Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition

BackgroundRecent studies suggest that statins can protect the vasculature in a manner that is independent of their lipid-lowering activity through inhibition of the small guanosine triphosphate-binding protein, Rho, and Rho-associated kinase. Little information is available on the inhibitory effect of statins on vein graft intimal hyperplasia, the main cause of late graft failure after bypass grafting. We therefore examined the effects of a hydrophilic statin on vein graft intimal hyperplasia in vivo and Rho-kinase activity in vitro.MethodsIn the first experiment, rabbits were randomized to a control group (n = 7) that was fed regular rabbit chow or to a pravastatin group (n = 7) that was fed regular rabbit chow supplemented with 10 mg/kg pravastatin sodium. The branches of the jugular vein were ligated and an approximately 3-cm segment of the jugular vein was taken for an autologous reversed-vein graft. The carotid artery was cut and replaced with the harvested autologous jugular vein. At 2 and 4 weeks after the operation, vein grafts in both groups were harvested, and intimal hyperplasia of the vein grafts was assessed. In the second experiment, human umbilical vein endothelial cells and vascular smooth muscle cells were cultured and then treated with 1 μmol/L and 30 μmol/L pravastatin for 24 hours and harvested. Immunoblotting was performed on the resulting precipitates. Quantitative evaluation of phosphorylated myosin binding subunit and endothelial nitric oxide synthase was performed by densitometric analysis.ResultsWe demonstrated that oral administration of the hydrophilic statin pravastatin to normocholesterolemic rabbits inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts 4 weeks after implantation (pravastatin group, 39.5 ± 3.5 μm vs control group, 64.0 ± 7.1 μm; n = 7; P < .05) and suppressed cell proliferation and apoptosis in the neointima 2 weeks after implantation. In addition, we found that pravastatin inhibited Rho-kinase activity and accelerated endothelial nitric oxide synthase expression in human umbilical vein endothelial cells but did not inhibit Rho-kinase activity in vascular smooth muscle cells.ConclusionsThese novel findings clearly demonstrate that a hydrophilic statin can suppress intimal hyperplasia of the vein graft in vivo and also show endothelial cell-tropic inhibition of Rho-kinase in vitro. Furthermore, these results strongly support the clinical use of hydrophilic statins to prevent intimal hyperplasia of the vein graft after bypass grafting.Clinical RelevanceLate graft failure caused by neointimal hyperplasia limits the efficacy of vein grafting. Various treatments were examined to reduce neointimal hyperplasia, but a standard clinical treatment has not yet been established. We report here the inhibitory effect of pravastatin on the development of vein graft intimal hyperplasia. In addition, we demonstrate that pravastatin showed endothelial cell-tropic benefits through both the inhibition of Rho-kinase activity and acceleration of eNOS expression in vitro. Because the clinical benefits and safety of pravastatin have been established to a certain extent through long-term clinical usage, pravastatin may soon become standard treatment after vein bypass grafting

External iliac venous aneurysm in a pregnant woman: a case report

AbstractWe report an external iliac venous aneurysm in a young pregnant woman who was diagnosed incidentally by ultrasound scanning. The aneurysm was successfully treated by tangential aneurysmectomy and lateral venorrhaphy. Primary iliac venous aneurysm is a rare vascular abnormality. The clinical significance of the disease is unknown. However, embolism, rupture, and thrombosis might occur as they can occur with popliteal venous aneurysm. In fact, three of four reported patients with iliac venous aneurysms had a thromboembolic event. For those reasons, prophylactic treatment is indicated. This is the first patient with an iliac venous aneurysm to be diagnosed without complication

Ezetimibe reduces intimal hyperplasia in rabbit jugular vein graft

BackgroundThe selective cholesterol transport inhibitor ezetimibe is widely used to prevent development of atherosclerosis in patients with hypercholesterolemia. However, whether this agent inhibits intimal hyperplasia in autologous vein grafts is unknown. The present study was undertaken to clarify if ezetimibe reduces cell proliferation and intimal hyperplasia in vein grafts.MethodsForty-four rabbits were randomly divided into two groups: one group received ezetimibe (0.6 mg/kg/d), and the control group did not. Ezetimibe administration was started 1 week before rabbits underwent interposition reversed autologous jugular vein grafts. The proliferative cells and apoptotic cells were counted in the vein grafts 14 days after implantation, and changes in acetylcholine-induced relaxation and endothelial intracellular concentration of Ca2+ ([Ca2+]i) were examined at 28 days.ResultsEzetimibe reduced serum cholesterol and triglyceride. There were fewer proliferating cells in the ezetimibe group (5.7% ± 0.2%, n = 7) than in the control group (12.8% ± 0.5%, n = 7; P < .0001) and more apoptotic cells in the ezetimibe group (5.3% ± 0.2%, n = 7) than in the control group (2.3% ± 0.2%, n = 7; P < .0001). Intimal hyperplasia was less in the ezetimibe group (46.1 ± 6.0 μm, n = 7) than in the control group (76.0 ± 2.5 μm, n = 7; P < .01). Acetylcholine-produced endothelium-dependent relaxation was observed only in the ezetimibe group, which was blocked by the nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine. Acetylcholine increased [Ca2+]i only in the ezetimibe group.ConclusionsEzetimibe reduced cell proliferation and enhanced cell apoptosis, thus inhibiting intimal hyperplasia in rabbit autologous vein grafts. Ezetimibe restored the acetylcholine-induced increase in [Ca2+]i in endothelial cells and improved endothelium-dependent NO-mediated relaxation in the vein graft. Our results suggest that ezetimibe enhances the function of endothelial NO through an increase in endothelial [Ca2+]i, thus reducing vein graft intimal hyperplasia.Clinical RelevanceIntimal hyperplasia is a major obstacle to patency after vein grafting. Various treatments have been examined to reduce neointimal hyperplasia; however, a standard clinical treatment has not yet been established. We report here that ezetimibe inhibits intimal hyperplasia in rabbit autologous vein grafts. More importantly, we demonstrated that ezetimibe improves acetylcholine-induced endothelium-dependent relaxation by restoring its endothelial cell [Ca2+]i–mobilizing activity in the grafts. The present results suggest that ezetimibe restores agonist-induced endothelial [Ca2+]i mobilization and enhances the function of endothelium-derived nitric oxide, thus reducing intimal hyperplasia in vein grafts. Our results support the notion that ezetimibe helps to prevent intimal hyperplasia in vein grafts