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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 cellPublikationsverlauf
Eingereicht: 25. Juli 2018
Angenommen: 13. Januar 2019
Publikationsdatum:
31. Januar 2019 (online)
© 2019. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
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References
- 1
Hamilton SJ,
Watts GF.
Endothelial dysfunction in diabetes: pathogenesis, significance, and treatment. Rev
Diabet Stud 2013; 10: 133-156
MissingFormLabel
- 2
Sena CM,
Pereira AM,
Seiça R.
Endothelial dysfunction – a major mediator of diabetic vascular disease. Biochim Biophys
Acta 2013; 1832: 2216-2231
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 5
Eriksson L,
Nyström T.
Antidiabetic agents and endothelial dysfunction-beyond glucose control. Basic Clin
Pharmacol Toxicol 2015; 117: 15-25
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 8
Fang J,
Zhang Y.
Icariin, an anti-atherosclerotic drug from Chinese medicinal herb horny goat weed.
Front Pharmacol 2017; 8: 734
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 16
King GL.
The role of hyperglycaemia and hyperinsulinaemia in causing vascular dysfunction in
diabetes. Ann Med 1996; 28: 427-432
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 21
van den Oever IA,
Raterman HG,
Nurmohamed MT,
Simsek S.
Endothelial dysfunction, inflammation, and apoptosis in diabetes mellitus. Mediators
Inflamm 2010; 2010: 792393
MissingFormLabel
- 22
Gilbert RE.
Augmenting endothelial repair in diabetes: role of bone marrow-derived cells. Can
J Diabetes 2013; 37: 315-318
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 29
Suzuki M,
Youle RJ,
Tjandra N.
Structure of Bax: coregulation of dimer formation and intracellular localization.
Cell 2000; 103: 645-654
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 37
Galle J,
Quaschning T,
Seibold S,
Wanner C.
Endothelial dysfunction and inflammation: what is the link?. Kidney Int Suppl 2003;
(84) S45-S49
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 40
Springer TA.
Adhesion receptors of the immune system. Nature 1990; 346: 425-434
MissingFormLabel
- 41
Carlos TM,
Harlan JM.
Leukocyte-endothelial adhesion molecules. Blood 1994; 84: 2068-2101
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 46
Baldwin jr. AS.
Series introduction: the transcription factor NF-κB and human disease. J Clin Invest
2001; 107: 3-6
MissingFormLabel
- 47
Barnes PJ,
Karin M.
Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases.
N Engl J Med 1997; 336: 1066-1071
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel