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Thromb Haemost 1998; 80(03): 388-392
DOI: 10.1055/s-0037-1615217
Rapid Communications
Schattauer GmbH

Effect of Cilostazol on Soluble Adhesion Molecules and Platelet-derived Microparticles in Patients with Diabetes[*]

Shosaku Nomura
1   From the First Department of Internal Medicine, Kansai Medical University, Osaka, Japan
,
Akira Shouzu
2   From the Second Department of Internal Medicine, Kansai Medical University, Osaka, Japan
,
Seitaro Omoto
2   From the Second Department of Internal Medicine, Kansai Medical University, Osaka, Japan
,
Takashi Hayakawa
2   From the Second Department of Internal Medicine, Kansai Medical University, Osaka, Japan
,
Hideo Kagawa
1   From the First Department of Internal Medicine, Kansai Medical University, Osaka, Japan
,
Mitsushige Nishikawa
2   From the Second Department of Internal Medicine, Kansai Medical University, Osaka, Japan
,
Mitsuo Inada
2   From the Second Department of Internal Medicine, Kansai Medical University, Osaka, Japan
,
Yoshihiro Fujimura
3   From the Department of Blood Transfusion, Nara Medical College, Kashihara, Japan
,
Yasuo Ikeda
4   From the Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
,
Shirou Fukuhara
1   From the First Department of Internal Medicine, Kansai Medical University, Osaka, Japan
› Author Affiliations
Further Information

Publication History

Received 06 March 1998

Accepted 13 May 1998

Publication Date:
08 December 2017 (online)

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Summary

We evaluated the plasma concentrations of soluble adhesion molecules and platelet-derived microparticles (PMP) in patients with non-insulin dependent diabetes mellitus (NIDDM) and studied the effect of cilostazol on PMP generation. There were differences in the levels of soluble adhesion molecules between NIDDM patients (N = 43) and the control subjects (N = 30) (soluble thrombomodulin: 11.5 ± 5.3 vs. 7.0 ± 1.2 TU/ml, p<0.0001; soluble vascular cell adhesion molecule-1: 708 ± 203 vs. 492 ± 113 ng/dl, p<0.0001; soluble intercellular cell adhesion molecules-1: 274 ± 65 vs. 206 ± 48 ng/dl, p<0.0001; soluble P-selectin: 194 ± 85 vs. 125 ± 43 ng/dl, p<0.0001). There were also differences in the levels of PMP and platelet activation markers between NIDDM patients and the controls (PMP: 943 ± 504 vs. 488 ± 219/10 4 plt, p<0.0001; platelet CD62P: 9.2 ± 4.6 vs. 4.4 ± 4.3%, p<0.001; platelet CD63: 10.2 ± 4.5 vs. 4.5 ± 3.3%, p<0.0001; platelet annexin V: 9.1 ± 3.9 vs. 5.3 ± 3.8%, p<0.001). To study the release of PMP into plasma, a modified cone-and-plate viscometer was used. Increased release of PMP from platelets was observed in diabetic plasma compared to normal plasma under high shear stress conditions (2,672 ± 645 vs. 1,498 ± 386/104 plt, p<0.05). Therefore, one cause of PMP elevation in NIDDM may be high shear stress. The levels of PMP, activated platelets, and soluble adhesion molecules all decreased significantly after treatment with cilostazol. These results suggest that cilostazol may be useful for the inhibition of both PMP-dependent and -independent vascular damage in NIDDM.

* Grant support: This work was partly supported by a Research Grant for Advanced Medical Care from the Ministry of Health and Welfare of Japan.


 

