Protective effects of bifunctional platelet GPIIIa49-66 ligand on myocardial ischemia-reperfusion injury in rats


Current antiplatelet drugs mainly focus on prevention rather than the more clinically relevant issue of clearance of an existing thrombus. We recently described a novel and effective therapeutic strategy for dissolution of preexisting platelet thrombus in a murine ischemic stroke model with a bifunctional platelet GPIIIa49-66 ligand (Single-chain antibody Linked first Kringle 1 of plasminogen, named SLK), which homes to newly deposited fibrin strands tangled of platelet thrombus and induces aggregated platelet fragmentation. In this study, we perform in-depth analysis of the effect of SLK on myocardial ischemia-reperfusion (IR) injury in rats. We show that SLK dose-dependently reduces lactate dehydrogenase (LDH) release as well as mean infarction size of left ventricle. Histological observation demonstrates that the arterial thrombi in coronary arteries of rat almost disappear after SLK injection. Optimal dose of SLK (37.5 μg/ individual) provides the myocardial protection at 2 hours post-infusion. However, there are no significant protective effects if SLK was given at 4 or 8 hours post-infusion. The combined application of SLK and urokinase (UK) demonstrates greater myocardial protection than UK alone at 2 hours post-infusion. Thus, SLK could be used as a thrombolytic alternative in other arterial vascular beds associated with thrombosis to enhance fibrinolysis.

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Fan, J. , Jing, F. , Dang, S. and Zhang, W. (2013) Protective effects of bifunctional platelet GPIIIa49-66 ligand on myocardial ischemia-reperfusion injury in rats. Health, 5, 15-20. doi: 10.4236/health.2013.57A3003.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Keeley, E.C., Boura, J.A. and Grines, C.L. (2003) Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomisedtrials. Lancet, 361, 13-20.
[2] Grines, C.L., Browne, K.F., Marco, J., Rothbaum, D., Stone, G.W., O’Keefe, J., Overlie, P., Donohue, B., Chelliah, N., Timmis, G.C.; The Primary Angioplasty in Myocardial Infarction Study Group (1993) A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. The New England Journal of Medicine, 328, 673-679. doi:10.1056/NEJM199303113281001
[3] The GUSTO-IIb investigators (1997) A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. The global use of strategies to open occluded coronary arteries in acute coronary syndromes (GUSTO IIb) Angioplasty substudy investigators. The New England Journal of Medicine, 336, 1621-1628. doi:10.1056/NEJM199706053362301
[4] Boersma, E., Primary Coronary Angioplasty vs. Thrombolysis Group (2006) Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients. European Heart Journal, 27, 779-788. doi:10.1093/eurheartj/ehi810
[5] Schwartz, B.G. and Kloner, R.A. (2012) Coronary no reflow. Journal of Molecular and Cellular Cardiology, 52, 873-882.
[6] Ovechkin, A.V., Lominadze, D., Sedoris, K.C., Robinson, T.W., Tyagi, S.C. and Roberts, A.M. (2007) Lung ischemia-reperfusion injury: Implications of oxidative stress and platelet-arteriolar wall interactions. Archives of Physiology and Biochemistry, 113, 1-12. doi:10.1080/13813450601118976
[7] Ogawa, K., Kondo, T., Tamura, T., Matsumura, H., Fukunaga, K., Oda, T. and Ohkohchi, N. (2013) Influence of Kupffer cells and platelets on ischemia-reperfusion injury in mild steatotic liver. World Journal of Gastroenterology, 19, 1396-1404. doi:10.3748/wjg.v19.i9.1396
[8] Reffelmann, T. and Kloner R.A. (2002) Microvascular reperfusion injury: Rapid expansion of anatomic no reflow during reperfusion in the rabbit. American Journal of Physiology—Heart and Circulatory Physiology, 283, H1099-H1107.
[9] Kloner, R.A., Rude, R.E., Carlson, N., Maroko, P.R., DeBoer, L.W. and Braunwald, E. (1980) Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: Which comes first? Circulation, 62, 945-952. doi:10.1161/01.CIR.62.5.945
[10] De Lemos, J.A., Antman, E.M., Gibson, C.M., McCabe, C.H., Giugliano, R.P., Murphy, S.A., Coulter, S.A., Anderson, K., Scherer, J., Frey, M.J., Van Der Wieken, R., Van De Werf, F. and Braunwald, E. (2000) Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction. Observations from the TIMI 14 trial. Circulation, 101, 239-243. doi:10.1161/01.CIR.101.3.239
[11] Petronio, A.S., De Carlo, M., Ciabatti, N., Amoroso, G., Limbruno, U., Palagi, C., Di Bello, V., Romano, M.F. and Mariani, M. (2005) Left ventricular remodeling after primary coronary angioplasty in patients treated with abciximab or intracoronary adenosine. American Heart Journal, 150, 1015. doi:10.1016/j.ahj.2005.07.012
[12] Gibson, C.M., Morrow, D.A., Murphy, S.A., Palabrica, T.M., Jennings, L.K., Stone, P.H., Lui, H.H., Bulle, T., Lakkis, N., Kovach, R., Cohen, D.J., Fish, P., McCabe, C.H., Braunwald, E., TIMI Study Group (2006) A randomized trial to evaluate the relative protection against post-percutaneous coronary intervention microvascular dysfunction, ischemia, and inflammation among antiplatelet and antithrombotic agents: The PROTECT-TIMI-30 trial. Journal of the American College of Cardiology, 47, 2364-2373. doi:10.1016/j.jacc.2005.12.077
[13] Van’t Hof, A.W., Ten Berg, J., Heestermans, T., Dill, T., Funck, R.C., van Werkum, W., Dambrink, J.H., Suryapranata, H., van Houwelingen, G., Ottervanger, J.P., Stella, P., Giannitsis, E. and Hamm, C. (2008) Ongoing Tirofiban In Myocardial infarction Evaluation (On-TIME) 2 study group.2008.Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): A multicentre, doubleblind, randomised controlled trial. Lancet, 372, 537-546. doi:10.1016/S0140-6736(08)61235-0
[14] Thiele, H., Schindler, K., Friedenberger, J., Eitel, I., Fürnau, G., Grebe, E., Erbs, S., Linke, A., Mobius-Winkler, S., Kivelitz, D. and Schuler, G. (2008) Intracoronary compared with intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: The randomized Leipzig immediate percutaneous coronary intervention abciximab IV versus IC in ST-elevation myocardial infarction trial. Circulation, 118, 49-57. doi:10.1161/CIRCULATIONAHA.107.747642
[15] Maioli, M., Bellandi, F., Leoncini, M., Toso, A. and Dabizzi, R.P. (2007) Randomized early versus late abciximab in acute myocardial infarction treated with primary coronary intervention (RELAx-AMI Trial). Journal of the American College of Cardiology, 49, 1517-1524. doi:10.1016/j.jacc.2006.12.036
[16] Michelson, A.D. (2010) Antiplatelet therapies for the treatment of cardiovascular disease. Nature Reviews Drug Discovery, 9, 154-169. doi:10.1038/nrd2957
[17] Shattil, S.J. and Ginsberg, M.H. (1997) Perspectives series: Cell adhesion in vascular biology. Integrin signaling in vascular biology. Journal of Clinical Investigation, 100, 1-5. doi:10.1172/JCI119500
[18] Nardi, M., Tomlinson, S., Greco, M.A. and Karpatkin, S. (2001) Complement-independent, peroxide-induced antibody lysis of platelets in HIV-1-related immune thrombocytopenia. Cell, 106, 551-561. doi:10.1016/S0092-8674(01)00477-9
[19] Nardi, M., Feinmark, S.J., Hu, L., Li, Z. and Karpatkin, S. (2004) Complement-independent Ab-induced peroxide lysis of platelets requires 12-lipoxygenase and a platelet NADPH oxidase pathway. Journal of Clinical Investigation, 113, 973-980. doi:10.1172/JCI200420726
[20] Li, Z., Nardi, M.A. and Karpatkin, S. (2005) Role of molecular mimicry to HIV-1 peptides inHIV-1-related immunologic thrombocytopenia. Blood, 106, 572-576. doi:10.1182/blood-2005-01-0243
[21] Zhang, W., Dang, S., Wang, J., Nardi, M.A., Zan, H., Casali, P. and Li, Z. (2010) Specific cross-reaction of anti-dsDNA antibody with platelet integrin GPIIIa49-66. Autoimmunity, 43, 682-689. doi:10.3109/08916934.2010.506207
[22] Zhang, W., Nardi, M.A., Borkowsky, W., Li, Z. and Karpatkin, S. (2009) Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia. Blood, 113, 4086-4093. doi:10.1182/blood-2008-09-181073
[23] Zhang, W., Li, Y.S., Nardi, M.A., Dang, S., Yang, J., Ji, Y., Li, Z., Karpatkin, S. and Wisniewski, T. (2010) Dissolution of arterial platelet thrombi in vivo with a bifunctional platelet GPIIIa49-66 ligand which specifically targets the platelet thrombus. Blood, 116, 2336-2344. doi:10.1182/blood-2010-01-264358
[24] Huang, S.S., Liu, S.M., Lin, S.M., Liao, P.H., Lin, R.H., Chen, Y.C., Chih, C.L. and Tsai, S.K. (2005) Antiarrhythmic effect of caffeic acid phenethyl ester (CAPE) on myocardial ischemia/reperfusion injury in rats. Clinical Biochemistry, 38, 943-947. doi:10.1016/j.clinbiochem.2005.07.003
[25] Johnston, K.M., MacLeod, B.A. and Walker, M.J. (1983) Responses to ligation of a coronary artery in conscious rats and the actions of antiarrhythmics. Canadian Journal of Physiology and Pharmacology, 61, 1340-1353. doi:10.1139/y83-193

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