Proteasome inhibitor prevents experimental arterial thrombosis in renovascular hypertensive rats

Justyna K. Ostrowska; Marek Z.Wojtukiewicz; Ewa Chabielska; Wlodzimierz Buczko; Halina Ostrowska

doi:10.1160/TH03-11-0707

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(01): 171-177
DOI: 10.1160/TH03-11-0707

Cell Signalling and Vessel Remodelling

Schattauer GmbH

Proteasome inhibitor prevents experimental arterial thrombosis in renovascular hypertensive rats

Authors

Justyna K. Ostrowska

¹Department of Oncology, Medical University of Bialystok, Poland
Marek Z.Wojtukiewicz

¹Department of Oncology, Medical University of Bialystok, Poland
Ewa Chabielska

²Department of Biopharmacy, Medical University of Bialystok, Poland
Wlodzimierz Buczko

³Department of Pharmacodynamics, Medical University of Bialystok, Poland
Halina Ostrowska

⁴Department of Biology, Medical University of Bialystok, Poland

Abstract

Summary

Recent studies indicate that highly selective proteasome inhibitors can be useful in prevention of some cardiovascular events. Here we demonstrate that proteasome inhibitor, Z-IleGlu (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 ± 0.91ohms 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 10μM 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.

Keywords

Arterial thrombosis - platelet aggregation - proteasome inhibitor - renovascular hypertension - rat

Full Text

References

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