BF061抗血小板、抗血栓作用及其机制的研究
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摘要
中风、冠心病为我国人民健康的首位杀手,抗血小板药(抗血栓药)预防、治疗效果可靠。临床使用的抗血小板药有环氧化酶抑制剂阿司匹林、噻吩吡啶类P2Y12受体拮抗剂氯吡格雷、纤维蛋白原受体拮抗剂和磷酸二酯酶抑制剂,因“阿司匹林抵抗”、“氯吡格雷抵抗”使前两类抗血小板药疗效受到影响,纤维蛋白原受体拮抗剂为静脉给药,价格昂贵,依赖进口,且出血副作用较大,磷酸二酯酶抑制剂对中风、冠心病的治疗主要在亚洲使用,在美国尚在进行临床研究。因此,很有必要研发疗效更好、副作用更低、具有自主知识产权的抗血小板新药用于中风、冠心病的治疗。P2Y12受体在血小板激活中起中心作用,以P2Y12受体为靶点的抗血小板药的研究一直是近年来的研究热点。我们通过对现有具有抗血小板作用的P2Y12受体拮抗剂进行结构改造,合成了一系列的新化合物,从中筛选出了一个具有良好的体外抗血小板活性的新化合物BF061。
我们研究了BF061对多种血小板激动剂诱导的血小板聚集、ATP释放的影响并研究了其作用机理,在FeCl3诱导小鼠肠系膜动脉血栓模型和激光诱导的小鼠提睾肌动脉血栓模型研究了BF061体内抗血栓作用。最后研究了BF061的出血副作用并与氯吡格雷做比较。
体外实验中,发现BF061对以2MeSADP为激动剂诱导的血小板聚集有很好的抑制作用,10μM BF061可以抑制血小板聚集80%同时完全抑制ATP释放,在0.10～100μM之间浓度依赖性地抑制2MeSADP诱导的人血小板聚集,IC50为3.2±1.6 pM。进一步的研究发现10μMBF061可以阻断由0.5 mM花生四烯酸或者1μM U46619诱导的血小板聚集和ATP释放；对2μg/mL胶原诱导的血小板聚集和ATP释放也有非常明显的抑制作用。
在此研究基础上,我们检测了P2Y12受体下游信号分子cAMP水平的变化。结果显示BF061可以逆转激动剂ADP诱导的cAMP下降,进一步升高forsklin诱导的cAMP升高,以及升高静息状态下血小板胞内cGMP水平。BF061升高cAMP的作用与其抑制ADP诱导的血小板激活、可能的P2Y12受体拮抗剂活性一致；升高静息状态下血小板胞内cGMP水平提示其可能还有PDE抑制的作用。
血小板胞内的PDE具有降解cAMP的作用,实验发现BF061在10～100μM浓度范围,浓度依赖性地抑制人血小板PDE酶的活性,直接证明BF061通过抑制PDE酶活,降低cAMP降解,在血小板中升高cAMP水平而发挥作用。
原子力显微镜的研究发现BF061可以减小ADP与P2Y12受体之间的作用力,从而直接证明BF061具有P2Y12受体拮抗剂的作用。
上述结果表明BF061通过拮抗P2Y12受体以及抑制PDE酶活性的双重作用从而达到发挥抗血小板作用。
为探究BF061在活体内是否也具有抗血小板、抗血栓作用,我们建立了小鼠肠系膜动脉血栓模型。在此血栓模型中,我们用FeCl3损伤肠系膜动脉,有道血栓形成,在激光共聚焦显微镜下观察、记录血栓形成情况。在实验中,我们观察到BF061 (25 mg/kg)通过尾静脉注射小鼠体内后,FeCl3诱导的血栓形成时间明显延长,血栓数减少,血栓大小减小,和氯吡格雷(30 mg/kg,一天一次,共两次)一样有效预防血栓形成,这表明BF061在体内也具有很好的抗血栓功能。激光诱导的小鼠提睾肌动脉血栓模型的研究进一步证实了BF061的抗血栓作用。另一方面,在小鼠断尾出血试验中发现,小鼠肠系膜动脉模型中相同剂量BF061处理组的小鼠断尾出血明显弱于氯吡格雷处理组。
综上所述,我们首次发现了一种具有P2Y12受体拮抗和PDE抑制双重作用、具有抗血小板、抗血栓活性的全新化合物。考虑到临床上抗血小板药的二联或三联用药,我们认为同时作用于P2Y12受体和PDE的BF061作为一种潜在的抗血小板药可能具有优于现有抗血小板药的治疗学优势,我们已有的结果也显示BF061具有和氯吡格雷相似的抗血栓作用,而出血副作用却明显弱于氯吡格雷。
Though antiplatelet drugs are proven beneficial to coronary heart disease and stroke patients, more effective and safer antiplatelet drugs are still needed. Previously we reported that an adenine derivative BF081 inhibits platelet activation via P2Y12 antagonism and PDE inhibition. By introducing a pentose group into BF0801, we developed a novel antiplatelet agent BF061. In the range of 0.10-100μM, BF061 concentration-dependently inhibited platelet aggregation induced by 100 nM 2MeSADP. At 10μM BF061 blocked platelet aggregation and ATP release induced by 0.5 mM arachidonic acid or 1μM U46619. Compared to BF0801. BF061 is more potent in inhibiting platelet aggregation and dense granule release induced by ADP, 2MeSADP, collagen, arachidonic acid and U46619 in human washed platelets. BF061 antagonized intracellular cAMP decrease induced by 2MeSADP and further increased