Atherosclerosis is a chronic inflammatory disorder of the vasculature regulated by cytokines. We have previously shown that extracellular signal-regulated kinase-1/2 (ERK1/2) plays an important role in serine 727 phosphorylation of signal transducer and activator of transcription-1 (STAT1) transactivation domain, which is required for maximal interferon-γ signaling, and the regulation of modified LDL uptake by macrophages in vitro. Unfortunately, the roles of ERK1/2 and STAT1 serine 727 phosphorylation in atherosclerosis are poorly understood and were investigated using ERK1 deficient mice (ERK2 knockout mice die in utero) and STAT1 knock-in mice (serine 727 replaced by alanine; STAT1 S727A). Mouse Atherosclerosis RT² Profiler PCR Array analysis showed that ERK1 deficiency and STAT1 S727A modification produced significant changes in the expression of 18 and 49 genes, respectively, in bone marrow-derived macrophages, with 17 common regulated genes that included those that play key roles in inflammation and cell migration. Indeed, ERK1 deficiency and STAT1 S727A modification attenuated chemokine-driven migration of macrophages with the former also impacting proliferation and the latter phagocytosis. In LDL receptor deficient mice fed a high fat diet, both ERK1 deficiency and STAT1 S727A modification produced significant reduction in plaque lipid content, albeit at different time points. The STAT1 S727A modification additionally caused a significant reduction in plaque content of macrophages and CD3 T cells and diet-induced cardiac hypertrophy index. In addition, there was a significant increase in plasma IL-2 levels and a trend toward increase in plasma IL-5 levels. These studies demonstrate important roles of STAT1 S727 phosphorylation in particular in the regulation of atherosclerosis-associated macrophage processes in vitro together with plaque lipid content and inflammation in vivo, and support further assessment of its therapeutical potential.

中文翻译：

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信号转导和转录激活因子 1 丝氨酸 727 磷酸化在 LDL 受体缺陷小鼠中通过调节斑块炎症的促动脉粥样硬化作用

动脉粥样硬化是一种由细胞因子调节的脉管系统慢性炎症性疾病。我们之前已经表明，细胞外信号调节激酶 1/2 (ERK1/2) 在信号转导和转录激活因子 1 (STAT1) 反式激活结构域的丝氨酸 727 磷酸化中起重要作用，这是最大干扰素-γ 所必需的信号传导，以及体外巨噬细胞对修饰的 LDL 摄取的调节。不幸的是，ERK1/2 和 STAT1 丝氨酸 727 磷酸化在动脉粥样硬化中的作用知之甚少，并使用 ERK1 缺陷小鼠（ERK2 敲除小鼠在子宫内死亡）进行了研究）和 STAT1 敲入小鼠（丝氨酸 727 被丙氨酸取代；STAT1 S727A）。小鼠动脉粥样硬化 RT² Profiler PCR Array 分析表明，ERK1 缺陷和 STAT1 S727A 修饰分别导致骨髓巨噬细胞中 18 个和 49 个基因的表达发生显着变化，其中 17 个常见的调节基因包括那些在炎症中起关键作用的基因和细胞迁移。事实上，ERK1 缺乏和 STAT1 S727A 修饰减弱了趋化因子驱动的巨噬细胞迁移，前者也影响增殖和后者的吞噬作用。在喂食高脂肪饮食的 LDL 受体缺陷小鼠中，ERK1 缺乏和 STAT1 S727A 修饰均导致斑块脂质含量显着降低，尽管时间点不同。STAT1 S727A 修饰还导致巨噬细胞和 CD3 T 细胞的斑块含量和饮食诱导的心脏肥大指数显着降低。此外，血浆IL-2水平显着升高，血浆IL-5水平呈升高趋势。这些研究证明了 STAT1 S727 磷酸化的重要作用，特别是在体外调节与动脉粥样硬化相关的巨噬细胞过程以及斑块脂质含量和体内炎症，并支持进一步评估其治疗潜力。