Molecular and Cellular Biochemistry

, Volume 373, Issue 1–2, pp 195–199 | Cite as

Sarpogrelate inhibits the expression of ICAM-1 and monocyte–endothelial adhesion induced by high glucose in human endothelial cells

  • Ying Su
  • Nan Mao
  • Min Li
  • Xia Dong
  • Fan-Zhen Lin
  • Ying Xu
  • Yan-Bo Li


Hyperglycemia is the major cause of diabetic angiopathy. Sarpogrelate hydrochloride is an antiplatelet drug, and expected to be useful in the treatment of chronic arterial occlusive diseases. The aim of our study was to evaluate the possible effects of sarpogrelate hydrochloride on adhesion molecule expression and its underlying mechanism in the prevention and treatment of cardiovascular disorders. Intercellular adhesion molecule-1 (ICAM-1) expression and superoxide dismutase (SOD) activity were determined after endothelial cells were exposed to high glucose in the absence and presence of sarpogrelate hydrochloride. Coincubation of endothelial cells with high glucose for 24 h resulted in a significant increase of monocyte–endothelial cell adhesion and the expression of ICAM-1 (P < 0.01). These effects were abolished by sarpogrelate hydrochloride and sarpogrelate hydrochloride significantly increased SOD activities (40 ± 8 vs. 47 ± 7, n = 8, P < 0.01). The low dose sarpogrelate group (0.1 μM) had significantly higher monocyte–endothelial cell adhesion and the expression of ICAM-1 than medium dose sarpogrelate group (1.0 μM) and high dose sarpogrelate group (10.0 μM) (P < 0.05 for comparison among three groups and P < 0.01 for difference between low and high dose sarpogrelate groups). These findings suggested that sarpogrelate hydrochloride was able to protect vascular endothelium from dysfunction induced by high glucose.


Sarpogrelate hydrochloride Endothelial cell Glucose ICAM-1 Adhesion 



This study was supported by a grant from the Education Department of Heilongjiang Province (11551201), Youth Science Foundation of Heilongjiang Province (QC2010080) and National Natural Science Foundation of China (81100574).


