Abstract
The platelet integrin receptor αIIbβ3 plays a critical role in thrombosis. We have shown previously that the octapeptide YMESRADR, corresponding to sequences 313 to 320 of the human αIIb subunit, inhibits human platelet activation and fibrinogen binding to αIIbβ3, possibly interacting with the ligand. We investigated the effect of YMESRADR on electrically induced carotid artery thrombosis in New Zealand white rabbits. Peptide was administered via the femoral vein, starting 60 min before and continuing for 90 min after the electrical stimulation. Carotid blood flow was monitored for 90 min after the electrical stimulation. The peptide effects on platelet aggregation, in vitro and ex vivo, and on various coagulation, bleeding, and hemostatic parameters were evaluated. YMESRADR significantly inhibited rabbit platelet aggregation in vitro in a dose-dependent manner. It is important that peptide administration in vivo, at doses ranging from 3 to 15 mg/kg, prolonged the duration of the patency of the carotid artery, and no artery occlusion was observed until the end of the study (90 min after electrical stimulation). Furthermore, YMESRADR administration reduced platelet aggregation ex vivo and thrombus weight; however, these reductions reached statistical significance, compared with the control group, at the peptide doses of 12 and 15 mg/kg. YMESRADR did not affect any coagulation parameter studied and the hemostatic response observed in control animals. Thus, YMESRADR represents a novel antiplatelet agent that can inhibit thrombus formation effectively and carotid artery occlusion without causing hemorrhagic complications in a rabbit model of arterial thrombosis.
Footnotes
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This work was supported by the Greek General Secretariat for Research and Technology [Grant YB/88].
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This work was previously presented at the following conferences: Papamichael ND, Stathopoulou EM, Roussa VD, Tsironis LD, Kotsia AP, Stanica R-M, Mousis V, Tsikaris V, Katsouras CS, Tselepis AD, et al. (2005) Effect of a synthetic peptide corresponding to residues 313 to 320 of the αIIb subunit of the human platelet integrin αIIbβ3 on carotid artery thrombosis in rabbits. XXth International Society on Thrombosis and Hemostasis (ISTH) Congress; 2005 Aug 6–12; Sydney, Australia; Papamichael ND, Stathopoulou EM, Roussa VD, Tsironis LD, Kotsia AP, Stanica R-M, Mousis V, Tsikaris V, Katsouras CS, Tselepis AD, et al. (2005) Effect of a synthetic peptide corresponding to residues 313 to 320 of the αIIb subunit of the human platelet integrin αIIbβ3 on carotid artery thrombosis in rabbits. European Society of Cardiology; 2005 Sept 3–7; Stockholm, Sweden; and Papamichael ND, Stathopoulou EM, Roussa VD, Tsironis LD, Kotsia AP, Stanica R-M, Mousis V, Tsikaris V, Katsouras CS, Tselepis AD, et al. (2008) Effect of a synthetic peptide corresponding to residues 313 to 320 of the αIIb subunit of the human platelet integrin αIIbβ3 on carotid artery thrombosis in rabbits. 77th European Atherosclerosis Society Congress; 2008 Apr 26–29; Istanbul, Turkey.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.150086.
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ABBREVIATIONS: PRP, platelet-rich plasma; AA, arachidonic acid; PAF, platelet-activating factor; aPTT, activated partial thromboplastin time; TT, thrombin time; Fmoc, fluorenylmethoxycarbonyl.
- Received December 20, 2008.
- Accepted February 23, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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