forskolin-elicited increase in human platelets. Basal and sodium prusside-stimulated intracellular cGMP levels in human washed platelets were also enhanced by BF061. Similar to AR-C69931MX, BF061 exhibited P2Y12 antagonism activity as evidenced by inhibiting the interaction between ADP and P2Y12 receptor expressed in CHO-K1 cells measured by atomic force microscopy. Similar to phosphodiesterase (PDE) inhibitor IBMX,BF061 robustly inhibited platelet PDE activity as measured by HPLC. Interestingly, despite being structurally similar to BF061, AR-C69931MX had no effect on human platelet PDE. Finally, we evaluated the antithrombotic role of B061 in mice using intravital microscopy. In the FeCl3 mesenteric arterial thrombosis model, a bolus injection of BF061 (25 mg/kg, intravenous) dramatically prolonged the stable thrombus formation time from 116±10 seconds to 418±55 seconds. BF061 also reduced thrombus volume in the laser-injured cremaster arteriole model. In contrast, BF061 induced dramatically less bleeding at antithrombotic dose compared to clopidogrel. In summary, we developed a novel antiplatelet and antithrombotic agent targeting both P2Y12 and PDE. Given the prevalence of combined antiplatelet therapy in clinical practice, an antiplatelet agent bearing dual activities may have therapeutic advantage as a potential antithrombotic drug.
我们研究了BF061对多种血小板激动剂诱导的血小板聚集、ATP释放的影响并研究了其作用机理,在FeCl3诱导小鼠肠系膜动脉血栓模型和激光诱导的小鼠提睾肌动脉血栓模型研究了BF061体内抗血栓作用。最后研究了BF061的出血副作用并与氯吡格雷做比较。
体外实验中,发现BF061对以2MeSADP为激动剂诱导的血小板聚集有很好的抑制作用,10μM BF061可以抑制血小板聚集80%同时完全抑制ATP释放,在0.10～100μM之间浓度依赖性地抑制2MeSADP诱导的人血小板聚集,IC50为3.2±1.6 pM。进一步的研究发现10μMBF061可以阻断由0.5 mM花生四烯酸或者1μM U46619诱导的血小板聚集和ATP释放；对2μg/mL胶原诱导的血小板聚集和ATP释放也有非常明显的抑制作用。
在此研究基础上,我们检测了P2Y12受体下游信号分子cAMP水平的变化。结果显示BF061可以逆转激动剂ADP诱导的cAMP下降,进一步升高forsklin诱导的cAMP升高,以及升高静息状态下血小板胞内cGMP水平。BF061升高cAMP的作用与其抑制ADP诱导的血小板激活、可能的P2Y12受体拮抗剂活性一致；升高静息状态下血小板胞内cGMP水平提示其可能还有PDE抑制的作用。
血小板胞内的PDE具有降解cAMP的作用,实验发现BF061在10～100μM浓度范围,浓度依赖性地抑制人血小板PDE酶的活性,直接证明BF061通过抑制PDE酶活,降低cAMP降解,在血小板中升高cAMP水平而发挥作用。
原子力显微镜的研究发现BF061可以减小ADP与P2Y12受体之间的作用力,从而直接证明BF061具有P2Y12受体拮抗剂的作用。
上述结果表明BF061通过拮抗P2Y12受体以及抑制PDE酶活性的双重作用从而达到发挥抗血小板作用。
为探究BF061在活体内是否也具有抗血小板、抗血栓作用,我们建立了小鼠肠系膜动脉血栓模型。在此血栓模型中,我们用FeCl3损伤肠系膜动脉,有道血栓形成,在激光共聚焦显微镜下观察、记录血栓形成情况。在实验中,我们观察到BF061 (25 mg/kg)通过尾静脉注射小鼠体内后,FeCl3诱导的血栓形成时间明显延长,血栓数减少,血栓大小减小,和氯吡格雷(30 mg/kg,一天一次,共两次)一样有效预防血栓形成,这表明BF061在体内也具有很好的抗血栓功能。激光诱导的小鼠提睾肌动脉血栓模型的研究进一步证实了BF061的抗血栓作用。另一方面,在小鼠断尾出血试验中发现,小鼠肠系膜动脉模型中相同剂量BF061处理组的小鼠断尾出血明显弱于氯吡格雷处理组。
综上所述,我们首次发现了一种具有P2Y12受体拮抗和PDE抑制双重作用、具有抗血小板、抗血栓活性的全新化合物。考虑到临床上抗血小板药的二联或三联用药,我们认为同时作用于P2Y12受体和PDE的BF061作为一种潜在的抗血小板药可能具有优于现有抗血小板药的治疗学优势,我们已有的结果也显示BF061具有和氯吡格雷相似的抗血栓作用,而出血副作用却明显弱于氯吡格雷。
