ABSTRACT
Mebendazole is an antihelminthic drug that exerts its effects via interference with microtubule function in parasites. To determine the utility of mebendazole as a potential treatment for vascular diseases involving proliferation of vascular smooth muscle cells, the effects of mebendazole on vascular smooth muscle cell proliferation were tested in vitro and in a mouse model of arterial injury. In vitro, mebendazole inhibited proliferation and migration of murine vascular smooth muscle cells and this was associated with altered intracellular microtubule organization. To determine in vivo effects of mebendazole following vascular injury, femoral arterial wire injury was induced in wild-type mice treated with either mebendazole or placebo control. Compared with placebo-treated mice, mebendazole-treated mice formed less neointima at the site of injury. Mebendazole is effective at inhibiting vascular smooth muscle cell proliferation and migration, and neointimal formation following arterial injury in mice.
Subject(s)
Mebendazole/pharmacology , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , Neointima/drug therapy , Vascular System Injuries/drug therapy , Animals , Apoptosis/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Hyperplasia , Male , Mebendazole/administration & dosage , Mice , Neointima/pathology , Vascular System Injuries/pathologyABSTRACT
Sickle cell disease (SCD) is associated with vascular complications including premature stroke. The role of atherothrombosis in these vascular complications is unclear. To determine the effect of SCD on atherosclerosis and thrombosis, mice with SCD along with controls were generated by transplantation of bone marrow from mice carrying the homozygous sickle cell mutation (Hbb(hßs/hßs) ) or wild-type mice (Hbb(+/+) ) into C57BL6/J or apolipoprotein E deficient (Apoe(-/-) ) recipient mice. At the time of sacrifice, 23-28 weeks following bone marrow transplantation, anaemia, reticulocytosis, and splenomegaly were present in mice receiving Hbb(hßs/hßs) bone marrow compared with control mice. Analysis of atherosclerosis involving the aortic root revealed reduced atherosclerotic lesion area with reduced macrophage content and increased collagen content in Apoe(-/-) , Hbb(hßs/hßs) mice compared to Apoe(-/-) , Hbb(+/+) mice. In a carotid thrombosis model, the time to thrombosis was prolonged in Hbb(hßs/hßs) mice compared to Hbb(+/+) mice. This apparent protective effect of SCD on atherosclerosis and thrombosis was diminished by inhibition of heme oxygenase-1 (HMOX1) using zinc protoporphyrin IX. We conclude that SCD in mice is paradoxically protective against atherosclerosis and thrombosis, highlighting the complexity of vascular events in SCD. This protective effect is at least partially mediated by induction of HMOX1.
