Download PDF
Planta Med 2013; 79(09): 731-736
DOI: 10.1055/s-0032-1328551
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Icariin Attenuates the Enhanced Prothrombotic State in Atherosclerotic Rabbits Independently of Its Lipid-Lowering Effects

Wei-ping Zhang
Department of Cardiovascular Medicine, The First Affiliated Hospital of Medical School, Xiʼan Jiaotong University, Shaanxi, China
,
Xiao-jun Bai
Department of Cardiovascular Medicine, The First Affiliated Hospital of Medical School, Xiʼan Jiaotong University, Shaanxi, China
,
Xiao-pu Zheng
Department of Cardiovascular Medicine, The First Affiliated Hospital of Medical School, Xiʼan Jiaotong University, Shaanxi, China
,
Xiao-lu Xie
Department of Cardiovascular Medicine, The First Affiliated Hospital of Medical School, Xiʼan Jiaotong University, Shaanxi, China
,
Zu-yi Yuan
Department of Cardiovascular Medicine, The First Affiliated Hospital of Medical School, Xiʼan Jiaotong University, Shaanxi, China
› Author Affiliations
Further Information

Publication History

received 15 August 2012
revised 21 March 2013

accepted 28 March 2013

Publication Date:
22 May 2013 (online)

    Permissions and Reprints

Abstract

Icariin is a major active component isolated from the traditional Chinese herb Epimedium brevicornum, with a wide range of pharmacological and biological activities. In this paper, we investigated the effects of icariin on hyperlipidemia, and further evaluated whether icariin could improve unfavorable hemorheological parameters, attenuate platelet activation and facilitate the balance between plasmic plasminogen activator inhibitor-1 and tissue-type plasminogen activator activities in rabbits fed a high-cholesterol diet. Icariin reduced the levels of serum total cholesterol and low-density lipoprotein cholesterol, as well as the atherosclerotic burden. In addition, this compound has been found to improve the imbalance between plasmic plasminogen activator inhibitor-1 and tissue-type plasminogen activator activities, reduce platelet adhesiveness and aggregation and modulate unfavorable hemorheological variables in hypercholesterolemia. In conclusion, icariin has lipid-lowering effects and may be used in the treatment and prevention of thrombosis in the atherosclerotic process.

Key words

icariin - lipid-lowering effect - prothrombotic state - atherosclerosis - Epimedium brevicornum - Berberidaceae
 