Though antiplatelet drugs are proven beneficial to coronary heart disease and stroke patients, more effective and safer antiplatelet drugs are still needed. Previously we reported that an adenine derivative BF081 inhibits platelet activation via P2Y12 antagonism and PDE inhibition. By introducing a pentose group into BF0801, we developed a novel antiplatelet agent BF061. In the range of 0.10-100μM, BF061 concentration-dependently inhibited platelet aggregation induced by 100 nM 2MeSADP. At 10μM BF061 blocked platelet aggregation and ATP release induced by 0.5 mM arachidonic acid or 1μM U46619. Compared to BF0801. BF061 is more potent in inhibiting platelet aggregation and dense granule release induced by ADP, 2MeSADP, collagen, arachidonic acid and U46619 in human washed platelets. BF061 antagonized intracellular cAMP decrease induced by 2MeSADP and further increased forskolin-elicited increase in human platelets. Basal and sodium prusside-stimulated intracellular cGMP levels in human washed platelets were also enhanced by BF061. Similar to AR-C69931MX, BF061 exhibited P2Y12 antagonism activity as evidenced by inhibiting the interaction between ADP and P2Y12 receptor expressed in CHO-K1 cells measured by atomic force microscopy. Similar to phosphodiesterase (PDE) inhibitor IBMX,BF061 robustly inhibited platelet PDE activity as measured by HPLC. Interestingly, despite being structurally similar to BF061, AR-C69931MX had no effect on human platelet PDE. Finally, we evaluated the antithrombotic role of B061 in mice using intravital microscopy. In the FeCl3 mesenteric arterial thrombosis model, a bolus injection of BF061 (25 mg/kg, intravenous) dramatically prolonged the stable thrombus formation time from 116±10 seconds to 418±55 seconds. BF061 also reduced thrombus volume in the laser-injured cremaster arteriole model. In contrast, BF061 induced dramatically less bleeding at antithrombotic dose compared to clopidogrel. In summary, we developed a novel antiplatelet and antithrombotic agent targeting both P2Y12 and PDE. Given the prevalence of combined antiplatelet therapy in clinical practice, an antiplatelet agent bearing dual activities may have therapeutic advantage as a potential antithrombotic drug.
引文
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Angelillo-Scherrer A, Burnier L, Flores N, Savi P, DeMol M, Schaeffer P, Herbert JM, Lemke G, Goff SP, Matsushima GK, Earp HS, Vesin C, Hoylaerts MF, Plaisance S, Collen D, Conway EM, Wehrle-Haller B and Carmeliet P (2005) Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J Clin Invest 115:237-246.
