The TNF alpha converting enzyme (TACE/ADAM17) is expressed in the atherosclerotic lesions of apolipoprotein E-deficient mice: possible contribution to elevated plasma levels of soluble TNF alpha receptors.

ABSTRACT

TNF alpha converting enzyme (TACE) critically regulates the inflammatory processes as it releases from the cell surface several transmembrane proteins, including TNFalpha (TNF) and its receptors TNFR1 and TNFR2. We investigated the expression of TACE in atherosclerotic lesions of apolipoproteinE-deficient (apoE (-/-)) mice. Five-week-old apoE(-/-) male mice were fed a high-fat diet and examined at 5, 10, 15 and 25 weeks of age. A group of wild-type C57BL/6 mice (WT) fed the high-fat diet for 25 weeks was included. In apoE(-/-) mice, lesions progressed with time in both aortic sinus and arch, in which TACE immunostaining also increased particularly between 5 and 15 weeks. TACE expression was also observed in human atherosclerotic plaques. The plasma levels of soluble TNFR1 and TNFR2 rose with atherosclerosis. In the 25-week-old WT mice, no lesions were observed and the plasma levels of TNFRs were 17% of those of age-matched apoE(-/-) mice. Incubated aortas of 25-week-old apoE(-/-) mice released much higher amounts of sTNF and sTNFRs than did aortas of 5-week-old apoE(-/-) mice or 25-week-old WT mice. Active TACE was expressed at the surface of macrophages isolated from apoE(-/-) mice. In conclusion, TACE expression is associated with lesions in atherosclerosis-prone sites. Our data suggest that atherosclerotic lesions-expressing TACE may contribute to the elevated levels of circulating sTNFRs.