Subscribe to RSS
DOI: 10.1055/a-0837-0975
Icariin Attenuates High Glucose-Induced Apoptosis, Oxidative Stress, and Inflammation in Human Umbilical Venous Endothelial Cells
Abstract
Endothelial dysfunction is closely associated with diabetic complications. Icariin, a flavonoid glycoside isolated from the Epimedium plant species, exhibits antidiabetic properties. However, its impact on endothelial function remains poorly understood, particularly under hyperglycemia. In this study, we investigated the potential protective effect of icariin on high glucose-induced detrimental effects on vascular endothelial cells. Human umbilical venous endothelial cells were incubated in media containing 5.5 mM glucose (normal glucose) or 25 mM glucose (high glucose) in the presence or absence of 50 µM icariin for 72 h. We found that high glucose markedly induced cell apoptosis, enhanced reactive oxygen species generation, and elevated expression levels of inflammatory factors and cell adhesion molecules, which were greatly subdued by icariin supplementation. In conclusion, icariin exerted a beneficial effect on high glucose-induced endothelial dysfunction. This new finding provides a promising strategy for future treatment of diabetic vascular complications.
Key words
icariin - antidiabetic - inflammation - apoptosis - Epimedium sp. - Berberidaceae - endothelial cellPublication History
Received: 25 July 2018
Accepted: 13 January 2019
Publication Date:
31 January 2019 (online)
© 2019. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Hamilton SJ, Watts GF. Endothelial dysfunction in diabetes: pathogenesis, significance, and treatment. Rev Diabet Stud 2013; 10: 133-156
- 2 Sena CM, Pereira AM, Seiça R. Endothelial dysfunction – a major mediator of diabetic vascular disease. Biochim Biophys Acta 2013; 1832: 2216-2231
- 3 Santi D, Granata AR, Guidi A, Pignatti E, Trenti T, Roli L, Bozic R, Zaza S, Pacchioni C, Romano S, Nofer JR, Rochira V, Carani C, Simoni M. Six months of daily treatment with vardenafil improves parameters of endothelial inflammation and of hypogonadism in male patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, prospective trial. Eur J Endocrinol 2016; 174: 513-522
- 4 Murata M, Tamemoto H, Otani T, Jinbo S, Ikeda N, Kawakami M, Ishikawa SE. Endothelial impairment and bone marrow-derived CD34(+)/133(+) cells in diabetic patients with erectile dysfunction. J Diabetes Investig 2012; 3: 526-533
- 5 Eriksson L, Nyström T. Antidiabetic agents and endothelial dysfunction-beyond glucose control. Basic Clin Pharmacol Toxicol 2015; 117: 15-25
- 6 Li C, Li Q, Mei Q, Lu T. Pharmacological effects and pharmacokinetic properties of icariin, the major bioactive component in Herba Epimedii. Life Sci 2015; 126: 57-68
- 7 Schluesener JK, Schluesener H. Plant polyphenols in the treatment of age-associated diseases: revealing the pleiotropic effects of icariin by network analysis. Mol Nutr Food Res 2014; 58: 49-60
- 8 Fang J, Zhang Y. Icariin, an anti-atherosclerotic drug from Chinese medicinal herb horny goat weed. Front Pharmacol 2017; 8: 734
- 9 Fu L, Li F, Bruckbauer A, Cao Q, Cui X, Wu R, Shi H, Xue B, Zemel MB. Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism. Diabetes Metab Syndr Obes 2015; 8: 227-239
- 10 Han Y, Jung HW, Park YK. Effects of Icariin on insulin resistance via the activation of AMPK pathway in C2C12 mouse muscle cells. Eur J Pharmacol 2015; 758: 60-63
- 11 Xin H, Zhou F, Liu T, Li GY, Liu J, Gao ZZ, Bai GY, Lu H, Xin ZC. Icariin ameliorates streptozotocin-induced diabetic retinopathy in vitro and in vivo . Int J Mol Sci 2012; 13: 866-878
- 12 Qi MY, Kai-Chen. Liu HR, Su YH, Yu SQ. Protective effect of Icariin on the early stage of experimental diabetic nephropathy induced by streptozotocin via modulating transforming growth factor β1 and type IV collagen expression in rats. J Ethnopharmacol 2011; 138: 731-736
- 13 Liu T, Xin H, Li WR, Zhou F, Li GY, Gong YQ, Gao ZZ, Qin XC, Cui WS, Shindel AW, Xin ZC. Effects of icariin on improving erectile function in streptozotocin-induced diabetic rats. J Sex Med 2011; 8: 2761-2772
