMed  Google Scholar 

  25. Si H, Wyeth RP, Liu D (2014) The flavonoid luteolin induces nitric oxide production and arterial relaxation. Eur J Nutr 53:269–275. https://doi.org/10.1007/s00394-013-0525-7

    Article  CAS  PubMed  Google Scholar 

  26. Wu J, Xu X, Li Y et al (2014) Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3-mediated inflammation and apoptosis with regulation of AMPK in endothelial cells. Eur J Pharmacol 745:59–68. https://doi.org/10.1016/j.ejphar.2014.09.046

    Article  CAS  PubMed  Google Scholar 

  27. Ou HC, Pandey S, Hung MY et al (2019) Luteolin: a natural flavonoid enhances the survival of HUVECs against oxidative stress by modulating AMPK/PKC pathway. Am J Chin Med 47:541–557. https://doi.org/10.1142/S0192415X19500289

    Article  CAS  PubMed  Google Scholar 

  28. Abbasi N, Akhavan MM, Rahbar-Roshandel N, Shafiei M (2014) The effects of low and high concentrations of luteolin on cultured human endothelial cells under normal and glucotoxic conditions: involvement of integrin-linked kinase and cyclooxygenase-2. Phytother Res 28:1301–1307. https://doi.org/10.1002/ptr.5128

    Article  CAS  PubMed  Google Scholar 

  29. El-Bassossy HM, Abo-Warda SM, Fahmy A (2013) Chrysin and luteolin attenuate diabetes-induced impairment in endothelial-dependent relaxation: effect on lipid profile, AGEs and NO generation. Phyther Res 27:1678–1684. https://doi.org/10.1002/ptr.4917

    Article  CAS  Google Scholar 

  30. Gentile D, Fornai M, Pellegrini C et al (2018) Luteolin prevents cardiometabolic alterations and vascular dysfunction in mice with HFD-induced obesity. Front Pharmacol 9:1–13. https://doi.org/10.3389/fphar.2018.01094

    Article  CAS  Google Scholar 

  31. Zhu M, Chen D, Li D et al (2013) Luteolin inhibits angiotensin II-induced human umbilical vein endothelial cell proliferation and migration through downregulation of src and Akt phosphorylation. Circ J 77:772–779. https://doi.org/10.1253/circj.CJ-12-0310

    Article  CAS  PubMed  Google Scholar 

  32. Matsuo M, Sasaki N, Saga K, Kaneko T (2005) Cytotoxicity of flavonoids toward cultured normal human cells. Biol Pharm Bull 28:253–259. https://doi.org/10.1248/bpb.28.253

    Article  CAS  PubMed  Google Scholar 

  33. Yi L, Jin X, Chen CY et al (2011) Chemical structures of 4-oxo-flavonoids in relation to inhibition of oxidized low-density lipoprotein (LDL)-induced vascular endothelial dysfunction. Int J Mol Sci 12:5471–5489. https://doi.org/10.3390/ijms12095471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fernandes DC, Wosniak J, Pescatore LA et al (2006) Analysis of DHE-derived oxidation products by HPLC in the assessment of superoxide production and NADPH oxidase activity in vascular systems. AJP Cell Physiol 292:C413–C422. https://doi.org/10.1152/ajpcell.00188.2006

    Article  CAS  Google Scholar 

  35. Nazarewicz RR, Bikineyeva A, Dikalov SI (2013) Rapid and specific measurements of superoxide using fluorescence spectroscopy. J Biomol Screen 18:498–503. https://doi.org/10.1177/1087057112468765

    Article  CAS  PubMed  Google Scholar 

  36. Tarpey MM, Beckman JS, Ischiropoulos H et al (1995) Peroxynitrite stimulates vascular smooth muscle cell cyclic GMP synthesis. FEBS Lett 364:314–318. https://doi.org/10.1016/0014-5793(95)00413-4

    Article  CAS  PubMed  Google Scholar 

  37. Zou MH, Ullrich V (1996) Peroxynitrite formed by simultaneous generation of nitric oxide and superoxide selectively inhibits bovine aortic prostacyclin synthase. FEBS Lett 382:101–104. https://doi.org/10.1016/0014-5793(96)00160-3