Banno F, Chauhan AK, Kokame K, Yang J, Miyata S, Wagner DD and Miyata T (2009) The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation. Blood 113:5323-5329.
Berlot C ed (1999) Expression and functional analysis of G protein alpha subunits in mammalian cells. CRC Press, Boca Raton.
Chauhan AK, Motto DG, Lamb CB, Bergmeier W, Dockal M, Plaimauer B, Scheiflinger F, Ginsburg D and Wagner DD (2006) Systemic antithrombotic effects of ADAMTS13. J Exp Med 203:767-776.
Chen KY, Rha SW, Li YJ, Poddar KL, Jin Z, Minami Y, Wang L, Kim EJ, Park CG, Seo HS, Oh DJ, Jeong MH, Ahn YK, Hong TJ, Kim YJ, Hur SH, Seong IW, Chae JK, Cho MC, Bae JH, Choi DH, Jang YS, Chae IH, Kim CJ, Yoon JH, Chung WS, Seung KB and Park SJ (2009) Triple versus dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation 119:3207-3214.
Ding Z, Bynagari YS, Mada SR, Jakubowski JA and Kunapuli SP (2009) Studies on the role of the extracellular cysteines and oligomeric structures of the P2Y receptor when interacting with antagonists. J Thromb Haemost 7:232-234.
Ding Z, Kim S and Kunapuli SP (2006) Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y12 Receptor. Mol Pharmacol 69:338-345.
Frenette PS, Johnson RC, Hynes RO and Wagner DD (1995) Platelets roll on stimulated endothelium in vivo:an interaction mediated by endothelial P-selectin. Proc Natl Acad Sci USA 92:7450-7454.
Han Y, Li Y, Wang S, Jing Q, Wang Z, Wang D, Shu Q and Tang X (2009) Cilostazol in addition to aspirin and clopidogrel improves long-term outcomes after percutaneous coronary intervention in patients with acute coronary syndromes:a randomized, controlled study. Am Heart J 157:733-739.
Hechler B, Nonne C, Roh EJ, Cattaneo M, Cazenave JP, Lanza F, Jacobson KA and Gachet C (2006) MRS2500 [2-Iodo-N6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate], a Potent, Selective, and Stable Antagonist of the Platelet P2Y1 Receptor with Strong Antithrombotic Activity in Mice. J Pharmacol Exp Ther 316:556-563.
Hinterdorfer P and Dufrene YF (2006) Detection and localization of single molecular recognition events using atomic force microscopy. Nat Methods 3:347-355.
Horber JK and Miles MJ (2003) Scanning probe evolution in biology. Science 302:1002-1005.
Lee K, Kim JY, Yoo BS, Yoon J, Hong MK, Ahn MS, Choe H and Lee SH (2010a) Cilostazol augments the inhibition of platelet aggregation in clopidogrel low-responders.J Thromb Haemost 8:2577-2579.
Lee SW, Park SW, Hong MK, Kim YH, Lee BK, Song JM, Han KH, Lee CW, Kang DH, Song JK, Kim JJ and Park SJ (2005) Triple versus dual antiplatelet therapy after coronary stenting:impact on stent thrombosis. J Am Coll Cardiol 46:1833-1837.
Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Kang SJ, Park SJ, Lee JH, Choi SW, Seong IW, Lee NH, Cho YH, Shin WY, Lee SJ, Lee SW, Hyon MS, Bang DW, Choi YJ, Kim HS, Lee BK, Lee K, Park HK, Park CB, Lee SG, Kim MK, Park KH and Park WJ (2011) A Randomized, Double-Blind, Multicenter Comparison Study of Triple Antiplatelet Therapy With Dual Antiplatelet Therapy to Reduce Restenosis After Drug-Eluting Stent Implantation in Long Coronary Lesions Results From the DECLARE-LONG II (Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients with Long Coronary Lesions) Trial. J Am Coll Cardiol 57:1264-1270.
Lee SW, Park SW, Yun SC, Kim YH, Park DW, Kim WJ, Lee JY, Lee CW, Hong MK, Kim JJ and Park SJ (2010b) Triple antiplatelet therapy reduces ischemic events after drug-eluting stent implantation:Drug-Eluting stenting followed by Cilostazol treatment REduces Adverse Serious cardiac Events (DECREASE registry). Am Heart J 159:284-291 e281.
