Koga Mitsuhisa, Kai Hisashi, Yasukawa Hideo, Kato Seiya, Yamamoto Tomoka, Kawai Yumiko, Kusaba Ken, Seki Yukihiko, Kai Mamiko, Egashira Kensuke, Kataoka Yasufumi, Imaizumi Tsutomu
Department of Internal Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine, Japan.
Hypertens Res. 2007 Mar;30(3):259-67. doi: 10.1291/hypres.30.259.
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.
γ干扰素对动脉粥样硬化斑块形成的影响尚不清楚。因此，我们通过过表达γ干扰素受体的可溶性突变体（sIFNγR）（一种γ干扰素抑制蛋白），研究了产后γ干扰素功能阻断对载脂蛋白E基因敲除（apoEKO）小鼠斑块形成的影响。小鼠从8周龄开始喂食西式饮食。在8周龄和10周龄时，将sIFNγR或空质粒（对照）注射到大腿肌肉中，因为单次sIFNγR基因转移后2天血清sIFNγR蛋白短暂升高，峰值出现在2天，并且在2周内保持升高。在12周龄时，对照apoEKO小鼠从升主动脉到主动脉弓出现明显的动脉粥样硬化斑块。主动脉根部的斑块有大量脂质核心和巨噬细胞浸润，纤维帽薄且平滑肌细胞少，表明斑块稳定性低。相比之下，sIFNγR处理的apoEKO小鼠的管腔斑块面积显著减少。sIFNγR处理不仅减少了脂质核心面积和巨噬细胞浸润，还增加了平滑肌细胞数量和纤维化面积，提示斑块稳定性得到改善。在对照组中，白细胞介素-1β、单核细胞趋化蛋白-1和血管细胞黏附分子-1在主动脉壁中显著上调。这些变化被sIFNγR显著逆转。sIFNγR处理对血清胆固醇水平没有影响。总之，sIFNγR处理通过抑制动脉壁的炎症变化预防了apoEKO小鼠的斑块形成。本研究为预防动脉粥样硬化提供了一种新策略。
