Nicotine Accelerates Atherosclerosis In Apoe-Deficient Mice By Activating ?7 Nicotinic Acetylcholine Receptor On Mast Cells

Background:Cigarette smoking is an independent risk factor for atherosclerogenesis.Nicotine is the addictive component of cigarettes,which has been demonstrated could induces mast cell activation.When mast cells are activated,they degranulate to release cytokines,a range of protease and inflammatory factors and contribute to atherogenesis.The purpose of this study is to determine whether nicotine accelerates atherosclerosis through mast cell-mediated mechanisms,and mast cells(MCs)stabilizer can prevent or reverse this atherosclerotic pathological process.The main aim of the research is to find out whether administration of the mast cell stabilizer,could prevent nicotine induced mast cell degranulation,and thus prevent or alleviate the nicotine augmented atherogenesis.Here we find out that the administration of mast cell stabilizer can significantly alleviate nicotine accelerated atherosclerosis,thus provide a potential therapeutic strategy to protect people who smoke or exposed to cigarette smoke from atherosclerosis.Methods and Results:Nicotine administration increased atherosclerotic lesion size in apolipoprotein e-deficient(Apoe-/-)mice fed on a western diet,which were accompanied by enhanced intra-plaque macrophage infiltration,lipid deposition,and decreased collagen and smooth muscle cell content.Mast cell deficiency in Apoe-/-mice(Apoe-/-KitW-sh/W-sh)diminished nicotine-augmented atherosclerosis.Meanwhile,we also found that nicotine activated bone marrow derived mast cells in vitro,which could be prevented by administration of mast cell stabilizer disodium cromoglycate(DSCG)or a non-selective nicotinic acetylcholine receptor blocker mecamylamine.Further study demonstrated that ?7 nicotinic acetylcholine receptor(?7nAChR)was the target for nicotine activation in mast cells.Finally,the Apoe-/-KitW-sh/W-sh mice reconstituted with a7nAChR deficient MCs from Apoe-/-?7nAChR-/-mice showed no augmented atherosclerotic lesion induced by nicotine treatment.Conclusions:Our research demonstrated that nicotine augments atherosclerosis in hypercholesterolemic mice by activating ?7nAChR on mast cells(MCs),and this process can be alleviated by mast cell stabilizer(DSCG),thus provid a protential therapeutic strategy for the prevention and cure of atherosclerosis.