Lenain N, Freund M, Leon C, Cazenave JP and Gachet C (2003) Inhibition of localized thrombosis in P2Y1-deficient mice and rodents treated with MRS2179, a P2Y1 receptor antagonist. J Thromb Haemost 1:1144-1149.
Ma T and Zhu X (1997) Interleukin-6 increases the levels of cyclic GMP and nitrite in rat hippocampal slices. Eur J Pharmacol 321:343-347.
Michelson AD (2008) P2Y12 antagonism:promises and challenges. Arterioscler Thromb Vasc Biol 28:s33-38.
Orlowski E, Chand R, Yip J, Wong C, Goschnick MW, Wright MD, Ashman LK and Jackson DE (2009) A platelet tetraspanin superfamily member, CD151, is required for regulation of thrombus growth and stability in vivo. J Thromb Haemost 7:2074-2084.
Paul BZ, Jin J and Kunapuli SP (1999) Molecular mechanism of thromboxane A(2)-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a) receptors. J Biol Chem 274:29108-29114.
Shankar H, Murugappan S, Kim S, Jin J, Ding Z, Wickman K and Kunapuli SP (2004) Role of G protein-gated inwardly rectifying potassium channels in P2Y12 receptor-mediated platelet functional responses. Blood 104:1335-1343.
Sibbing D, Steinhubl SR, Schulz S, Schomig A and Kastrati A (2010) Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients:initial evidence of a therapeutic window. J Am Coll Cardiol 56:317-318.
Spoto G, Whitehead E, Ferraro A, Di Terlizzi PM, Turano C and Riva F (1991) A reverse-phase HPLC method for cAMP phosphodiesterase activity. Anal Biochem 196:207-210.
Stolla M, Stefanini L, Roden RC, Chavez M, Hirsch J, Greene T, Ouellette TD, Maloney SF, Diamond SL, Poncz M, Woulfe DS and Bergmeier W (2011) The kinetics of alphaIIbbeta3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy. Blood 117:1005-1013.
Suh JW, Lee SP, Park KW, Lee HY, Kang HJ, Koo BK, Cho YS, Youn TJ, Chae IH, Choi DJ, Rha SW, Bae JH, Kwon TG, Bae JW, Cho MC and Kim HS (2011) Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease:Results of the CILON-T (Influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial. J Am Coll Cardiol 57:280-289.
Tang HF, Song YH, Chen JC, Chen JQ and Wang P (2005) Upregulation of phosphodiesterase-4 in the lung of allergic rats. Am J Respir Crit Care Med 171:823-828.
Zhang S, Hu L, Du H, Guo Y, Zhang Y, Niu H, Jin J, Zhang J, Liu J, Zhang X, Kunapuli SP and Ding Z (2010) BF0801, a novel adenine derivative, inhibits platelet activation via phosphodiesterase inhibition and P2Y12 antagonism. Thromb Haemost 104:845-857.
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23. Shankar H, Murugappan S, Kim S, Jin J, Ding Z, Wickman K, Kunapuli SP:Role of G protein-gated inwardly rectifying potassium channels in P2Y12 receptor-mediated platelet functional responses. Blood 2004,104:1335-1343.
24. Ding Z, Bynagari YS, Mada SR, Jakubowski JA, Kunapuli SP:Studies on the role of the extracellular cysteines and oligomeric structures of the P2Y receptor when interacting with antagonists. J Thromb Haemost 2009,7:232-234.
25. Zhang S, Hu L, Du H, Guo Y, Zhang Y, Niu H, Jin J, Zhang J, Liu J, Zhang X, et al: BF0801, a novel adenine derivative, inhibits platelet activation via PDE inhibition and P2Y12 antagonism. Thromb Haemost 2010,104.
26. Berlot C (Ed.). Expression and functional analysis of G protein alpha subunits in mammalian cells. Boca Raton:CRC Press; 1999.
27. Ma T, Zhu X:Interleukin-6 increases the levels of cyclic GMP and nitrite in rat hippocampal slices. Eur J Pharmacol 1997,321:343-347.
28. Spoto G, Whitehead E, Ferraro A, Di Terlizzi PM, Turano C, Riva F:A reverse-phase HPLC method for cAMP phosphodiesterase activity. Anal Biochem 1991,196:207-210.