  • References

  • 1 Turney JH, Woods HF, Fewell MR, Weston MJ. Factor VIII complex in uraemia and effects of haemodialysis. Br Med J 1981; 282: 1653-6.
    CrossrefPubMedGoogle Scholar
  • 2 Ron D, Oren I, Aviram M, Better OS, Brook JG. Accumulation of lipoprotein remnants in patients with chronic renal failure. Atherosclerosis 1983; 46: 67-75.
    CrossrefPubMedGoogle Scholar
  • 3 Lopes-Virella MF, Virella G. Immune mechanisms of atherosclerosis in diabetes mellitus. Diabetes 1992; 41 (Suppl. 02) 86-91.
    CrossrefPubMedGoogle Scholar
  • 4 Carmassi F, Morale M, Puccetti R, De Negri F, Monzani F, Navalesi R, Mariani G. Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thromb Res 1992; 67: 643-54.
    CrossrefPubMedGoogle Scholar
  • 5 Chobanian AV. Single risk factor intervention may be inadequate to inhibit atherosclerosis progression when hypertension and hypercholesterolemia co-exist. Hypertension 1991; 18: 130-1.
    CrossrefPubMedGoogle Scholar
  • 6 Le Quan Sang KH, Mazeaud M, Astarie C, Duranthon V, Driss F, Devynck MA. Plasma lipids and platelet membrane fluidity in essential hypertension. Thromb Haemost 1993; 69: 70-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Baumgartner-Parzer SM, Wagner L, Pettermann M, Gessl A, Waldhausl W. Modulation by high glucose of adhesion molecule expression in cultured endothelial cells. Diabetologia 1995; 38: 1367-70.
    CrossrefPubMedGoogle Scholar
  • 8 Springer TA. Adhesion receptors of the immune system. Nature 1990; 346: 425-34.
    CrossrefPubMedGoogle Scholar
  • 9 Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol 1993; 11: 767-804.
    CrossrefPubMedGoogle Scholar
  • 10 Lampeter ER, Kishimoto TK, Rothlein R, Mainolfi EA, Bertrams J, Kolb H, Martin S. Elevated levels of circulating adhesion molecules in IDDM patients and in subjects at risk for IDDM. Diabetes 1992; 41: 1668-71.
    CrossrefPubMedGoogle Scholar
  • 11 Steiner M, Reinhardt KM, Krammer B, Ernst B, Blann AD. Increased levels of soluble adhesion molecules in type 2 (non-insulin dependent) diabetes mellitus are independent of glycaemic control. Thromb Haemost 1994; 72: 979-84.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Cominacini L, Fratta Pasini A, Garbin U, Davoli A, De Santis A, Campagnola M, Rigoni A, Zenti MG, Moghetti P, Lo Cascio V. Elevated levels of soluble E-selectin in patients with IDDM and NIDDM; relation to metabolic control. Diabetologia 1995; 38: 1122-4.
    CrossrefPubMedGoogle Scholar
  • 13 Sims PJ, Wiedmer T, Esmon CT, Weiss HJ, Shattil SJ. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. J Biol Chem 1989; 264: 17049-57.
    PubMedGoogle Scholar
  • 14 Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress induced platelet aggregation. J Clin Invest 1986; 78: 1456-61.
    CrossrefPubMedGoogle Scholar
  • 15 O’Brien JR. Shear-induced platelet aggregation. Lancet 1990; 335: 711-3.
    CrossrefPubMedGoogle Scholar
  • 16 Ikeda Y, Handa M, Kawano K, Kamata T, Murata M, Araki Y, Anbo H, Kawai Y, Watanabe K, Itagaki I, Sakai K, Ruggeri ZM. The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress. J Clin Invest 1991; 87: 1234-40.
    CrossrefPubMedGoogle Scholar
  • 17 Ruggeri ZM. Mechanisms of shear-induced platelet aggregation. Thromb Haemost 1993; 70: 119-23.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Butler J. Shear stress platelet activation. Lancet 1995; 346: 841.
    PubMedGoogle Scholar
  • 19 Miyazaki Y, Nomura S, Miyake T, Kagawa H, Kitada C, Taniguchi H, Komiyama Y, Fujimura Y, Ikeda Y, Fukuhara S. High shear stress can initiate both platelet aggregation and shedding of procoagulant containing micro-particles. Blood 1996; 88: 3456-64.
    PubMedGoogle Scholar
  • 20 Umekawa H, Tanaka T, Kimura Y, Hidaka H. Purification of cyclic adeno-sine monophosphate phosphodiesterase from human platelets using new-inhibitor sepharose chromatography. Biochem Pharmacol 1984; 33: 3339-44.
    CrossrefPubMedGoogle Scholar
  • 21 Minami N, Suzuki Y, Yamamoto M, Kihira H, Imai E, Wada H, Kimura Y, Ikeda Y, Shiku H, Nishikawa M. Inhibition of shear stress-induced platelet aggregation by cilostazol, a specific inhibitor of cGMP-inhibited phosphodiesterase, in vitro and ex vivo. Life Sci 1997; 61: PL383-9.