- 14 Siasos G, Gouliopoulos N, Moschos MM, Oikonomou E, Kollia C, Konsola T, Athanasiou D, Siasou G, Mourouzis K, Zisimos K, Papavassiliou AG, Stefanadis C, Tousoulis D. Role of endothelial dysfunction and arterial stiffness in the development of diabetic retinopathy. Diabetes Care 2015; 38: e9-e10
- 15 Leoni LA, Fukushima AR, Rocha LY, Maifrino LB, Rodrigues B. Physical activity on endothelial and erectile dysfunction: a literature review. Aging Male 2014; 17: 125-130
- 16 King GL. The role of hyperglycaemia and hyperinsulinaemia in causing vascular dysfunction in diabetes. Ann Med 1996; 28: 427-432
- 17 Kim MH, Kang HM, Kim CE, Han S, Kim SW. Ramipril inhibits high glucose-stimulated up-regulation of adhesion molecules via the ERK1/2 MAPK signaling pathway in human umbilical vein endothelial cells. Cell Mol Biol Lett 2015; 20: 937-947
- 18 Detaille D, Guigas B, Chauvin C, Batandier C, Fontaine E, Wiernsperger N, Leverve X. Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes 2005; 54: 2179-2187
- 19 Hattori Y, Suzuki K, Hattori S, Kasai K. Metformin inhibits cytokine-induced nuclear factor κB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 2006; 47: 1183-1188
- 20 Xie Z, Zhang J, Wu J, Viollet B, Zou MH. Upregulation of mitochondrial uncoupling protein-2 by the AMP-activated protein kinase in endothelial cells attenuates oxidative stress in diabetes. Diabetes 2008; 57: 3222-3230
- 21 van den Oever IA, Raterman HG, Nurmohamed MT, Simsek S. Endothelial dysfunction, inflammation, and apoptosis in diabetes mellitus. Mediators Inflamm 2010; 2010: 792393
- 22 Gilbert RE. Augmenting endothelial repair in diabetes: role of bone marrow-derived cells. Can J Diabetes 2013; 37: 315-318
- 23 Zhang H, Dellsperger KC, Zhang C. The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: an update. Basic Res Cardiol 2012; 107: 237
- 24 Nakagami H, Kaneda Y, Ogihara T, Morishita R. Endothelial dysfunction in hyperglycemia as a trigger of atherosclerosis. Curr Diabetes Rev 2005; 1: 59-63
- 25 Zhang H, Li P, Li J, Song T, Wang L, Li E, Wang J, Wang L, Wei N, Wang Z. Icariin induces apoptosis in acute promyelocytic leukemia by targeting PIM1. Pharmacol Rep 2017; 69: 1270-1281
- 26 Fan C, Yang Y, Liu Y, Jiang S, Di S, Hu W, Ma Z, Li T, Zhu Y, Xin Z, Wu G, Han J, Li X, Yan X. Icariin displays anticancer activity against human esophageal cancer cells via regulating endoplasmic reticulum stress-mediated apoptotic signaling. Sci Rep 2016; 6: 21145
- 27 Qiao C, Ye W, Li S, Wang H, Ding X. Icariin modulates mitochondrial function and apoptosis in high glucose-induced glomerular podocytes through G protein-coupled estrogen receptors. Mol Cell Endocrinol 2018; 473: 146-155
- 28 Mi B, Wang J, Liu Y, Liu J, Hu L, Panayi AC, Liu G, Zhou W. Icariin activates autophagy via down-regulation of the NF-κB signaling-mediated apoptosis in chondrocytes. Front Pharmacol 2018; 9: 605
- 29 Suzuki M, Youle RJ, Tjandra N. Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 2000; 103: 645-654
- 30 Li Q, Lin Y, Wang S, Zhang L, Guo L. GLP-1 inhibits high-glucose-induced oxidative injury of vascular endothelial cells. Sci Rep 2017; 7: 8008
- 31 Iori E, Pagnin E, Gallo A, Calò L, Murphy E, Ostuni F, Fadini GP, Avogaro A. Heme oxygenase-1 is an important modulator in limiting glucose-induced apoptosis in human umbilical vein endothelial cells. Life Sci 2008; 82: 383-392
- 32 Wang YK, Huang ZQ. Protective effects of icariin on human umbilical vein endothelial cell injury induced by H2O2 in vitro . Pharmacol Res 2005; 52: 174-182
- 33 Maamoun H, Zachariah M, McVey JH, Green FR, Agouni A. Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity. Biochem Pharmacol 2017; 127: 46-59
- 34 Dymkowska D, Drabarek B, Podszywałow-Bartnicka P, Szczepanowska J, Zabłocki K. Hyperglycaemia modifies energy metabolism and reactive oxygen species formation in endothelial cells in vitro . Arch Biochem Biophys 2014; 542: 7-13
- 35 Xu H, Goettsch C, Xia N, Horke S, Morawietz H, Förstermann U, Li H. Differential roles of PKCα and PKCε in controlling the gene expression of Nox4 in human endothelial cells. Free Radic Biol Med 2008; 44: 1656-1667
- 36 Piconi L, Quagliaro L, Assaloni R, Da Ros R, Maier A, Zuodar G, Ceriello A. Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction. Diabetes Metab Res Rev 2006; 22: 198-203
