title: Proteasome inhibitor prevents experimental arterial thrombosis in renovascular hypertensive rats.
abstract: Recent studies indicate that highly selective proteasome inhibitors can be useful in prevention of some cardiovascular events. Here we demonstrate that proteasome inhibitor, Z-Ile-Glu (Ot-Bu) Ala-Leucinal (PSI), is active in the prevention of platelet-dependent arterial thrombosis induced in renovascular hypertensive rats (two-kidney, one clip Goldblatt model, and 2K1C, n=5). The administration of PSI intravenously at a single dose of 0.3 mg/kg before induction of arterial thrombosis markedly increased carotid final flow rate, as compared to control (vehicle) group (10.36 +/- 1.8 ml/min and 1.2 +/- 1.2 ml/min, respectively), significantly decreased the wet (1.23 +/- 0.23 mg and 4.1 +/- 0.94 mg, respectively), and dry (0.46 +/- 0.145 mg and 1.46 +/- 0.39, respectively) thrombus weight, and completely prevented arterial occlusion. Moreover, platelets from PSI - treated thrombotic 2K1C rats, showed in response to collagen a significant inhibition of aggregation in the whole blood (10.26 +/- 0.6 ohms vs. 15.51 +/- 0.91 ohms in the control group). In contrast, collagen-induced platelet aggregation was not inhibited in vitro, after pre-treatment of the blood with PSI at the concentration of 10 microM that effectively inhibited the 20S proteasome activity in platelets, indicating that ex vivo anti-aggregatory effect of PSI proceeds through an indirect mechanism not associated with suppression of 20S proteasome activity in platelets. In conclusion, our in vivo findings demonstrate that proteasome inhibitor, Z-Ile-Glu(Ot-Bu)Ala-Leucinal, prevents the development of arterial thrombosis in renovascular hypertensive rats and effectively suppresses platelet aggregation by an indirect mechanism. Thus the data provide a new insight into the potential role for the proteasome-dependent pathway in cardiovascular events.
authors.affiliation: Department of Oncology, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland.
authors.forename: Justyna K
authors.initials: JK
authors.lastname: Ostrowska
authors.forename: Marek Z
authors.initials: MZ
authors.lastname: Wojtukiewicz
authors.forename: Ewa
authors.initials: E
authors.lastname: Chabielska
authors.forename: Wlodzimierz
authors.initials: W
authors.lastname: Buczko
authors.forename: Halina
authors.initials: H
authors.lastname: Ostrowska
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D002341:Carotid Artery Thrombosis / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D003094:Collagen / Q000494:pharmacology; D006978:Hypertension, Renovascular / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D066298:In Vitro Techniques; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000097:blood; D061988:Proteasome Inhibitors; D051381:Rats; D017208:Rats, Wistar
chemical_list: D009842:Oligopeptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; D003094:Collagen; D046988:Proteasome Endopeptidase Complex