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, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
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
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
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
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
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
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
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
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
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
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
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
Ischiropoulos H (2009) Protein tyrosine nitration—an update. Arch Biochem Biophys 484:117–121. https://doi.org/10.1016/j.abb.2008.10.034
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
Rothe CF (1993) Mean circulatory filling pressure: its meaning and measurement. J Appl Physiol 74:499–509. https://doi.org/10.1152/jappl.19188.8.131.529
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Sabik JF (2011) Understanding saphenous vein graft patency. Circulation 124:273–275. https://doi.org/10.1161/CIRCULATIONAHA.111.039842
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
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
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
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).
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).
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures were approved and performed in accordance with the guidelines of the Ethics Committee of UNIFESP (Protocol No. 2689270319).
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
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 (2021). https://doi.org/10.1007/s11010-020-04025-w
- Venous endothelium
- Nitric oxide