Loss of STAT1 is associated with increased aortic rupture in an experimental model of aortic dissection and aneurysm formation
Loss of STAT1 is associated with increased aortic rupture in an experimental model of aortic dissection and aneurysm formation
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DOI：
10.1016/j.jvs.2009.11.075
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发表时间：
2010-04-01
影响因子：
4.3
通讯作者：
Graham, Linda M.
中科院分区：
文献类型：
--
作者：
Eagleton, Matthew J.;Xu, Jun;Graham, Linda M.
背景：转录因子信号转导和转录激活因子(STAT)1与多种病理状态有关，涉及基质重塑，但其在主动脉病理中的作用尚未见报道。本研究假设STAT1调节动脉瘤样变性，并在人腹主动脉瘤(AAA)和主动脉夹层小鼠模型中评价其作用。方法：在载脂蛋白E基因敲除小鼠(ApoE-/-)或ApoE/STAT1双基因敲除小鼠(ApoE/STAT1-/-)中注入1000 ng/kg/min血管紧张素II。处死时，用数字显微镜测量主动脉直径和动脉瘤形成范围。用酶联免疫吸附试验检测ApoE-/-小鼠0、7、14和28天(n=8/时间点)的STAT1和磷酸化STAT1蛋白水平。组织学采用苏木精-伊红(H&E)和Movat染色。统计分析包括卡方检验、t检验和方差分析。结果：人AAA组的STAT1信使RNA和总蛋白高于非AAA组。此外，在ApoE-/-小鼠中，分别有8%、50%和80%的小鼠在7、14和28天出现动脉瘤。在血管紧张素II输注过程中，总STAT1水平没有改变。磷酸化的STAT1水平在第7天达到峰值，是基线的1.4倍(P<；0.05)。在第3、5和28天，ApoE/STAT1-/-小鼠的动脉瘤发生率分别为0%、100%和100%。在血管紧张素II输注3天的小鼠中，ApoE/STAT-/-小鼠(53%比19%，P<；0.05)和更早的时间点(4.0+/-0.5d比9.2+/-0.77天，P<；0.05)比ApoE-/-小鼠更容易发生主动脉破裂。在血管紧张素II输注期间，两组间的SBP没有差异。28天时，ApoE/STAT1-/-小鼠的动脉瘤比ApoE-/-小鼠大(2.7+/-0.4vs1.9+/-0.1 mm，P<；0.05)，而且范围更广。H&E和Movat染色未显示ApoE-/-和ApoE/STAT1-/-小鼠在基线时的主动脉壁结构含量的差异。结论：在动脉瘤变性过程中，磷酸化的STAT1水平升高。在主动脉夹层的小鼠模型中，它的丢失与较高的急性主动脉破裂和更广泛的动脉瘤有关。有必要进行进一步的研究，以确定这些观察结果是否继发于基础的主动脉壁异常或血管壁基质重塑的改变。(《花瓶外科杂志》2010；51：951-61。)
Background: Transcription factor signal transducer and activator of transcription (STAT) 1 has been linked to a variety of pathologic states involved with matrix remodeling, but its role in aortic pathology has not been previously described. The current study hypothesized that STAT1 regulates aneurysmal degeneration and its role was evaluated in human abdominal aortic aneurysm (AAA) and in a mouse model of aortic dissection.Methods: Apolipoprotein E knockout mice (ApoE-/-) or ApoE/STAT1 double knockout mice (ApoE/STAT1-/-) were infused with 1000 ng/kg/min of angiotensin II. Systolic blood pressure (SBP) was measured in the rodent tail. At sacrifice, aortic diameters and extent of aneurysm formation were measured by digital microscopy. STAT1 and phosphorylated-STAT1 protein levels were assessed in ApoE-/- mice at 0, 7, 14, and 28 days (n = 8/time point) by enzyme-linked immunosorbent assay. Histology was performed using hematoxylin and eosin (H&E) and Movat stains. Statistical analyses included chi(2) test, t test, and analysis of variance.Results: STAT1 messenger RNA and total protein were greater in human AAA vs non-AAA controls. In addition, aneurysms occurred in 8%, 50%, and 80% of ApoE-/- mice at 7, 14, and 28 days, respectively. Total STAT1 levels were not altered during the course of angiotensin II infusion. Phosphorylated STAT1 levels peaked at 7 days with a 1.4-fold increase over baseline (P < .05). Aneurysms occurred in 0%, 100%, and 100% of ApoE/STAT1-/- mice at 3, 5, and 28 days. In mice infused with angiotensin II for >3 days, aortic rupture occurred more frequently in ApoE/STAT-/- mice (53% vs 19%, P < .05) and at earlier time points (4.0 +/- 0.5 vs 9.2 +/- 0.77 days, P < .05) vs ApoE-/- mice. SBP did not differ between the groups during angiotensin II infusion. By 28 days, aneurysms were larger in ApoE/STAT1-/- mice compared with ApoE-/- mice (2.7 +/- 0.4 vs 1.9 +/- 0.1 mm, P < .05) and were more extensive. H&E and Movat stain did not reveal differences in aortic wall structural content at baseline between ApoE-/- and ApoE/STAT1-/- mice. Both groups demonstrated equal disorganization in the aneurysmal state.Conclusions:Phosphorylated STAT1 is elevated during aneurysmal degeneration. Its loss is associated with a higher rate of acute aortic rupture and more extensive aneurysms in a mouse model of aortic dissection. Further investigation is necessary to determine whether these observations are secondary to an underlying aortic wall abnormality or alterations in vessel wall matrix remodeling. (J Vase Surg 2010;51:951-61.)