Section of Vascular Surgery, Department of Surgery, Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, MI, USA.
J Am Coll Surg. 2012 Nov;215(5):668-680.e1. doi: 10.1016/j.jamcollsurg.2012.06.414. Epub 2012 Aug 21.
It is hypothesized that activation of extracellular signal-related kinase (ERK) is critical in activating matrix metalloproteinases (MMPs) during abdominal aortic aneurysm (AAA) formation.
C57BL/6 male mice underwent either elastase or heat-inactivated elastase aortic perfusion (n = 9 per group). Mouse aortic smooth muscle cells were transfected with ERK-1 and 2 siRNA along with or without elastase treatment. Mouse and human aortic tissue were analyzed by Western blots, zymograms, and immunohistochemistry, and statistical analysis was done using Graphpad and Image J softwares.
Western blot and immunohistochemistry documented increased phospho-mitogen-activated protein kinase kinase-1/2 (pMEK-1/2; 153%, p = 0.270 by Western) and pERK (171%, p = 0.004 by Western blot) in the elastase perfused aortas. Male ERK-1(-/-) mice underwent elastase perfusion, and aortic diameter was determined at day 14. ERK-1(-/-) mice failed to develop AAA, and histologic analysis depicted intact collagen and elastin fibers in the aortas. Zymography of aortas of elastase-treated ERK-1(-/-) mice showed lower levels of proMMP2 (p < 0.005) and active MMP2 (p < 0.0001), as well as proMMP9 (p = 0.037) compared with C57BL/6 mice. siRNA transfection of ERK-1 and -2 significantly reduced formation of pro- and active MMP2 (p < 0.01 for both isoforms) in aortic smooth muscle cells treated with elastase in vitro. Human AAA tissue had significantly elevated levels of pMEK-1/2 (150%, p = 0.014) and pERK (159%, p = 0.013) compared with control tissues.
The MAPK (mitogen-activated protein kinase)/ERK pathway is an important modulator of MMPs during AAA formation. Targeting the ERK pathway by reagents that inhibit either the expression or phosphorylation of ERK isoforms could be a potential therapy to prevent AAA formation.
据推测，细胞外信号相关激酶（ERK）的激活在腹主动脉瘤（AAA）形成过程中对于激活基质金属蛋白酶（MMPs）至关重要。
C57BL/6 雄性小鼠接受弹性蛋白酶或热失活弹性蛋白酶主动脉灌注（每组 9 只）。用 ERK-1 和 2 siRNA 转染小鼠主动脉平滑肌细胞，并进行弹性蛋白酶处理。通过 Western 印迹、酶谱和免疫组织化学分析小鼠和人主动脉组织，并使用 Graphpad 和 Image J 软件进行统计分析。
Western 印迹和免疫组织化学记录表明，弹性蛋白酶灌注的主动脉中磷酸化丝裂原活化蛋白激酶激酶-1/2（pMEK-1/2；Western 印迹 153%，p = 0.270）和 pERK（171%，p = 0.004）增加。雄性 ERK-1（-/-）小鼠接受弹性蛋白酶灌注，在第 14 天测量主动脉直径。ERK-1（-/-）小鼠未能发展为 AAA，并且主动脉的组织学分析显示胶原和弹性纤维完整。弹性蛋白酶处理的 ERK-1（-/-）小鼠的主动脉酶谱显示前 MMP2（p < 0.005）和活性 MMP2（p < 0.0001）以及前 MMP9（p = 0.037）水平较低与 C57BL/6 小鼠相比。ERK-1 和 -2 的 siRNA 转染显着减少了体外弹性蛋白酶处理的主动脉平滑肌细胞中前 MMP2 和活性 MMP2 的形成（两种同工型均为 p <0.01）。与对照组织相比，人 AAA 组织中 pMEK-1/2（150%，p = 0.014）和 pERK（159%，p = 0.013）水平显着升高。
MAPK（丝裂原活化蛋白激酶）/ERK 途径是 AAA 形成过程中 MMPs 的重要调节剂。通过抑制 ERK 同工型的表达或磷酸化的试剂靶向 ERK 途径可能是预防 AAA 形成的潜在治疗方法。
