Postnatal blocking of interferon-γ function prevented atherosclerotic plaque formation in apolipoprotein E-knockout mice

Abstract

It is unknown whether interferon-γ has a positive or negative impact on atherosclerotic plaque formation. Thus, we examined the effects of postnatal interferon-γ function blocking on plaque formation in apolipoprotein E-knockout (apoEKO) mice by overexpressing a soluble mutant of interferon-γ receptor (sIFNγR), an interferon-γ inhibitory protein. Mice were fed a Western-type diet from 8 weeks of age. sIFNγR or mock plasmid (control) was injected into the thigh muscle at 8 and 10 weeks' age, because serum sIFNγR protein was transiently increased with a peak at 2 days after a single sIFNγR 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 sIFNγR-treated apoEKO mice. sIFNγR 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, interieukin-1β, monocyte chemoattractant protein-1, and vascular cell adhesion molecules-1 were remarkably upregulated in the aortic wall. These changes were significantly reversed by sIFNγR. sIFNγR treatment had no effects on serum cholesterol levels. In conclusion, sIFNγR 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.