CFTR Protects Against Vascular Inflammation And Atherogenesis In Apolipoprotein E-deficient Mice

Objective:Dysfunction of cystic fibrosis transmembrane conductance regulator（CFTR）has been shown to result in inflammatory responses in cystic fibrosis（CF）patients.However,little is known about the role of CFTR in vascular inflammation and atherogenesis.This article focuses on whether CFTR inhibits vascular inflammation and reduces atherosclerosis in apolipoprotein E-deficient mice.Methods:We first observed whether plaque stability of apoE^-/-mice fed a high-fat diet can be improved after in vivo administration of CFTR adenovirus（Ad-CFTR）to apolipoprotein E deficient(apoE^-/-)mice.Confocal microscopy was then used to explore the infiltration of T lymphocytes,neutrophils and macrophages in the aortic sinus in Ad-CFTR treated apoE^-/-mice.Then in vitro experiments to explore the overexpression of CFTR and ox-LDL（oxidized low density lipoprotein）induced peritoneal macrophage migration.Results:Aortic and aortic sinus atherosclerosis in apoE^-/-mice is mainly manifested as macrophages in atherosclerotic plaques.CFTR reduces arterial pressure by reducing lipid accumulation and necrosis area and increasing smooth muscle cell content and collagen hardening.In vivo administration of CFTR adenovirus（Ad-CFTR）improves plaque stability in apoE^-/-mice fed a high-fat diet.Ad-CFTR-treated mice also showed reduced levels of proinflammatory cytokines in aortas and peritoneal macrophages while anti-inflammatory M2 macrophage markers increased.Confocal microscopy revealed that the infiltration of T-lymphocytes,neutrophils and macrophages in aortic sinus was markedly attenuated in Ad-CFTR-treated apoE^-/-mice.The Ad-CFTR-treated mice also displayed reduced proinflammatory cytokines levels in aorta and peritoneal macrophages,whereas the anti-inflammatory M2 macrophage markers were increased.Our results showed that CFTR was dominantly expressed in macrophages of atherosclerotic plaque and reduced in aorta and aortic sinus from atherosclerotic apolipoprotein E-deficient(apoE^-/-)mice.In vivo administration of CFTR adenovirus（Ad-CFTR）with apoE^-/-mice fed high-fat diet improved plaque stability by decreasing lipid accumulation and necrotic area and increasing smooth muscle cell content and collagen.Conclusions:Firstly,the expression of CFTR was reduced in mouse atherosclerotic plaques.Secondly,overexpression of CFTR reduced atherosclerosis progression in apoE^-/-mice.Thirdly,CFTR reduced vascular inflammation and promoted M2 macrophage polarization during atherogenesis.Finally,up-regulation of CFTR inhibited the recruitment of immune cells in atherosclerotic plaque.Taken together,our data suggest that CFTR may present a potential therapeutic target for the treatment of vascular inflammation and development of atherosclerotic disease.