Study on the mechanism of atherosclerotic lesion formation using cytokine-knockout mouse

1.在对TNF-α^<-/-> apoE^<-/->双KO小鼠与apoE^<-/->双KO小鼠的比较研究中，双KO小鼠动脉粥样硬化病变面积明显减少。此外，双KO小鼠黏附分子icam -1、vcam -1的表达也被显著抑制。这些发现表明，粘附分子的增强表达至少在一定程度上参与了TNF-α 2的动脉粥样硬化作用。与apoE^<-/-> KO小鼠相比，IFN-γ^<-/-> apoE^<-/->双KO小鼠的动脉粥样硬化病变显著减少，ICAM-1和VCAM-1 mRNA水平显著降低。提示包括单核细胞在内的单核细胞被IL-1β募集到动脉壁上，导致动脉粥样硬化病变的形成。IFN-γ^<-/->BMT小鼠在主动脉窦、主动脉弓和腹主动脉的动脉粥样硬化病变大于IFN-γ^<+/+>BMT小鼠。这些发现表明，骨髓源性细胞产生的IFN-γ延缓了动脉粥样硬化的进展，而对血浆脂质没有任何影响，这种抑制可能是由于细胞外基质沉积减少。在本研究中，我们在体内研究中阐明了TNF-α和IL-1β通过增加粘附分子的表达来加速动脉粥样硬化。然而，来自骨髓的IFN-y至少在初始阶段抑制动脉粥样硬化。

1.In the study on the comparison of TNF-α^<-/-> apoE^<-/-> double KO mouse with apoE^<-/-> KO mice, the area of atherosclerotic lesion was significantly reduced in double KO mice. In addition, the expression of adhesion molecules such as ICAM-1and VCAM-1was also significantly suppressed in double KO mouse. These fidings suggest that augumented expression of adhesion molecules is, at least in part, involved in the atherosclerotic action of TNF-α.2.The atherosclerotic lesion was significantly reduced in IFN-γ^<-/-> apoE^<-/-> double KO mice compared with apoE^<-/-> KO mice and mRNA levels of ICAM-1 and VCAM-1 were significantly decreased in double KO mice. It is suggested that mononuclear cells including monocytes are recruited to arterial wall by IL-1β, resulting in the formation of atherosclerotic lesion.3.The atherosclerotic lesions of IFN-γ^<-/->BMT mice were larger than those of IFN-γ^<+/+>BMT mice at the aortic sinus, aortic arch and abdominal aorta. These findings show that IFN-γ produced by bone marrow-derived cells delays the progression of atherosclerosis without any effects on plasma lipids, and this suppression may be due to decreased extracellular matrix deposition.In this study, we clarified that TNF-α and IL-1β accelerate atherosclerosis via the augumented expression of adhesion molecules in vivo study. However, IFN-y derived from bone marrow rather suppressed atherosclerosis at least in the initial stage.