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

血管疾病中血管紧张素 II 受体与细胞因子之间的相互作用

基本信息

批准号：
12470156
负责人：
HORIUCHI Masatsugu
金额：
$ 8.7万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470156/
关键词：
angioteasin receptor vascular remodeling cytokine transcription factor gene-engineered mouse vascular inflammation IRF-1

项目摘要

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.

在AT 2受体敲除小鼠中，血管平滑肌细胞（VSMC）中的新生内膜形成和DNA合成在股动脉中被放大，但在AT 1a受体敲除小鼠中被抑制。AT 1a受体敲除小鼠血管平滑肌细胞凋亡数明显增加，而AT 2受体敲除小鼠血管平滑肌细胞凋亡数明显减少。此外，袖带放置增加了MCP-1，炎症细胞因子如TNF-α，IL-6和IL-1b的表达以及损伤动脉中CD 45阳性白细胞和巨噬细胞的浸润，并进一步增强了AT 2受体敲除小鼠，表明AT 1和AT 2受体与血管炎症的拮抗作用。我们还证实了AT 2受体在人冠状动脉粥样硬化病变中表达。我们已经在-453和-225位之间的负调控区中鉴定了干扰素调节因子（IRF）结合基序，并证明在这些细胞中AT 2受体的表达是通过两个相关IRF的竞争性结合来转录调节的（IRF-1和IRF-2），并证明IFN-g通过激活细胞内Jak/STAT途径和产生IRF-1上调R3 T3细胞中AT 2受体的表达。为了测试IRF-1在血管重塑中的作用的生理相关性，我们采用IRF-1裸小鼠，并观察到与野生型小鼠相比，IRF-1裸小鼠的损伤动脉中AT 2受体表达低，与新生内膜形成增加、VSMC中DNA合成增加和VSMC中凋亡变化减少相关。