Van Vickle-Chavez Sarah J, Tung William S, Absi Tarek S, Ennis Terri L, Mao Dongli, Cobb J Perren, Thompson Robert W
Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
J Vasc Surg. 2006 May;43(5):1010-20. doi: 10.1016/j.jvs.2006.01.004.
To characterize temporal changes in mouse aortic wall gene expression associated with the development of experimental abdominal aortic aneurysms.
C57BL/6 mice underwent transient perfusion of the abdominal aorta with either elastase (n = 61) or heat-inactivated elastase as a control (n = 68). Triplicate samples of radiolabeled aortic wall complementary DNA were prepared at intervals of 0, 3, 7, 10, and 14 days, followed by hybridization to nylon microarrays (1181 genes). Autoradiographic intensity data were normalized by conversion to z scores, and differences in gene expression were defined by two-tailed z tests at a significance threshold of P < .01.
Elastase perfusion caused a progressive increase in aortic diameter up to 14 days accompanied by transmural inflammation and destructive remodeling of the elastic media. No aneurysms occurred in the control group. Compared with healthy aorta, 336 genes exhibited significant alterations during at least 1 interval after elastase perfusion (135 at more than 1 interval and 14 at all intervals), with pronounced increases for interleukin 6, cyclin E2, interleukin 1beta, osteopontin, CD14/lipopolysaccharide receptor, P-selectin glycoprotein ligand 1, and gelatinase B/matrix metalloproteinase 9 (all >20-fold on day 3). Sixty-two genes exhibited synchronous alterations in the elastase and control groups, thus suggesting a nonspecific response. By direct comparisons between the elastase and control groups, there were 384 genes with significant differences in expression for at least 1 interval after aortic perfusion, including 234 with differential upregulation (eg, p44MAPK/ERK1, osteopontin, heat shock protein 84, hypoxia-inducible factor 1alpha, apolipoprotein E, monocyte chemotactic protein 3, MIG (monokine induced by gamma interferon), and interleukin 2 receptor gamma) and 163 with differential downregulation (eg, prothrombin, granzyme B, ataxia telangiectasia mutated, and interleukin-converting enzyme).
Development of elastase-induced abdominal aortic aneurysms in mice is accompanied by altered aortic wall expression of genes associated with acute and chronic inflammation, matrix degradation, and vascular tissue remodeling. Knowledge of these alterations will facilitate further studies on the functional molecular mechanisms that underlie aneurysmal degeneration.
描述与实验性腹主动脉瘤发展相关的小鼠主动脉壁基因表达的时间变化。
C57BL/6小鼠接受腹主动脉短暂灌注弹性蛋白酶（n = 61）或热灭活弹性蛋白酶作为对照（n = 68）。在0、3、7、10和14天的间隔时间制备放射性标记的主动脉壁互补DNA的一式三份样本，随后与尼龙微阵列（1181个基因）杂交。通过转换为z分数对放射自显影强度数据进行归一化，并通过双尾z检验在P <.01的显著性阈值下定义基因表达差异。
弹性蛋白酶灌注导致主动脉直径在14天内逐渐增加，伴有透壁炎症和弹性中膜的破坏性重塑。对照组未发生动脉瘤。与健康主动脉相比，336个基因在弹性蛋白酶灌注后的至少1个间隔期内表现出显著变化（135个在多个间隔期内变化，14个在所有间隔期内变化），白细胞介素6、细胞周期蛋白E2、白细胞介素1β、骨桥蛋白、CD14/脂多糖受体、P-选择素糖蛋白配体1和明胶酶B/基质金属蛋白酶9显著增加（第3天均>20倍）。62个基因在弹性蛋白酶组和对照组中表现出同步变化，因此提示为非特异性反应。通过弹性蛋白酶组和对照组之间的直接比较，在主动脉灌注后的至少1个间隔期内有384个基因表达存在显著差异，包括234个上调差异基因（如p44MAPK/ERK1、骨桥蛋白、热休克蛋白84、缺氧诱导因子1α、载脂蛋白E、单核细胞趋化蛋白3、MIG（γ干扰素诱导的单核因子）和白细胞介素2受体γ）和163个下调差异基因（如凝血酶原、颗粒酶B、共济失调毛细血管扩张突变基因和白细胞介素转化酶）。
小鼠弹性蛋白酶诱导的腹主动脉瘤的发展伴随着与急性和慢性炎症、基质降解及血管组织重塑相关的主动脉壁基因表达改变。了解这些改变将有助于进一步研究动脉瘤退变的功能分子机制。
