Major Vault Protein Deficiency Exacerbates Atherosclerosis By Promoting Macrohage Inflammation And Lipid Accumulation In Mice

Atherosclerosis is a chronic inflammatory disease,associated with inflammation and lipid metabolism disorders.Macrophages play a prominent role during the generation and development of atherosclerosis.However,detailed mechanisms underlying it are not fully understood.Major vault protein(MVP)is an inflammation-related protein in cells.In order to investigate the role of MVP in the pathogenesis of atherosclerosis,we performed the current study.It was shown that MVP level was up-regulated in atherosclerotic lesions in Apo E-/-mice,suggesting an association of MVP with atherosclerosis.We next generated the MVP-/-ApoE-/-mice fed by a high-lipid diet.We found that atherosclerotic plaque areas were dramatically increased in MVP-/-ApoE-/-mice compared with ApoE-/-mice.Immunohistochemical staining and flow cytometer measurements showed that the numbers of macrophages and lymphocytes in atherosclerotic plaque were elevated in MVP-/-ApoE-/-mice compared with ApoE-/-mice fed by a high-lipid diet.The MVP-/-macrophages exhibited greater migration ability and produced higher levels of TNF,IL-6,IL-1,CCL2,CCL5 and CXCL1.These results suggest that MVP deficiency cause stronger inflammatory responses in macrophages.We also examined role of MVP in lipids accumulation in macrophages.We found that the MVP-/-macrophage exhibited an increased uptake of ox-LDL but unchanged binding of ox-LDL.The increased lipid accumulation in macrophage was found in MVP-/-macrophage in contrast with WT.In addition,we found that the inflammation and lipid uptake was conducted through MKK4/MAPK/NF-KB/AP-1 pathway in MVP-/-macrophages.Taken together,our study,for the first time,demonstrated that MVP deficiency aggravate atherosclerosis through promoting macrohage inflammation and lipid accumulation.Thus,down regulation of MVP in macrophage may be developed as a therapeutic approach to atherosclerosis.