29. Tang HF, Song YH, Chen JC, Chen JQ, Wang P:Upregulation of phosphodiesterase-4 in the lung of allergic rats. Am J Respir Crit Care Med 2005,171:823-828.
30. Horber JK, Miles MJ:Scanning probe evolution in biology. Science 2003, 302:1002-1005.
31. Ding Z, Kim S, Kunapuli SP:Identification of a potent inverse agonist at a constitutively active mutant of human P2Y12 receptor. Mol Pharmacol 2006,69:338-345.
32. Hinterdorfer P, Dufrene YF:Detection and localization of single molecular recognition events using atomic force microscopy. Nat Methods 2006,3:347-355.
33. Banno F, Chauhan AK, Kokame K, Yang J, Miyata S, Wagner DD, Miyata T:The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation. Blood 2009,113:5323-5329.
34. Chauhan AK, Motto DG, Lamb CB, Bergmeier W, Dockal M, Plaimauer B, Scheiflinger F, Ginsburg D, Wagner DD:Systemic antithrombotic effects of ADAMTS13. J Exp Med 2006,203:767-776.
35. Frenette PS, Johnson RC, Hynes RO, Wagner DD:Platelets roll on stimulated endothelium in vivo:an interaction mediated by endothelial P-selectin. Proc Natl Acad Sci U S A 1995,92:7450-7454.
36. Angelillo-Scherrer A, Burnier L, Flores N, Savi P, DeMol M, Schaeffer P, Herbert JM, Lemke G, Goff SP, Matsushima GK, et al:Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J Clin Invest 2005,115:237-246.
37. Stolla M, Stefanini L, Roden RC, Chavez M, Hirsch J, Greene T, Ouellette TD, Maloney SF, Diamond SL, Poncz M, et al:The kinetics of alphallbbeta3 activation determines the size and stability of thrombi in mice:implications for antiplatelet therapy. Blood 2011, 117:1005-1013.
38. Paul BZ, Jin J, Kunapuli SP:Molecular mechanism of thromboxane A(2)-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a) receptors. J Biol Chem 1999, 274:29108-29114.
39. Orlowski E, Chand R, Yip J, Wong C, Goschnick MW, Wright MD, Ashman LK, Jackson DE:A platelet tetraspanin superfamily member, CD151, is required for regulation of thrombus growth and stability in vivo. J Thromb Haemost 2009, 7:2074-2084.
40. Michelson AD:P2Y12 antagonism:promises and challenges. Arterioscler Thromb Vasc Biol 2008,28:s33-38.
41. Lee K, Kim JY, Yoo BS, Yoon J, Hong MK, Ahn MS, Choe H, Lee SH:Cilostazol augments the inhibition of platelet aggregation in clopidogrel low-responders. J Thromb Haemost 2010,8:2577-2579.
42. Lenain N, Freund M, Leon C, Cazenave JP, Gachet C:Inhibition of localized thrombosis in P2Y1-deficient mice and rodents treated with MRS2179, a P2Y1 receptor antagonist. J Thromb Haemost 2003,1:1144-1149.
43. Hechler B, Nonne C, Roh EJ, Cattaneo M, Cazenave JP, Lanza F, Jacobson KA, Gachet C:MRS2500[2-Iodo-N6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate], a Potent, Selective, and Stable Antagonist of the Platelet P2Y1 Receptor with Strong Antithrombotic Activity in Mice. J Pharmacol Exp Ther 2006,316:556-563.
44. Chen KY, Rha SW, Li YJ, Poddar KL, Jin Z, Minami Y, Wang L, Kim EJ, Park CG, Seo HS, et al:Triple versus dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation 2009,119:3207-3214.
45. Lee SW, Park SW, Yun SC, Kim YH, Park DW, Kim WJ, Lee JY, Lee CW, Hong MK, Kim JJ, Park SJ:Triple antiplatelet therapy reduces ischemic events after drug-eluting stent implantation:Drug-Eluting stenting followed by Cilostazol treatment REduces Adverse Serious cardiac Events (DECREASE registry). Am Heart J 2010,159:284-291 e281.
46. Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Kang SJ, Park SJ, Lee JH, Choi SW, et al:A Randomized, Double-Blind, Multicenter Comparison Study of Triple Antiplatelet Therapy With Dual Antiplatelet Therapy to Reduce Restenosis After Drug-Eluting Stent Implantation in Long Coronary Lesions Results From the DECLARE-LONG II (Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients with Long Coronary Lesions) Trial. J Am Coll Cardiol 2011, 57:1264-1270.