  • References

  • 1 Iwamoto T, Jingzi J, Sugiyama T, Umahara T, Takasaki M. Prognosis of the elderly with asymptomatic atherosclerotic plaques of the carotid arteries. Intern Med 2002; 41: 526-531
    CrossrefPubMedGoogle Scholar
  • 2 Slager CJ, Wentzel JJ, Gijsen FJ, Thury A, van der Wal AC, Schaar JA, Serruys PW. The role of shear stress in the destabilization of vulnerable plaques and related therapeutic implications. Nat Clin Pract Cardiovasc Med 2005; 2: 456-464
    CrossrefPubMedGoogle Scholar
  • 3 Jiang Y, Kohara K, Hiwada K. Association between risk factors for atherosclerosis and mechanical forces in carotid artery. Stroke 2002; 31: 2319-2324
    PubMedGoogle Scholar
  • 4 Velcheva I, Antonova N, Titianova E, Damianov P, Dimitrov N, Ivanov I. Hemorheological parameters in correlation with the risk factors for carotid atherosclerosis. Clin Hemorheol Microcirc 2006; 35: 195-198
    PubMedGoogle Scholar
  • 5 Massberg S, Brand K, Grüner S, Page S, Müller E, Müller I, Bergmeier W, Richter T, Lorenz M, Konrad I, Nieswandt B, Gawaz M. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 2002; 196: 887-896
    CrossrefPubMedGoogle Scholar
  • 6 Weber C. Platelets and chemokines in atherosclerosis: partners in crime. Circ Res 2005; 96: 612-616
    CrossrefPubMedGoogle Scholar
  • 7 Reininger AJ, Bernlochner I, Penz SM, Ravanat C, Smethurst P, Farndale RW, Gachet C, Brandl R, Siess W. A 2-step mechanism of arterial thrombus formation induced by human atherosclerotic plaques. J Am Coll Cardiol 2010; 55: 1147-1158
    CrossrefPubMedGoogle Scholar
  • 8 Lupu F, Bergonzelli GE, Heim DA, Cousin E, Genton CY, Bachmann F, Kruithof EK. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb 1993; 13: 1090-1100
    CrossrefPubMedGoogle Scholar
  • 9 Eitzman DT, Westrick RJ, Xu Z, Tyson J, Ginsburg D. Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. Blood 2000; 96: 4212-4215
    PubMedGoogle Scholar
  • 10 Notarbartolo A, Davì G, Averna M, Barbagallo CM, Ganci A, Giammarresi C, La Placa FP, Patrono C. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type II a hypereholesterolemia. Arterioscler Thromb Vasc Biol 1995; 15: 247-251
    CrossrefPubMedGoogle Scholar
  • 11 Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 1996; 2: 800-803
    CrossrefPubMedGoogle Scholar
  • 12 Wu J, Du J, Xu C, Le J, Xu Y, Liu B, Dong J. Icariin attenuates social defeat-induced down-regulation of glucocorticoid receptor in mice. Pharmacol Biochem Behav 2011; 98: 273-278
    CrossrefPubMedGoogle Scholar
  • 13 Song YH, Cai H, Gu N, Qian CF, Cao SP, Zhao ZM. Icariin attenuates cardiac remodelling through down-regulating myocardial apoptosis and matrix metalloproteinase activity in rats with congestive heart failure. J Pharm Pharmacol 2011; 63: 541-549
    CrossrefPubMedGoogle Scholar
  • 14 Xu CQ, Liu BJ, Wu JF, Xu YC, Duan XH, Cao YX, Dong JC. Icariin attenuates LPS-induced acute inflammatory responses: involvement of PI3K/Akt and NF-κB signaling pathway. Eur J Pharmacol 2010; 642: 146-153
    CrossrefPubMedGoogle Scholar
  • 15 Koizumi H, Yu J, Hashimoto R, Ouchi Y, Okabe T. Involvement of androgen receptor in nitric oxide production induced by icariin in human umbilical vein endothelial cells. FEBS Lett 2010; 584: 2440-2444
    CrossrefPubMedGoogle Scholar
  • 16 Zhang ZB, Yang QT. The testosterone mimetic properties of icariin. Asian J Androl 2006; 8: 601-605
    CrossrefPubMedGoogle Scholar
  • 17 Nathan L, Shi W, Dinh H, Mukherjee TK, Wang X, Lusis AJ, Chaudhuri G. Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase. Proc Natl Acad Sci USA 2001; 98: 3589-3593
    CrossrefPubMedGoogle Scholar
  • 18 Liu LY, Wen JF, Tu JH, Zhong ZL, Wu JX. The effects of HOE 642 against atherosclerosis induced by high lipid diet in rabbits. Chin J Arterioscler 2002; 10: 1-5
    PubMedGoogle Scholar
  • 19 Lolekha PH, Srisawasdi P, Jearanaikoon P, Wetprasit N, Sriwanthana B, Kroll MH. Performance of four sources of cholesterol oxidase for serum cholesterol determination by the enzymatic endpoint method. Clin Chim Acta 2004; 339: 135-145
    CrossrefPubMedGoogle Scholar
  • 20 Sikka M, Tandon R, Rusia U, Madan N. Validation of ESR analyzer using Westergren ESR method. Indian J Pathol Microbiol 2007; 50: 634-635