  1. 1.
    Malakul W, Thirawarapan S, Suvitayavat W, Woodman OL (2008) Type 1 diabetes and hypercholesterolaemia reveal the contribution of endothelium-derived hyperpolarizing factor to endothelium-dependent relaxation of the rat aorta. Clin Exp Pharmacol Physiol 35:192–200PubMedGoogle Scholar
  2. 2.
    McNulty PH, Tulli MA, Robertson BJ, Lendel V, Harach LA, Scott S, Boehmer JP (2007) Effect of simulated postprandial hyperglycemia on coronary blood flow in cardiac transplant recipients. Am J Physiol Heart Circ Physiol 293:H103–H108PubMedCrossRefGoogle Scholar
  3. 3.
    Narendhirakannan RT, Subramanian S, Kandaswamy M (2006) Biochemical evaluation of antidiabetogenic properties of some commonly used Indian plants on streptozotocin-induced diabetes in experimental rats. Clin Exp Pharmacol Physiol 33:1150–1157PubMedCrossRefGoogle Scholar
  4. 4.
    Sorensen VR, Mathiesen ER, Clausen P, Flyvbjerg A, Feldt-Rasmussen B (2005) Impaired vascular function during short-term poor glycaemic control in type 1 diabetic patients. Diabet Med 22:871–876PubMedCrossRefGoogle Scholar
  5. 5.
    Ceriello A, Kumar S, Piconi L, Esposito K, Giugliano D (2007) Simultaneous control of hyperglycemia and oxidative stress normalizes endothelial function in type 1 diabetes. Diabetes Care 30:649–654PubMedCrossRefGoogle Scholar
  6. 6.
    De Mattia G, Bravi MC, Laurenti O, Moretti A, Cipriani R, Gatti A, Mandosi E, Morano S (2008) Endothelial dysfunction and oxidative stress in type 1 and type 2 diabetic patients without clinical macrovascular complications. Diabetes Res Clin Pract 79:337–342PubMedCrossRefGoogle Scholar
  7. 7.
    Van Dam B, van Hinsbergh VW, Stehouwer CD, Versteilen A, Dekker H, Buytenhek R, Princen HM, Schalkwijk CG (2006) Vitamin E inhibits lipid peroxidation-induced adhesion molecule expression in endothelial cells and decreases soluble cell adhesion molecules in healthy subjects. Cardiovasc Res 57:563–571Google Scholar
  8. 8.
    Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801–809PubMedCrossRefGoogle Scholar
  9. 9.
    Ross R (1999) Atherosclerosis: an inflammatory disease. New Engl J Med 340:115–126PubMedCrossRefGoogle Scholar
  10. 10.
    Jagroop IA, Mikhailidis DP (2001) Doxazosin, an α1-adrenoceptor antagonist, inhibits serotonin-induced shape change in human platelets. J Hum Hypertens 15:203–207PubMedCrossRefGoogle Scholar
  11. 11.
    Hasegawa Y, Suehiro A, Higasa S, Namba M, Kakishita E (2002) Enhancing effect of advanced glycation end products on serotonin-induced platelet aggregation in patients with diabetes mellitus. Thromb Res 107:319–323PubMedCrossRefGoogle Scholar
  12. 12.
    Nagatomo T, Rashid M, Abul Muntasir H, Komiyama T (2004) Functions of 5-HT2A receptor and its antagonists in the cardiovascular system. Pharmacol Ther 104:59–81PubMedCrossRefGoogle Scholar
  13. 13.
    Ozawa H, Abiko Y, Akimoto T (2003) A 50-year history of new drugs in Japan—the development and trends of hemostatics and antithrombotic drugs. Yakushigaku Zasshi 38:93–105PubMedGoogle Scholar
  14. 14.
    Uchiyama S, Ozaki Y, Satoh K, Kondo K, Nishimaru K (2007) Effect of sarpogrelate, a 5-HT(2A) antagonist, on platelet aggregation in patients with ischemic stroke: clinical-pharmacological dose–response study. Cerebrovasc Dis 24:264–270PubMedCrossRefGoogle Scholar
  15. 15.
    Doggrell SA (2004) Sarpogrelate: cardiovascular and renal clinical potential. Expert Opin Investig Drugs 13:865–874PubMedCrossRefGoogle Scholar
  16. 16.
    Gong H, Nakamura T, Hattori K, Ohnuki T, Rashid M, Nakazawa M, Watanabe K, Nagatomo T (2000) A novel 5-HT2 antagonist, sarpogrelate hydrochloride, shows inhibitory effects on both contraction and relaxation mediated by 5-HT receptor subtypes in porcine coronary arteries. Pharmacology 61:263–268PubMedCrossRefGoogle Scholar
  17. 17.
    Nonogaki K, Nozue K, Oka Y (2006) Increased hypothalamic 5-HT2A receptor gene expression and effects of pharmacologic 5-HT2A receptor inactivation in obese Ay mice. Biochem Biophys Res Commun 351:1078–1082PubMedCrossRefGoogle Scholar
  18. 18.
    Borghi MO, Panzeri P, Shattock R, Sozzani S, Dobrina A, Meroni PL (2000) Interaction between chronically HIV-infected promonocytic cells and human umbilical vein endothelial cells: role of proinflammatory cytokines and chemokines in viral expression modulation. Clin Exp Immunol 120:93–100PubMedCrossRefGoogle Scholar
  19. 19.
    Dorffel Y, Latsch C, Stuhlmuller B, Schreiber S, Scholze S, Burmester GR, Scholze J (1999) Preactivated peripheral blood monocytes in patients with essential hypertension. Hypertension 34:113–117PubMedCrossRefGoogle Scholar
  20. 20.
    Hiraoka M, Nitta N, Nagai M, Shimokado K, Yoshida M (2004) MCP-1-induced enhancement of THP-1 adhesion to vascular endothelium was modulated by HMG-CoA reductase inhibitor through RhoA GTPase-, but not ERK1/2-dependent pathway. Life Sci 75:1333–1341PubMedCrossRefGoogle Scholar
