Effect Of Apoe And Ldlr Knockout On Rattus Macrophage Immune Function And Lipid Efflux

Apoe and Ldlr gene knockout mice are common models for atherosclerosis,with spontaneously plaque formation,hypercholesterolemia,and severe chronicinflammation.Compared with mice rats have advantages in mimic human diseases related to lipid metabolism.In addition,rats have a higher rate of homologous genes to humans,as well as convenience in sampling and long-term real-time monitoring.Apoe,Ldlr single gene knockout and double knockout rat models have been established in our laboratory for studying atherosclerosis study.It was reported that during atherosclerotic inflammatory response process in human,macrophages seem to play a critical role.Study of Apoe,Ldlr knockout mice found that Apoe,Ldlr can affect macrophage and mononuclear precursor cells in many aspects of their function.Here we use the established Apoe,Ldlr knockout rats,try to figure out the difference in the macrophage function of Apoe.Ldlr gene knockout rats.Results show that compared with the wild type rats,levels of total cholesterol and LDL increased significantly in blood of all three mutants including Apoe^-/-,Ldlr^-/-and Apoe^-/-Ldlr^-/-,whereas ox-LDL had no significant difference.In high cholesterol diet feeding group,Spleen/Body weight ratio of Ldlr^-/-increased significantly compared to wild type,while proportions of spleen macrophages in Apoe^-/-and Ldlr^-/-were reduced.There was no change in macrophage proportions in the peripheral blood.Most importantly,we analyzed macrophage funcitons associated with the course of atherosclerosis.Results found that mononuclear cell migration ability in Apoe^-/-rats was significantly increased than the wild type and Ldlr^-/-and Apoe^-/-Ldlr^-/-.In high cholesterol feeding group,there were more apotosis cells in Ldlr^-/-than in the other three groups and Ldlr^-/-macrophages showed dysfunction in cholesterol and lipid efflux.Also the phagocytosis of macrophage of Ldlr^-/-was the strongest compared to other three groups.In addition expression of phagocytosis related genes CD36 and SR-A1 did not show consistent correlation with that reported in mice.To our knowledge,this is the first systemic comparison of macrophage functions in Apoe^-/-,Ldlr^-/-and Apoe^-/-Ldlr^-/-rats in the homogenous genetic background.In conclusion,Apoe,Ldlr gene knockout in rat produce very different effects in macrophages.Apoe^-/-mainly influence migration ability of progenitor cells of macrophagewhile Ldlr^-/-enhance apoptosis and lead to dysfuncion in cholesterol efflux.These alterations in macrophage function lead to increased inflammation,which is closely related to development of AS.In addition,we should select different model when we want to study different aspects of inflammation or immune regulation in AS.