    CrossrefPubMedGoogle Scholar
  • 22 Nomura S, Suzuki M, Kido H, Yamaguchi K, Fukuroi T, Yanabu M, Soga T, Nagata H, Kokawa T, Yasunaga K. Differences between platelet and microparticle glycoprotein IIb/IIIa. Cytometry 1992; 13: 621-9.
    CrossrefPubMedGoogle Scholar
  • 23 Nomura S, Komiyama Y, Miyake T, Miyazaki Y, Kido H, Suzuki M, Kagawa H, Yanabu M, Takahashi H, Fukuhara S. Amyloid β-protein precursor rich platelet microparticles in thrombotic disease. Thromb Haemost 1994; 72: 519-22.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Nomura S, Suzuki M, Katsura K, Xie GL, Miyazaki Y, Miyake T, Kido H, Kagawa H, Fukuhara S. Platelet-derived microparticles may influence the development of atherosclerosis in diabetes mellitus. Atherosclerosis 1995; 116: 235-40.
    CrossrefPubMedGoogle Scholar
  • 25 Miyake T, Nomura S, Komiyama Y, Miyazaki Y, Kagawa H, Masuda M, Takahashi H, Fujimura Y, Ikeda Y, Fukuhara S. Effect of a new monoclonal anti-glycoprotein IX antibody, KMP-9, on high shear-induced platelet aggregation. Thromb Haemost 1997; 78: 902-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Nomura S, Nagata H, Oda K, Kokawa T, Yasunaga K. Effects of EDTA on membrane glycoprotein IIb-IIIa complex: analysis using flow cytometry. Thromb Res 1987; 47: 47-58.
    CrossrefPubMedGoogle Scholar
  • 27 Yanabu M, Ozaki Y, Nomura S, Miyake T, Miyazaki Y, Kagawa H, Yamanaka Y, Asazuma N, Satoh K, Kume S, Komiyama Y, Fukuhara S. Tyro-sine phosphorylation and p72 syk activation by an anti-glycoprotein Ib monoclonal antibody. Blood 1997; 89: 1590-8.
    PubMedGoogle Scholar
  • 28 Ikeda Y, Handa M, Kamata T, Kawana K, Kawai Y, Watanabe K, Kawakami K, Sakai K, Fukuyama M, Itagaki I, Yoshioka A, Ruggeri ZM. Trans-membrane calcium influx associated with von Willebrand factor binding to GPIb in the initiation of shearñinduced platelet aggregation. Thromb Haemost 1993; 69: 496-502.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Steiner G. Atherosclerosis, the major complication of diabetes. Adv Exp Med Biol 1985; 189: 277-297.
    PubMedGoogle Scholar
  • 30 Uusitupa MI, Niskanen LK, Siitonen O, Voutilainen E, Pyorala K. Ten years cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Diabetologia 1993; 36: 1175-84.
    CrossrefPubMedGoogle Scholar
  • 31 Schmidt AM, Crandall J, Hori O, Cao R, Lakatta E. Elevated plasma levels of vascular cell adhesion molecule-1 (VCAM-1) in diabetic patients with microalbuminuria: a marker of vascular dysfunction and progressive vascular disease. Br J Haematol 1996; 92: 747-50.
    CrossrefPubMedGoogle Scholar
  • 32 Cominacini L, Pasini AF, Garbin U, Campagnola M, Davoli A, Rigoni A, Zenti MG, Pastorino AM, Cascio VL. E-selectin plasma concentration is influenced by glycaemic control in NIDDM patients: possible role of oxidative stress. Diabetlogia 1997; 40: 584-9.
    PubMedGoogle Scholar
  • 33 Gearing AJ, Newman W. Circulating adhesion molecules in disease. Immunol Today 1993; 14: 506-12.
    CrossrefPubMedGoogle Scholar
  • 34 Zwaal RFA, Comfurius P, Bevers EM. Platelet procoagulant activity and microvesicle formation: its putative role in hemostasis and thrombosis. Biochim Biophys Acta 1992; 1180: 1-8.
    CrossrefPubMedGoogle Scholar
  • 35 Tans G, Rosing J, Thomassen MC, Heeb MJ, Zwaal RFA, Griffin JH. Comparison of anticoagulant and procoagulant activities of stimulated platelets and platelet-derived microparticles. Blood 1991; 77: 2641-8.
    PubMedGoogle Scholar
  • 36 Dahlback B, Wiedmer T, Sims PJ. Binding of anticoagulant vitamin K dependent protein S to platelet-derived microparticles. Biochemistry 1992; 31: 12769-77.
    CrossrefPubMedGoogle Scholar
  • 37 Gilbert GE, Sims PJ, Wiedmer T, Furie B, Furie BC, Shattil SJ. Platelet-derived microparticles express high affinity receptors for factor VIII. J Biol Chem 1991; 266: 17261-8.
    PubMedGoogle Scholar
  • 38 Comfurius P, Senden JMG, Tilly RHJ, Schroit AJ, Bevers EM, Zwaal RFA. Loss of membrane phospholipid asymmetry in platelets and red cells may be associated with calcium-induced shedding of plasma membrane and inhibition of amminophospholipid translocase. Biochim Biophys Acta 1990; 1026: 153-60.
    CrossrefPubMedGoogle Scholar
