title: Inhibition of progression and stabilization of plaques by postnatal interferon-gamma function blocking in ApoE-knockout mice.
abstract: 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 (sIFNgammaR), an interferon-gamma inhibitory protein, into the thigh muscle every 2 weeks. When sIFNgammaR treatment was started at 12 w (atherosclerotic stage), sIFNgammaR not only prevented plaque progression but also stabilized advanced plaques at 16 w: sIFNgammaR decreased accumulations of the lipid and macrophages and increased fibrotic area with more smooth muscle cells. Moreover, sIFNgammaR downregulated expressions of proinflammatory cytokines, chemokines, adhesion molecules, and matrix metalloproteinases but upregulated procollagen type I. sIFNgammaR did not affect serum cholesterol levels. In conclusion, postnatal blocking of interferon-gamma function by sIFNgammaR treatment would be a new strategy to inhibit plaque progression and to stabilize advanced plaques through the antiinflammatory effects.
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, Kurume University, Fukuoka, Japan.
authors.forename: Mitsuhisa
authors.initials: M
authors.lastname: Koga
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kai
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Tomoka
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kawai
authors.forename: Seiya
authors.initials: S
authors.lastname: Kato
authors.forename: Ken
authors.initials: K
authors.lastname: Kusaba
authors.forename: Mamiko
authors.initials: M
authors.lastname: Kai
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kataoka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010957:Plasmids; D017471:Receptors, Interferon / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D001057:Apolipoproteins E; D019013:CD40 Antigens; D023201:CD40 Ligand; D004041:Dietary Fats; D007371:Interferon-gamma; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse