Inhibition of progression and stabilization of plaques by postnatal interferon-gamma 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 (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.
Koga
Mitsuhisa
M
Department of Internal Medicine, Division of Cardiovascular Medicine, Kurume University, Fukuoka, Japan.
Kai
Hisashi
H
Yasukawa
Hideo
H
Yamamoto
Tomoka
T
Kawai
Yumiko
Y
Kato
Seiya
S
Kusaba
Ken
K
Kai
Mamiko
M
Egashira
Kensuke
K
Kataoka
Yasufumi
Y
Imaizumi
Tsutomu
T
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
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