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

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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.