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

Area of Science:

• Cardiovascular Research
• Immunology
• Molecular Biology

Background:

• Apolipoprotein E (apo E) deficiency in mice is a common model for studying atherosclerosis.
• Tenascin-C (TNC) is an extracellular matrix protein implicated in various biological processes, including inflammation and tissue repair.
• The role of inflammatory cytokines in the pathogenesis of atherosclerosis in apo E-/- mice, particularly in relation to TNC, requires further elucidation.

Purpose of the Study:

• To investigate the impact of Tenascin-C (TNC) gene deletion on inflammatory cytokine profiles in apolipoprotein E-deficient (apo E-/-) mice.
• To determine the specific role of eotaxin, a key inflammatory chemokine, in the development of atherosclerosis in this mouse model.
• To explore the regulatory mechanisms by which TNC influences eotaxin expression and subsequent mast cell recruitment.

Main Methods:

• Comparative analysis of circulating inflammatory cytokine profiles using antibody arrays and ELISA in apo E-/- and apo E-/- TNC-/- double knockout mice.
• In vitro studies using endothelial cells and tissue culture to assess eotaxin expression and regulation.
• Reporter gene assays to investigate TNC's transcriptional control over eotaxin expression.
• Histochemical analysis of aortic sections and mast cell migration assays to evaluate the in vivo effects.

Main Results:

• TNC gene deletion in apo E-/- mice led to a marked and selective increase in circulating eotaxin levels.
• Eotaxin levels directly correlated with the extent of atherosclerosis in apo E-/- mice.
• TNC regulates eotaxin expression at the transcriptional level, with TNC deficiency enhancing eotaxin production by endothelial cells.
• Apo E-/- TNC-/- mice exhibited massive mast cell accumulation in aortic lesions, a phenomenon not observed in control mice.
• Plasma from double knockout mice significantly stimulated mast cell migration, unlike plasma from control mice.

Conclusions:

• Tenascin-C (TNC) expression critically controls eotaxin levels in apo E-/- mice.
• Eotaxin plays a pivotal role in the development of atherosclerosis, partly through TNC-mediated regulation and mast cell recruitment.
• These findings suggest TNC as a potential therapeutic target for atherosclerosis.