    PubMedGoogle Scholar
  • 21 Pinthong D, Songsermsakul P, Rattanachamnong P, Kendall DA. The effects of imidazoline agents on the aggregation of human platelets. J Pharm Pharmacol 2004; 56: 213-220
    CrossrefPubMedGoogle Scholar
  • 22 Chandler BW, Trimble SL, Loo SC, Mornin D. Effect of PAI-1 levels on the molar concentrations of active tissue plasminogen activator (t-PA) and t-PA/PAI-1 complex in plasma. Blood 1990; 5: 930-937
    PubMedGoogle Scholar
  • 23 Johnstone MT, Perez AS, Nasser I, Stewart R, Vaidya A, Al Ammary F, Schmidt B, Horowitz G, Dolgoff J, Hamilton J, Quist WC. Angiotensin receptor blockade with candesartan attenuates atherosclerosis, plaque disruption, and macrophage accumulation within the plaque in a rabbit model. Circulation 2004; 110: 2060-2065
    CrossrefPubMedGoogle Scholar
  • 24 Alessi MC, Juhan-Vague I. PAI-1 and the metabolic syndrome: links, causes, and consequences. Arterioscler Thromb Vasc Biol 2006; 26: 2200-2207
    CrossrefPubMedGoogle Scholar
  • 25 Farndale RW, Sixma JJ, Barnes MJ, de Groot PG. The role of collagen in thrombosis and hemostasis. J Thromb Haemost 2004; 2: 561-573
    CrossrefPubMedGoogle Scholar
  • 26 Andrews HE, Aitken JW, Hassall DG, Skinner VO, Bruckdorfer KR. Intracellular mechanisms in the activation of human platelets by low-density lipoproteins. Biochem J 1987; 242: 559-564
    PubMedGoogle Scholar
  • 27 Spieker LE, Ruschitzka F, Badimon JJ, Noll G, Corti R. Shear stress-dependent platelet function after LDL cholesterol apheresis. Thromb Res 2004; 113: 395-398
    CrossrefPubMedGoogle Scholar
  • 28 Hanke H, Hanke S, Bruck B, Brehme U, Gugel N, Finking G, Mück AO, Schmahl FW, Hombach V, Haasis R. Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis. Atherosclerosis 1996; 121: 129-138
    CrossrefPubMedGoogle Scholar
  • 29 Langer C, Gansz B, Goepfert C, Engel T, Uehara Y, von Dehn G, Jansen H, Assmann G, von Eckardstein A. Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochem Biophys Res Commun 2002; 296: 1051-1057
    CrossrefPubMedGoogle Scholar
  • 30 Hwang SY, Son DJ, Kim IW, Kim DM, Sohn SH, Lee JJ, Kim SK. Korean red ginseng attenuates hypercholesterolemia-enhanced platelet aggregation through suppression of diacylglycerol liberation in high-cholesterol-diet-fed rabbits. Phytother Res 2008; 22: 778-783
    CrossrefPubMedGoogle Scholar
  • 31 Kensey KR, Cho YI, Chang M. Effects of whole blood viscosity on atherogenesis. J Invasive Cardiol 1997; 9: 17-24
    PubMedGoogle Scholar
  • 32 Holme PA, Orvim U, Hamers MJ, Solum NO, Brosstad FR, Barstad RM, Sakariassen KS. Shear-induced platelet activation and platelet microparticle formation at blood flow conditions as in arteries with a severe stenosis. Arterioscler Thromb Vasc Biol 1997; 17: 646-653
    CrossrefPubMedGoogle Scholar
  • 33 De Taeye B, Smith LH, Vaughan DE. Plasminogen activator inhibitor-1: a common denominator in obesity, diabetes and cardiovascular disease. Curr Opin Pharmacol 2005; 5: 149-154
    CrossrefPubMedGoogle Scholar
  • 34 Johnstone MT, Perez AS, Nasser I, Stewart R, Vaidya A, Al Ammary F, Schmidt B, Horowitz G, Dolgoff J, Hamilton J, Quist WC. Angiotensin receptor blockade with candesartan attenuates atherosclerosis, plaque disruption, and macrophage accumulation within the plaque in a rabbit model. Circulation 2004; 110: 2060-2065
    CrossrefPubMedGoogle Scholar
  • 35 Kario K, Matsuo T, Hoshide S, Kobayashi H, Sakata T, Mizuno O, Mitsuhashi T, Ikeda U, Miyata T, Shimada K. Lipid-lowering therapy corrects endothelial cell dysfunction in a short time but does not affect hypercoagulable state even after long-term use in hyperlipidemic patients. Blood Coagul Fibrinolysis 1999; 10: 269-276
    CrossrefPubMedGoogle Scholar
  • 36 Goglia L, Tosi V, Sanchez AM, Flamini MI, Fu XD, Zullino S, Genazzani AR, Simoncini T. Endothelial regulation of eNOS, PAI-1 and t-PA by testosterone and dihydrotestosterone in vitro and in vivo . Mol Hum Reprod 2010; 16: 761-769
    CrossrefPubMedGoogle Scholar
  • 37 Campelo AE, Cutini PH, Massheimer VL. Testosterone modulates platelet aggregation and endothelial cell growth through nitric oxide pathway. J Endocrinol 2012; 213: 77-87
    CrossrefPubMedGoogle Scholar