47. Han Y, Li Y, Wang S, Jing Q, Wang Z, Wang D, Shu Q, Tang X:Cilostazol in addition to aspirin and clopidogrel improves long-term outcomes after percutaneous coronary intervention in patients with acute coronary syndromes:a randomized, controlled study. Am Heart J 2009,157:733-739.
48. Lee SW, Park SW, Hong MK, Kim YH, Lee BK, Song JM, Han KH, Lee CW, Kang DH, Song JK, et al:Triple versus dual antiplatelet therapy after coronary stenting:impact on stent thrombosis. J Am Coll Cardiol 2005,46:1833-1837.
49. Sibbing D, Steinhubl SR, Schulz S, Schomig A, Kastrati A:Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients:initial evidence of a therapeutic window. J Am Coll Cardiol 2010,56:317-318.
Angelillo-Scherrer A, Burnier L, Flores N, Savi P, DeMol M, Schaeffer P, Herbert JM, Lemke G, Goff SP, Matsushima GK, Earp HS, Vesin C, Hoylaerts MF, Plaisance S, Collen D, Conway EM, Wehrle-Haller B and Carmeliet P (2005) Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J Clin Invest 115:237-246.
Banno F, Chauhan AK, Kokame K, Yang J, Miyata S, Wagner DD and Miyata T (2009) The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation. Blood 113:5323-5329.
Berlot C ed (1999) Expression and functional analysis of G protein alpha subunits in mammalian cells. CRC Press, Boca Raton.
Chauhan AK, Motto DG, Lamb CB, Bergmeier W, Dockal M, Plaimauer B, Scheiflinger F, Ginsburg D and Wagner DD (2006) Systemic antithrombotic effects of ADAMTS13. J Exp Med 203:767-776.
Chen KY, Rha SW, Li YJ, Poddar KL, Jin Z, Minami Y, Wang L, Kim EJ, Park CG, Seo HS, Oh DJ, Jeong MH, Ahn YK, Hong TJ, Kim YJ, Hur SH, Seong IW, Chae JK, Cho MC, Bae JH, Choi DH, Jang YS, Chae IH, Kim CJ, Yoon JH, Chung WS, Seung KB and Park SJ (2009) Triple versus dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation 119:3207-3214.
Ding Z, Bynagari YS, Mada SR, Jakubowski JA and Kunapuli SP (2009) Studies on the role of the extracellular cysteines and oligomeric structures of the P2Y receptor when interacting with antagonists. J Thromb Haemost 7:232-234.
Ding Z, Kim S and Kunapuli SP (2006) Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y12 Receptor. Mol Pharmacol 69:338-345.
Frenette PS, Johnson RC, Hynes RO and Wagner DD (1995) Platelets roll on stimulated endothelium in vivo:an interaction mediated by endothelial P-selectin. Proc Natl Acad Sci USA 92:7450-7454.
Han Y, Li Y, Wang S, Jing Q, Wang Z, Wang D, Shu Q and Tang X (2009) Cilostazol in addition to aspirin and clopidogrel improves long-term outcomes after percutaneous coronary intervention in patients with acute coronary syndromes:a randomized, controlled study. Am Heart J 157:733-739.
Hechler B, Nonne C, Roh EJ, Cattaneo M, Cazenave JP, Lanza F, Jacobson KA and Gachet C (2006) MRS2500 [2-Iodo-N6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate], a Potent, Selective, and Stable Antagonist of the Platelet P2Y1 Receptor with Strong Antithrombotic Activity in Mice. J Pharmacol Exp Ther 316:556-563.
Hinterdorfer P and Dufrene YF (2006) Detection and localization of single molecular recognition events using atomic force microscopy. Nat Methods 3:347-355.
Horber JK and Miles MJ (2003) Scanning probe evolution in biology. Science 302:1002-1005.
Lee K, Kim JY, Yoo BS, Yoon J, Hong MK, Ahn MS, Choe H and Lee SH (2010a) Cilostazol augments the inhibition of platelet aggregation in clopidogrel low-responders.J Thromb Haemost 8:2577-2579.
