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Antithrombotic properties of water-soluble carbon monoxide-releasing molecules.
Kramkowski K., Leszczynska A., Mogielnicki A., Chlopicki S., Fedorowicz A., Grochal E., Mann B., Brzoska T., Urano T., Motterlini R. et al
Arteriosclerosis, Thrombosis, and Vascular Biology 32, 9 (2012) 2149-57 - http://www.hal.inserm.fr/inserm-00732395
Antithrombotic properties of water-soluble carbon monoxide-releasing molecules.
Karol Kramkowski1, Agnieszka Leszczynska1, Andrzej Mogielnicki1, Stefan Chlopicki2, 3, Andrzej Fedorowicz2, Elzbieta Grochal2, 3, Brian Mann4, Tomasz Brzoska5, Tetsumei Urano5, Roberto Motterlini4, Wlodzimierz Buczko () 1
1 :  Department of Pharmacodynamics
Medical University of Bialystok
2 :  JCET - Jagiellonian Centre for Experimental Therapeutics
Jagiellonian University
3 :  Department of Experimental Pharmacology
Jagiellonian University Medical College
4 :  Biomécanique Cellulaire et Respiratoire
INSERM : U955 – CNRS : ERL7240 – Institut Mondor de Recherche Biomédicale (IMRB) – Université Paris-Est Créteil Val-de-Marne (UPEC) – IFR10
Faculté de Médecine - 8 rue du général Sarrail 94011 Créteil
5 :  Department of Medical Physiology
Hamamatsu University Medical School of Medicine
1-20-1, Handa-yama, Hamamatsu, 431-3192
Anti-thrombotic properties of CO-RMs
OBJECTIVE: We compared the antithrombotic effects in vivo of 2 chemically different carbon monoxide-releasing molecules (CORM-A1 and CORM-3) on arterial and venous thrombus formation and on hemostatic parameters such as platelet activation, coagulation, and fibrinolysis. The hypotensive response to CORMs and their effects on whole blood gas analysis and blood cell count were also examined. METHODS AND RESULTS: CORM-A1 (10-30 µmol/kg, i.v.), in a dose-dependent fashion, significantly decreased weight of electrically induced thrombus in rats, whereas CORM-3 inhibited thrombosis only at the highest dose used (30 µmol/kg). CORM-A1 showed a direct and stronger inhibition of platelet aggregation than CORM-3 in healthy rats, both in vitro and in vivo. The antiaggregatory effect of CORM-A1, but not CORM-3, correlated positively with weight of the thrombus. Concentration of active plasminogen activator inhibitor-1 in plasma also decreased in response to CORM-A1, but not to CORM-3. Neither CORM-A1 nor CORM-3 had an effect on plasma concentration of active tissue plasminogen activator. CORM-3, but not CORM-A1, decreased the concentration of fibrinogen, fibrin generation, and prolonged prothrombin time. Similarly, laser-induced venous thrombosis observed intravitally via confocal system in green fluorescent protein mice was significantly decreased by CORMs. Although both CORM-A1 and CORM-3 (30 µmol/kg) decreased platelets accumulation in thrombus, only CORM-A1 (3-30 µmol/kg) inhibited platelet activation to phosphatidylserine on their surface. CONCLUSIONS: CORM-3 and CORM-A1 inhibited thrombosis in vivo, however CORM-A1, which slowly releases carbon monoxide, and displayed a relatively weak hypotensive effect had a more pronounced antithrombotic effect associated with a stronger inhibition of platelet aggregation associated with a decrease in active plasminogen activator inhibitor-1 concentration. In contrast, the fast CO releaser CORM-3 that displayed a more pronounced hypotensive effect inhibited thrombosis primarily through a decrease in fibrin generation, but had no direct influence on platelet aggregation and fibrynolysis.
Sciences du Vivant/Biochimie, Biologie Moléculaire

Articles dans des revues avec comité de lecture
Arteriosclerosis, Thrombosis, and Vascular Biology (Arterioscler Thromb Vasc Biol)
Publisher American Heart Association
ISSN 1079-5642 (eISSN : 1524-4636)

carbon monoxide (CO) – CO-releasing molecules (CO-RMs) – thrombosis – platelet aggregation – fibrin generation – plasminogen activator inhibitor-1 (PAI-1)
This work was supported by Polish Ministry of Science and Higher Education (grant no. NN405 260437). Supplementary funding was provided by the European Union from the resources of the European Regional Development Fund under the Innovative Economy Programme (grant coordinated by JCET-UJ, No POIG.01.01.02-00-069/09) and Grant-in-Aid for Scientific Research (C:21590230 from the Japan Society for the Promotion of Science (JSPS).
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