Tenascin-C deficiency in apo E−/− mouse increases eotaxin levels: Implications for atherosclerosis

AimTo investigate the potential role of inflammatory cytokines in apo E−/− mouse in response to deletion of Tenascin-C (TNC) gene.Methods and resultsWe used antibody array and ELISA to compare the profile of circulating inflammatory cytokines in apo E−/− mice and apo E−/− TNC−/− double knockout mice. In addition, tissue culture studies were performed to investigate the activity of cells from each mouse genotype in vitro. Cytokine array analysis and subsequent ELISA showed that circulating eotaxin levels were selectively and markedly increased in response to TNC gene deletion in apo E−/− mice. In addition, considerable variation was noted in the circulating level of eotaxin among the control apo E−/− mouse group. Inbreeding of apo E−/− mice with high or low levels of plasma eotaxin showed that the level of eotaxin per se determines the extent of atherosclerosis in this mouse genotype. While endothelial cells from apo E−/− mice had low level of eotaxin expression, cells derived from apo E−/− TNC−/− mice expressed a high level of eotaxin. Transient transfection of eotaxin promoter-reporter constructs revealed that eotaxin expression is regulated at the transcriptional level by TNC. Histochemical analysis of aortic sections revealed the massive accumulation of mast cells in the adventitia of double KO mice lesions whereas no such accumulation was detected in the control group. Plasma from the apo E−/− TNC−/− mice markedly stimulated mast cell migration whereas plasma from the apo E−/− mice had no such effect.ConclusionThese observations support the emerging hypothesis that TNC expression controls eotaxin level in apo E−/− mice and that this chemokine plays a key role in the development of atherosclerosis.

► Tenascin-C (TNC) is a matricellular protein that exhibits athero-protective activity. ► Deletion of TNC selectively upregulates expression of eotaxin. ► The level of plasma eotaxin level correlates with extends of atherosclerosis in apo E−/− mice. ► Eotaxin level in endothelial cells and smooth muscle cells are regulated by TNFα and oxidized LDL. ► The plasma level of eotaxin correlates with accumulation of mast cells in the adventitia of aortic lesions in apo E−/− mice.