  21. 21.
    Rothlein R, Czajkowski M, O’Neill MM, Marlin SD, Mainolfi E, Merluzzi VJ (1988) Induction of intercellular adhesion molecule 1 on primary and continuous cell lines by pro-inflammatory cytokines. Regulation by pharmacologic agents and neutralizing antibodies. J Immunol 141:1665–1669PubMedGoogle Scholar
  22. 22.
    Carmeli E, Maor M, Kodesh E (2009) Expression of superoxide dismutase and matrix metalloproteinase type 2 in diaphragm muscles of young rats. J Physiol Pharmacol 60:31–36PubMedGoogle Scholar
  23. 23.
    Liang KW, Lee WJ, Lee WL, Chen YT, Ting CT, Sheu WH (2008) Diabetes exacerbates angiographic coronary lesion progression in subjects with metabolic syndrome independent of CRP levels. Clin Chim Acta 388:41–45PubMedCrossRefGoogle Scholar
  24. 24.
    Lei H, Venkatakrishnan A, Yu S, Kazlauskas A (2007) Protein kinase A-dependent translocation of Hsp90 alpha impairs endothelial nitric-oxide synthase activity in high glucose and diabetes. J Biol Chem 282:9364–9371PubMedCrossRefGoogle Scholar
  25. 25.
    Vane JR, Anggard EE, Botting RM (1990) Regulatory functions of the vascular endothelium. N Engl J Med 323:27–36PubMedCrossRefGoogle Scholar
  26. 26.
    McDuffie JE, Motley ED, Limbird LE, Maleque MA (2000) 5-Hydroxytryptamine stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures. J Cardiovasc Pharmacol 35:398–402PubMedCrossRefGoogle Scholar
  27. 27.
    Saini HK, Takeda N, Goyal RK, Kumamoto H, Arneja AS, Dhalla NS (2004) Therapeutic potentials of sarpogrelate in cardiovascular disease. Cardiovasc Drug Rev 22:27–54PubMedCrossRefGoogle Scholar
  28. 28.
    Doggrell SA (2004) Sarpogrelate: cardiovascular and renal clinical potential. Expert Opin Investig Drugs 13:865–874PubMedCrossRefGoogle Scholar
  29. 29.
    Hara H, Osakabe M, Kitajima A, Tamao Y, Kikumoto R (1991) MCI-9042, a new antiplatelet agent is a selective S2-serotonergic receptor antagonist. Thromb Haemost 65:415–420PubMedGoogle Scholar
  30. 30.
    Fujita M, Minamino T, Sanada S, Asanuma H, Hirata A, Ogita H, Okada K, Tsukamoto O, Takashima S, Tomoike H, Node K, Hori M, Kitakaze M (2004) Selective blockade of serotonin 5-HT2A receptor increases coronary blood flow via augmented cardiac nitric oxide release through 5-HT1B receptor in hypoperfused canine hearts. Mol Cell Cardiol 37:1219–1223Google Scholar
  31. 31.
    Iwabayashi M, Taniyama Y, Sanada F, Azuma J, Iekushi K, Kusunoki H, Chatterjee A, Okayama K, Rakugi H, Morishita R (2012) Atherosclerosis 220:337–342PubMedCrossRefGoogle Scholar
  32. 32.
    Miyazaki M, Higashi Y, Goto C, Chayama K, Yoshizumi M, Sanada H, Orihashi K, Sueda T (2007) Sarpogrelate hydrochloride, a selective 5-HT2A antagonist, improves vascular function in patients with peripheral arterial disease. J Cardiovasc Pharmacol 49:221–227PubMedCrossRefGoogle Scholar
  33. 33.
    Yamada K, Niki H, Nagai H, Nishikawa M, Nakagawa H (2012) Serotonin potentiates high-glucose-induced endothelial injury: the role of serotonin and 5-HT(2A) receptors in promoting thrombosis in diabetes. J Pharmacol Sci 119:243–250PubMedCrossRefGoogle Scholar
  34. 34.
    Miyata K, Shimokawa H, Higo T, Yamawaki T, Katsumata N, Kandabashi T, Tanaka E, Takamura Y, Yogo K, Egashira K, Takeshita A (2000) Sarpogrelate, a selective 5-HT2A serotonergic receptor antagonist, inhibits serotonin-induced coronary artery spasm in a porcine model. J Cardiovasc Pharmacol 35:294–301PubMedCrossRefGoogle Scholar
  35. 35.
    Kodama A, Komori K, Hattori K, Yamanouchi D, Kajikuri J, Itoh T (2009) Sarpogrelate hydrochloride reduced intimal hyperplasia in experimental rabbit vein graft. J Vasc Surg 49:1272–1281PubMedCrossRefGoogle Scholar
  36. 36.
    Lin SJ, Shyue SK, Shih MC, Chu TH, Chen YH, Ku HH, Chen JW, Tam KB, Chen YL (2007) Superoxide dismutase and catalase inhibit oxidized low-density lipoprotein-induced human aortic smooth muscle cell proliferation: role of cell-cycle regulation, mitogen-activated protein kinases, and transcription factors. Atherosclerosis 190:124–134PubMedCrossRefGoogle Scholar
  37. 37.
    Lin SJ, Shyue SK, Hung YY, Chen YH, Ku HH, Chen JW, Tam KB, Chen YL (2005) Superoxide dismutase inhibits the expression of vascular cell adhesion molecule-1 and intracellular cell adhesion molecule-1 induced by tumor necrosis factor-alpha in human endothelial cells through the JNK/p38 pathways. Arterioscler Thromb Vasc Biol 25:334–340PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Ying Su
    • 1
  • Nan Mao
    • 1
  • Min Li
    • 1
  • Xia Dong
    • 1
  • Fan-Zhen Lin
    • 1
  • Ying Xu
    • 1
  • Yan-Bo Li
    • 1
  1. 1.Department of EndocrinologyThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina

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