- 37 Galle J, Quaschning T, Seibold S, Wanner C. Endothelial dysfunction and inflammation: what is the link?. Kidney Int Suppl 2003; (84) S45-S49
- 38 Wang D, Wang Q, Yan G, Qiao Y, Sun L, Zhu B, Tang C, Gu Y. High glucose and interleukin 1β-induced apoptosis in human umbilical vein endothelial cells involves in down-regulation of monocarboxylate transporter 4. Biochem Biophys Res Commun 2015; 466: 607-614
- 39 Daemen MA, van ʼt Veer C, Denecker G, Heemskerk VH, Wolfs TG, Clauss M, Vandenabeele P, Buurman WA. Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation. J Clin Invest 1999; 104: 541-549
- 40 Springer TA. Adhesion receptors of the immune system. Nature 1990; 346: 425-434
- 41 Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 1994; 84: 2068-2101
- 42 Comba A, Çaltepe G, Yank K, Gör U, Yüce Ö, Kalayc AG. Assessment of endothelial dysfunction with adhesion molecules in patients with celiac disease. J Pediatr Gastroenterol Nutr 2016; 63: 247-252
- 43 Kouroedov A, Eto M, Joch H, Volpe M, Lüscher TF, Cosentino F. Selective inhibition of protein kinase Cβ2 prevents acute effects of high glucose on vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 2004; 110: 91-96
- 44 Quagliaro L, Piconi L, Assaloni R, Da Ros R, Maier A, Zuodar G, Ceriello A. Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C and mitochondrial superoxide production. Atherosclerosis 2005; 183: 259-267
- 45 Tsuneki H, Sekizaki N, Suzuki T, Kobayashi S, Wada T, Okamoto T, Kimura I, Sasaoka T. Coenzyme Q10 prevents high glucose-induced oxidative stress in human umbilical vein endothelial cells. Eur J Pharmacol 2007; 566: 1-10
- 46 Baldwin jr. AS. Series introduction: the transcription factor NF-κB and human disease. J Clin Invest 2001; 107: 3-6
- 47 Barnes PJ, Karin M. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997; 336: 1066-1071
- 48 Nichols TC, Fischer TH, Deliargyris EN, Baldwin jr. AS. Role of nuclear factor-kappa B (NF-κ B) in inflammation, periodontitis, and atherogenesis. Ann Periodontol 2001; 6: 20-29
- 49 Zhao Q, Lee FS. Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-κB through IκB kinase-α and IκB kinase-β. J Biol Chem 1999; 274: 8355-8358
- 50 Jiang B, Xu S, Hou X, Pimentel DR, Brecher P, Cohen RA. Temporal control of NF-κB activation by ERK differentially regulates interleukin-1β-induced gene expression. J Biol Chem 2004; 279: 1323-1329
- 51 Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, Pehamberger H, Kraut N, Beug H, Wirth T. NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004; 114: 569-581
- 52 Chung BH, Kim JD, Kim CK, Kim JH, Won MH, Lee HS, Dong MS, Ha KS, Kwon YG, Kim YM. Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells. Biochem Biophys Res Commun 2008; 376: 404-408
- 53 Hu Y, Liu K, Yan M, Zhang Y, Wang Y, Ren L. Icariin inhibits oxidized low-density lipoprotein-induced proliferation of vascular smooth muscle cells by suppressing activation of extracellular signal-regulated kinase 1/2 and expression of proliferating cell nuclear antigen. Mol Med Rep 2016; 13: 2899-2903
- 54 Kong L, Liu J, Wang J, Luo Q, Zhang H, Liu B, Xu F, Pang Q, Liu Y, Dong J. Icariin inhibits TNF-α/IFN-γ induced inflammatory response via inhibition of the substance P and p38-MAPK signaling pathway in human keratinocytes. Int Immunopharmacol 2015; 29: 401-407
- 55 Tang Y, Jacobi A, Vater C, Zou L, Zou X, Stiehler M. Icariin promotes angiogenic differentiation and prevents oxidative stress-induced autophagy in endothelial progenitor cells. Stem Cells 2015; 33: 1863-1877
- 56 Hu Y, Liu K, Yan M, Zhang Y, Wang Y, Ren L. Effects and mechanisms of icariin on atherosclerosis. Int J Clin Exp Med 2015; 8: 3585-3589
- 57 Jiang P, Zhang D, Qiu H, Yi X, Zhang Y, Cao Y, Zhao B, Xia Z, Wang C. Tiron ameliorates high glucose-induced cardiac myocyte apoptosis by PKCδ-dependent inhibition of osteopontin. Clin Exp Pharmacol Physiol 2017; 44: 760-770
- 58 Cheng HS, Sivachandran N, Lau A, Boudreau E, Zhao JL, Baltimore D, Delgado-Olguin P, Cybulsky MI, Fish JE. MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways. EMBO Mol Med 2013; 5: 1017-1034
- 59 Ding Z, An K, Xie L, Wu W, Zhang R, Wang D, Fang Y, Chen H, Xiao S, Fang L. Transmissible gastroenteritis virus infection induces NF-κB activation through RLR-mediated signaling. Virology 2017; 507: 170-178