Pravastatin inhibits platelet and leukocyte adhesion to radiation-induced activated endothelial cells (EC).
M.H Gaugler, V. Vereycken-Holler, C. Squiban, M. Benderitter, Congrès annuel de la nouvelle société française d'athérosclérose, 10-12 juin 2004, Biarritz (France).
Pravastatin inhibits platelet and leukocyte adhesion to radiation-induced activated endothelial cells (EC). The role of EC in the pathogenesis of radiation atherosclerosis, fibrosis and thrombosis has been widely suggested but only recently a link between the persistence of endothelial dysfunction and radiation pathologies has been proposed. We have previously shown that irradiation induced an early and sustained activation of EC resulting in maintained functional pro-inflammatory and thrombogenic properties of EC. Furthermore, we have demonstrated a persistent inhibitory effect of pravastatin on the radiation-induced activation of EC. Therefore, the aim of this study was to investigate whether pravastatin could modulate the increased blood-EC interactions induced by irradiation. Confluent cultures of human microvascular endothelial cells from lung were irradiated at 10 Gy (137Cs source, g rays, 0.7 Gy/min). Mevalonate (400 µM) and/or pravastatin (100 µM) were added right before irradiation and 3 days after irradiation. Platelet- and leukocyte-EC interactions were assessed in a flow chamber where EC were perfused with fluorescently labelled whole blood at low (25 s-1) and high (500 s-1) wall shear rates. Concerning leukocyte-EC interactions at low wall shear rate, treatment with pravastatin did not modify the number of rolling leukocytes on irradiated HMVEC-L (144 ± 5, n = 5) compared to control irradiated HMVEC-L (145 ± 11). In contrast, pravastatin inhibited significantly (p < 0.05) the number of firmly adherent leukocytes from 9.7 ± 3.0 to 4.2 ± 1.5 (n = 7). The effect of pravastatin on leukocyte adhesion was limited by simultaneous treatment with mevalonate (5.7 ± 2.0). Concerning platelet-EC interactions, treatment of HMVEC-L with pravastatin inhibited completely the radiation-induced increased adhesion of single platelets and thrombi on EC at both wall shear rates and whatever the time following radiation exposure. For example, 7 days after irradiation and at high wall shear rate, the surface covered with platelets was 10470 ± 733 µm2/field (control) and 5027 ± 448 (pravastatin). This inhibitory effect of pravastatin was reversed completely with mevalonate. Our results add another potential mechanism to the vascular protective effects exerted by statins as they demonstrated, for the first time, an antithrombotic effect of pravastatin via an action on endothelial cells.