    Article  CAS  PubMed  Google Scholar 

  38. Zou M, Martin C, Ullrich V (1997) Tyrosine nitration as a mechanism of selective inactivation of prostacyclin synthase by peroxynitrite. Biol Chem 378:707–713. https://doi.org/10.1515/bchm.1997.378.7.707

    Article  CAS  PubMed  Google Scholar 

  39. Zou MH (2007) Peroxynitrite and protein tyrosine nitration of prostacyclin synthase. Prostaglandins Other Lipid Mediators 82:119–127. https://doi.org/10.1016/j.prostaglandins.2006.05.005

    Article  CAS  PubMed  Google Scholar 

  40. Polagruto JA, Schramm DD, Wang-Polagruto JF et al (2003) Effects of flavonoid-rich beverages on prostacyclin synthesis in humans and human aortic endothelial cells: association with ex vivo platelet function. J Med Food 6:301–308. https://doi.org/10.1089/109662003772519840

    Article  CAS  PubMed  Google Scholar 

  41. Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376. https://doi.org/10.1038/288373a0

    Article  CAS  PubMed  Google Scholar 

  42. Rubira MC, Consolim-Colombo FM, Rabelo ER et al (2007) Venous or arterial endothelium evaluation for early cardiovascular dysfunction in hypertensive patients? J Clin Hypertens (Greenwich) 9:859–865. https://doi.org/10.1111/j.1524-6175.2007.06643.x

    Article  Google Scholar 

  43. Gresele P, Momi S, Migliacci R (2010) Endothelium, venous thromboembolism and ischaemic cardiovascular events. Thromb Haemost 103:56–61. https://doi.org/10.1160/TH09-08-0562

    Article  CAS  PubMed  Google Scholar 

  44. Newby AC, Zaltsman AB (2000) Molecular mechanisms in intimal hyperplasia. J Pathol 190:300–309. https://doi.org/10.1002/(SICI)1096-9896(200002)190:3<300::AID-PATH596>3.0.CO;2-I

    Article  CAS  PubMed  Google Scholar 

  45. Sabik JF (2011) Understanding saphenous vein graft patency. Circulation 124:273–275. https://doi.org/10.1161/CIRCULATIONAHA.111.039842

    Article  PubMed  Google Scholar 

  46. Pocock ES, Alsaigh T, Mazor R, Schmid-Schönbein GW (2014) Cellular and molecular basis of venous insufficiency. Vasc Cell 6:1–8. https://doi.org/10.1186/s13221-014-0024-5

    Article  CAS  Google Scholar 

  47. Horecka A, Biernacka J, Hordyjewska A et al (2018) Antioxidative mechanism in the course of varicose veins. Phlebology 33:464–469. https://doi.org/10.1177/0268355517721055

    Article  PubMed  Google Scholar 

  48. Szasz T, Thakali K, Fink GD, Watts SW (2007) A comparison of arteries and veins in oxidative stress: producers, destroyers, function, and disease. Exp Biol Med 232:27–37. https://doi.org/10.3181/00379727-207-2320027

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Wilson Dias Segura for technical assistance. This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (2017/22028-5; 2017/21834-8), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Funding

This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (2017/22028-5; 2017/21834-8), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Author information

Authors and Affiliations

Authors

Contributions

H.C.R.A.: Conceptualization; Methodology; Investigation. Y.M.C.C.: Conceptualization; Methodology; Investigation. J.S.B.: Conceptualization; Methodology; Investigation. R.C.T.G.: Conceptualization; Visualization; Funding acquisition. L.F.: Writing—Review & Editing; Supervision; Project administration; Funding acquisition.

Corresponding author

Correspondence to Liliam Fernandes.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures were approved and performed in accordance with the guidelines of the Ethics Committee of UNIFESP (Protocol No. 2689270319).

Additional information

Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Assunção, H.C.R., Cruz, Y.M.C., Bertolino, J.S. et al. Protective effects of luteolin on the venous endothelium. Mol Cell Biochem 476, 1849–1859 (2021). https://doi.org/10.1007/s11010-020-04025-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-020-04025-w

Keywords

Navigation