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.