title: Postnatal blocking of interferon-gamma function prevented atherosclerotic plaque formation in apolipoprotein E-knockout mice.
abstract: It is unknown whether interferon-gamma has a positive or negative impact on atherosclerotic plaque formation. Thus, we examined the effects of postnatal interferon-gamma function blocking on plaque formation in apolipoprotein E-knockout (apoEKO) mice by overexpressing a soluble mutant of interferon-gamma receptor (sIFNgammaR), an interferon-gamma inhibitory protein. Mice were fed a Western-type diet from 8 weeks of age. sIFNgammaR or mock plasmid (control) was injected into the thigh muscle at 8 and 10 weeks' age, because serum sIFNgammaR protein was transiently increased with a peak at 2 days after a single sIFNgammaR gene transfer and remained elevated for 2 weeks. At 12 weeks' age, control apoEKO mice showed marked atherosclerotic plaques from the ascending aorta to the aortic arch. The plaques in the aortic root had massive lipid cores and macrophage infiltration with thin fibrous cap and few smooth muscle cells, demonstrating low plaque stability. In contrast, the luminal plaque area was remarkably reduced in sIFNgammaR-treated apoEKO mice. sIFNgammaR treatment not only reduced lipid core areas and macrophage infiltration but also increased smooth muscle cell count and fibrotic area, suggesting improved plaque stability. In controls, interleukin-1beta, monocyte chemoattractant protein-1, and vascular cell adhesion molecules-1 were remarkably upregulated in the aortic wall. These changes were significantly reversed by sIFNgammaR. sIFNgammaR treatment had no effects on serum cholesterol levels. In conclusion, sIFNgammaR treatment prevented plaque formation in apoEKO mice by inhibiting inflammatory changes in the arterial wall. The present study provides insight into a new strategy for preventing atherosclerosis.
authors.affiliation: Department of Internal Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine, 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: Seiya
authors.initials: S
authors.lastname: Kato
authors.forename: Tomoka
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kawai
authors.forename: Ken
authors.initials: K
authors.lastname: Kusaba
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Seki
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 / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D050197:Atherosclerosis / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D002097:C-Reactive Protein / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D004247:DNA / Q000235:genetics / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000502:physiology*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D010538:Peritonitis / Q000503:physiopathology; D017471:Receptors, Interferon / Q000235:genetics / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D001057:Apolipoproteins E; D002097:C-Reactive Protein; D018932:Chemokine CCL2; D008076:Cholesterol, HDL; D004247:DNA; D007371:Interferon-gamma; D053583:Interleukin-1beta; D017471:Receptors, Interferon; D019010:Vascular Cell Adhesion Molecule-1; D000096743:Interferon gamma Receptor; C491768:Ccl2 protein, mouse