Inhibition of progression and stabilization of plaques by postnatal interferon-γ function blocking in ApoE-Knockout mice

A role of interferon- gamma is suggested in early development of atherosclerosis. However, the role of interferon- gamma in progression and destabilization of advanced atherosclerotic plaques remains unknown. Thus, the aim of this study was to determine whether postnatal inhibition of interferon- gamma signaling could inhibit progression of atherosclerotic plaques and stabilize the lipid- and macrophage- rich advanced plaques. Atherosclerotic plaques were induced in ApoE- knockout ( KO) mice by feeding high- fat diet from 8 weeks old ( w). Interferon- gamma function was postnatally inhibited by repeated gene transfers of a soluble mutant of interferon- gamma receptors ( sIFN gamma R), an interferon- gamma inhibitory protein, into the thigh muscle every 2 weeks. When sIFN gamma R treatment was started at 12 w ( atherosclerotic stage), sIFN gamma R not only prevented plaque progression but also stabilized advanced plaques at 16 w: sIFN gamma R decreased accumulations of the lipid and macrophages and increased fibrotic area with more smooth muscle cells. Moreover, sIFN gamma R downregulated expressions of proinflammatory cytokines, chemokines, adhesion molecules, and matrix metalloproteinases but upregulated procollagen type I. sIFN gamma R did not affect serum cholesterol levels. In conclusion, postnatal blocking of interferon- gamma function by sIFN gamma R treatment would be a new strategy to inhibit plaque progression and to stabilize advanced plaques through the antiinflammatory effects.