Cross-talk between angiotensin II receptor and cytokines in vascular disease

在没有AT2受体的小鼠中，股动脉袖带植入后血管平滑肌细胞（VSMC）的新内膜形成和DNA合成被夸大，但在没有AT1a受体的小鼠中被抑制。AT1a受体缺失小鼠损伤动脉VSMC中凋亡细胞数量明显增加，AT2受体缺失小鼠凋亡细胞数量明显减少。此外，袖带的放置增加了MCP-1、炎症细胞因子如TNF-a、IL-6和IL-1b的表达以及cd45阳性白细胞和巨噬细胞在损伤动脉中的浸润，并在AT2受体缺失的小鼠中进一步增强，提示AT1和AT2受体对血管炎症的拮抗作用。我们也证实了AT2受体在人类冠状动脉粥样硬化病变中表达。我们在-453和-225位之间的负调控区发现了干扰素调节因子（IRF）结合基序，并证明了AT2受体在这些细胞中的表达受到两个相关IRF （IRF-1和IRF-2）的竞争性结合的转录调节，并证明了IFN-g通过激活细胞内Jak/STAT通路和IRF-1的产生来上调AT2受体在R3T3细胞中的表达。为了测试IRF-1在血管重构中的生理相关性，我们使用IRF-1缺失小鼠，观察到与野生型小鼠相比，IRF-1缺失小鼠损伤动脉中AT2受体表达与新内膜形成增加、VSMC DNA合成增加以及VSMC凋亡变化减少的相关性较低。

Neointimal formation and DNA synthesis in vascular smooth muscle cell (VSMC) after cuff placement in the femoral artery were exaggerated in AT2 receptor null mice, but suppressed in AT1a receptor null mice. The number of apoptotic cells in VSMC in the injured artery was significantly increased in AT1a receptor null mice, but decreased in AT2 receptor null mice. Moreover, cuff placement increased the expression of MCP-1, inflammatory cytokines such as TNF-a, IL-6, and IL-1b and infiltration of CD45-positive leukocytes and macrophage in the injured arteries and further enhanced in AT2 receptor null mice, suggesting the antagonistic effects of AT1 and AT2 receptors and vascular inflammation. We also demonstrated that AT2 receptor was expressed in human coronary atherosclerotic lesions. We have identified the interferon regulatory factor (IRF) binding motif in a negative regulatory region between positions -453 and -225, and demonstrated that the expression of AT2 receptor in these cells is transcriptionally regulated by the competitive binding of two related IRFs (IRF-1 and IRF-2) and demonstrated that that IFN-g upregulated AT2 receptor expression in R3T3 cells via the activation of the intracellular Jak/STAT pathway and production of IRF-1. To test the physiological relevance of the role of IRF-1 in vascular remodeling, we employed IRF-1 null mice and observed that AT2 receptor expression was low associated with increase in neointimal formation, increase in DNA synthesis in VSMC, and decrease in apoptotic changes in VSMC in the injured artery of IRF-1 null mice compared to those in wild type mice.