Résumé
Excessive neointima formation often occurs after arterial injury. Interleukin-1β (IL-1β) is a potent pleiotropic cytokine that has been shown to regulate neointimal proliferation. We investigated the effects of the IL-1β modulator gevokizumab in a rat carotid denudation model.
Sprague–Dawley rats were subjected to balloon denudation of the right carotid artery and were then randomized to receive a single subcutaneous infusion immediately after balloon injury of saline (control group, n = 13) or gevokizumab (gevokizumab groups, n = 15 in each group: 1, 10 and 50 mg/kg). We evaluated the treatment effects on carotid intima-media thickness (IMT) using ultrasonography, on endothelial regrowth using Evans Blue staining and on inflammatory response using histology. We also assessed the effects of IL-1β and gevokizumab on human umbilical vein endothelial cells (HUVEC) and rat smooth muscle cells.
We found that carotid IMT, in the proximal part of the denuded artery at day 28, was decreased by gevokizumab 1 mg/kg compared with controls. Neointima area and the intima/media area ratio were both reduced in the gevokizumab 1 mg/kg-treated group. Gevokizumab at the 1 mg/kg dose also improved endothelial regrowth. No effect was observed with gevokizumab 10 or 50 mg/kg. Gevokizumab also decreased the inflammatory effect of IL-1β in in vitro cell experiments and protected HUVECs from IL-1β's deleterious effects on cell migration, apoptosis and proliferation.
A single administration of gevokizumab 1 mg/kg improves endothelial regrowth and reduces neointima formation in rats following carotid denudation, at least in part through its beneficial effects on endothelial cells.
•We evaluated the interest of gevokizumab (an interleukin-1β modulator) in a rat model of carotid denudation.•Three gevokizumab doses (1 mg/kg, 10 mg/kg and 50 mg/kg) were compared to placebo.•Carotid intima-media thickness was decreased by gevokizumab 1 mg/kg in the proximal part of the denuded artery at day 28.•Neointimal area and the intima/media area ratio were both reduced in the gevokizumab 1 mg/kg-treated group.•Gevokizumab 1 mg/kg dose also improved endothelial regrowth.