Lee SW, Park SW, Hong MK, Kim YH, Lee BK, Song JM, Han KH, Lee CW, Kang DH, Song JK, Kim JJ and Park SJ (2005) Triple versus dual antiplatelet therapy after coronary stenting:impact on stent thrombosis. J Am Coll Cardiol 46:1833-1837.
Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Kang SJ, Park SJ, Lee JH, Choi SW, Seong IW, Lee NH, Cho YH, Shin WY, Lee SJ, Lee SW, Hyon MS, Bang DW, Choi YJ, Kim HS, Lee BK, Lee K, Park HK, Park CB, Lee SG, Kim MK, Park KH and Park WJ (2011) A Randomized, Double-Blind, Multicenter Comparison Study of Triple Antiplatelet Therapy With Dual Antiplatelet Therapy to Reduce Restenosis After Drug-Eluting Stent Implantation in Long Coronary Lesions Results From the DECLARE-LONG II (Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients with Long Coronary Lesions) Trial. J Am Coll Cardiol 57:1264-1270.
Lee SW, Park SW, Yun SC, Kim YH, Park DW, Kim WJ, Lee JY, Lee CW, Hong MK, Kim JJ and Park SJ (2010b) Triple antiplatelet therapy reduces ischemic events after drug-eluting stent implantation:Drug-Eluting stenting followed by Cilostazol treatment REduces Adverse Serious cardiac Events (DECREASE registry). Am Heart J 159:284-291 e281.
Lenain N, Freund M, Leon C, Cazenave JP and Gachet C (2003) Inhibition of localized thrombosis in P2Y1-deficient mice and rodents treated with MRS2179, a P2Y1 receptor antagonist. J Thromb Haemost 1:1144-1149.
Ma T and Zhu X (1997) Interleukin-6 increases the levels of cyclic GMP and nitrite in rat hippocampal slices. Eur J Pharmacol 321:343-347.
Michelson AD (2008) P2Y12 antagonism:promises and challenges. Arterioscler Thromb Vasc Biol 28:s33-38.
Orlowski E, Chand R, Yip J, Wong C, Goschnick MW, Wright MD, Ashman LK and Jackson DE (2009) A platelet tetraspanin superfamily member, CD151, is required for regulation of thrombus growth and stability in vivo. J Thromb Haemost 7:2074-2084.
Paul BZ, Jin J and Kunapuli SP (1999) Molecular mechanism of thromboxane A(2)-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a) receptors. J Biol Chem 274:29108-29114.
Shankar H, Murugappan S, Kim S, Jin J, Ding Z, Wickman K and Kunapuli SP (2004) Role of G protein-gated inwardly rectifying potassium channels in P2Y12 receptor-mediated platelet functional responses. Blood 104:1335-1343.
Sibbing D, Steinhubl SR, Schulz S, Schomig A and Kastrati A (2010) Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients:initial evidence of a therapeutic window. J Am Coll Cardiol 56:317-318.
Spoto G, Whitehead E, Ferraro A, Di Terlizzi PM, Turano C and Riva F (1991) A reverse-phase HPLC method for cAMP phosphodiesterase activity. Anal Biochem 196:207-210.
Stolla M, Stefanini L, Roden RC, Chavez M, Hirsch J, Greene T, Ouellette TD, Maloney SF, Diamond SL, Poncz M, Woulfe DS and Bergmeier W (2011) The kinetics of alphaIIbbeta3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy. Blood 117:1005-1013.
Suh JW, Lee SP, Park KW, Lee HY, Kang HJ, Koo BK, Cho YS, Youn TJ, Chae IH, Choi DJ, Rha SW, Bae JH, Kwon TG, Bae JW, Cho MC and Kim HS (2011) Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease:Results of the CILON-T (Influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial. J Am Coll Cardiol 57:280-289.
Tang HF, Song YH, Chen JC, Chen JQ and Wang P (2005) Upregulation of phosphodiesterase-4 in the lung of allergic rats. Am J Respir Crit Care Med 171:823-828.
Zhang S, Hu L, Du H, Guo Y, Zhang Y, Niu H, Jin J, Zhang J, Liu J, Zhang X, Kunapuli SP and Ding Z (2010) BF0801, a novel adenine derivative, inhibits platelet activation via phosphodiesterase inhibition and P2Y12 antagonism. Thromb Haemost 104:845-857.