Jobst Vascular Research Laboratory, Department of Surgery, University of Michigan, Ann Arbor, USA.
Am J Physiol Heart Circ Physiol. 2012 Apr 1;302(7):H1378-86. doi: 10.1152/ajpheart.00620.2011. Epub 2012 Feb 3.
The serine proteases, along with their inhibitor plasmin activator inhibitor-1 (PAI-1), have been shown to play a role in abdominal aortic aneurysm (AAA) formation. The aim of this study is to determine if PAI-1 may be a protective factor for AAA formation and partially responsible for the gender difference observed in AAAs. Male and female wild-type (WT) C57BL/6 and PAI-1(-/-) mice 8-12 wk of age underwent aortic perfusion with porcine pancreatic elastase. Animals were harvested 14 days following perfusion and analyzed for phenotype, PAI-1 protein levels, and matrix metalloproteinase (MMP)-9 and -2 activity. WT males had an average increase in aortic diameter of 80%, whereas females only increased 32% (P < 0.001). PAI-1(-/-) males increased 204% and females 161%, significantly more than their WT counterparts (P < 0.001). Western blot revealed 61% higher PAI-1 protein levels in the WT females compared with the WT males (P = 0.01). Zymography revealed higher levels of pro-MMP-2 and active MMP-2 in the PAI-1(-/-) males and females compared with their WT counterparts. PAI-1(-/-) females had significantly higher serum plasmin levels compared with WT females (P = 0.003). In conclusion, WT female mice are protected from aneurysm formation and have higher levels of PAI-1 compared with males during experimental aneurysm formation. Additionally, both male and female PAI-1(-/-) animals develop significantly larger aneurysms than WT animals, correlating with higher pro- and active MMP-2 levels. These findings suggest that PAI-1 is protective for aneurysm formation in the elastase model of AAA and plays a role in the gender differences seen in AAA formation.
丝氨酸蛋白酶及其抑制剂纤溶酶原激活物抑制剂-1（PAI-1）已被证明在腹主动脉瘤（AAA）形成中发挥作用。本研究旨在确定 PAI-1 是否可能是 AAA 形成的保护因素，并部分解释在 AAAs 中观察到的性别差异。8-12 周龄的雄性和雌性野生型（WT）C57BL/6 和 PAI-1（-/-）小鼠接受猪胰腺弹性蛋白酶主动脉灌注。灌注后 14 天收获动物，并分析表型、PAI-1 蛋白水平以及基质金属蛋白酶（MMP）-9 和 -2 活性。WT 雄性的主动脉直径平均增加 80%，而雌性仅增加 32%（P < 0.001）。PAI-1（-/-）雄性增加 204%，雌性增加 161%，明显高于其 WT 对应物（P < 0.001）。Western blot 显示 WT 雌性的 PAI-1 蛋白水平比 WT 雄性高 61%（P = 0.01）。酶谱法显示 PAI-1（-/-）雄性和雌性的前 MMP-2 和活性 MMP-2 水平明显高于其 WT 对应物。PAI-1（-/-）雌性的血清纤溶酶水平明显高于 WT 雌性（P = 0.003）。结论：在实验性动脉瘤形成期间，WT 雌性小鼠免受动脉瘤形成的影响，并且比雄性具有更高水平的 PAI-1。此外，PAI-1（-/-）雄性和雌性动物的动脉瘤均比 WT 动物大得多，与前 MMP-2 和活性 MMP-2 水平升高相关。这些发现表明 PAI-1 对弹性蛋白酶 AAA 模型中的动脉瘤形成具有保护作用，并在 AAA 形成中的性别差异中发挥作用。