  • 39 Jy W, Horstmann LL, Arce M, Ahn YS. Clinical significance of platelet microparticles in autoimmune thrombocytopenias. J Lab Clin Med 1992; 119: 334-45.
    PubMedGoogle Scholar
  • 40 Tschoepe D, Driesch E, Schwippert B, Nieuwenhuis HK, Gries FA. Exposure of adhesion molecules on activated platelets in patients with newly diagnosed IDDM is not normalized by near-normoglycemia. Diabetes 1995; 44: 890-4.
    CrossrefPubMedGoogle Scholar
  • 41 Tschoepe D, Driesch E, Schwippert B, Lampeter EF. Activated platelets in subjects at increased risk of IDDM. DENIS Study Group. Deutsche Nikotinamid Interventions studies. Diabetologia 1997; 40: 573-7.
    CrossrefPubMedGoogle Scholar
  • 42 Holme PA, Orvim U, Hamers MJAG, Solum NO, Brosstad ER, Barstad RM, Sakariassen KS. Shear-induced platelet activation and platelet micro-particle formation at blood flow conditions as in arteries with a severe stenosis. Arterioscler Thromb Vasc Biol 1997; 17: 646-53.
    CrossrefPubMedGoogle Scholar
  • 43 Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD. Shear-induced platelet aggregation can be mediated by vWF released from platelets, as well as by exogenous large or unusually large vWF multimers, requires adenosine diphosphate, and is resistant to aspirin. Blood 1988; 58: 1366-74.
    PubMedGoogle Scholar
  • 44 Savage B, Saldivar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84: 289-97.
    CrossrefPubMedGoogle Scholar
  • 45 Galajda P, Martinka E, Mokan M, Kubisz P. Endothelial markers in diabetes mellitus. Thromb Res 1997; 85: 63-5.
    CrossrefPubMedGoogle Scholar
  • 46 Shimano H, Takahashi K, Kawakami M, Gotoda T, Harada K, Shimada M, Yazaki Y, Yamada N. Elevated serum and urinary thrombomodulin levels in patients with non-insulin-dependent diabetes mellitus. Clin Chim Acta 1994; 225: 89-96.
    CrossrefPubMedGoogle Scholar
  • 47 Gabat S, Keller C, Kempe HP, Amiral J, Ziegler R, Ritz E, Bergis KH, Wahl P, Nawroth P. Plasma thrombomodulin: a marker for microvascular complications in diabetes mellitus. Vasa 1996; 25: 233-41.
    PubMedGoogle Scholar
  • 48 Okuda Y, Mizutani M, Ikegami T, Ueno E, Yamashita K. Hemodynamic effect of cilostazol on peripheral artery in patients with diabetic neuropathy. Arzneimittel-Forschung/Drug Res 1992; 42: 540-2.
    PubMedGoogle Scholar
  • 49 Takahashi S, Oida K, Fujiwara R, Maeda H, Hayashi S, Takai H, Tamai T, Nakai T, Miyabo S. Effect of cilostazol, a cyclic AMP phosphodiesterase inhibitor, on the proliferation of rat aortic smooth muscle cells in culture. J Cardiovasc Pharmacol 1992; 20: 900-6.
    CrossrefPubMedGoogle Scholar
  • 50 Ikeda U, Ikeda M, Kano S, Kanbe T, Shimada K. Effect of cilostazol, a cAMP phosphodiesterase inhibitor, on nitric oxide production by vascular smooth muscle cells. Eur J Pharmacol 1996; 314: 197-202.
    CrossrefPubMedGoogle Scholar
  • 51 Niu XF, Smith CW, Kubes P. Intracellular oxidative stress induced by nitric oxide synthesis inhibition increases endothelial cell adhesion to neutrophils. Circ Res 1994; 74: 1133-40.
    CrossrefPubMedGoogle Scholar
  • 52 Mizutani M, Okuda Y, Yamashita K. Effect of cilostazol on the production of platelet-derived growth factor in cultured human vascular endothelial cells. Biochem Mol Med 1996; 57: 156-8.
    CrossrefPubMedGoogle Scholar
  • 53 Ross R. The pathogenesis of atherosclerosis – an update. N Engl J Med 1986; 314: 488-500.
    CrossrefPubMedGoogle Scholar
  • 54 Morishita R, Higaki J, Hayashi SI, Yo Y, Aoki M, Nakamura S, Moriguchi A, Matsushita H, Matsumoto K, Nakamura T, Ogihara T. Role of hepatocyte growth factor in endothelial regulation: prevention of high D-glucose-induced endothelial cell death by prostaglandins and phosphodiesterase type 3 inhibitor. Diabetologia 1997; 40: 1053-61.
    CrossrefPubMedGoogle Scholar
  • 55 Kayanoki Y, Che W, Kawata S, Matsuzawa Y, Higashiyama S, Taniguchi N. The effect of cilostazol, a cyclic nucleotide phosphodiesterase III inhibitor, on heparine-binding EGF-like growth factor expression in macrophages and vascular smooth muscle cells. Biochem Biophys Res Commun 1997; 238: 478-81.
    CrossrefPubMedGoogle Scholar
  • 56 Barry OP, Pratico D, Lawson JA, FitzGerald GA. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J Clin Invest 1997; 99: 2118-27.
    CrossrefPubMedGoogle Scholar