DiMusto Paul D, Lu Guanyi, Ghosh Abhijit, Roelofs Karen J, Sadiq Omar, McEvoy Brendan, Su Gang, Laser Adriana, Bhamidipati Castigliano M, Ailawadi Gorav, Henke Peter K, Eliason Jonathan L, Upchurch Gilbert R
Jobst Vascular Research Laboratory, University of Michigan, Ann Arbor, Michigan, USA.
J Surg Res. 2012 Aug;176(2):687-95. doi: 10.1016/j.jss.2011.11.1024. Epub 2011 Dec 14.
In humans, there is a 4:1 male:female ratio in the incidence of abdominal aortic aneurysms (AAAs). c-Jun-N-terminal kinase (JNK) is an important upstream regulator of several enzymes involved in AAA formation, including the matrix metalloproteinases (MMPs). The purpose of this study was to determine if there is a gender difference between males and females in JNK during AAA formation.
Male and female C57/B6 mice underwent aortic perfusion with elastase or heat inactivated elastase with aortas harvested at d 3 and 14 for phenotype determination, RT-PCR, Western blot, and zymography. Additionally, in vitro experiments using siRNA were conducted to define JNK regulation of matrix metalloproteinases (MMPs). A t-test was used to compare between groups.
Males formed larger AAAs at d 14 compared with females (P < 0.001), with significantly higher levels of JNK1 protein, proMMP9, proMMP2, and active MMP2. At d 3, males had more JNK1 mRNA, protein, and MMP activity. Knockdown of JNK 1 or 2 in vitro decreased MMP activity, while knockdown of JNK 1 and 2 together blocked all MMP activity.
Alterations in JNK between genders is partially responsible for the differential rates of experimental AAA formation, likely through differential regulation of MMPs.
在人类中，腹主动脉瘤（AAA）的发病率存在4:1的男性与女性比例。c-Jun氨基末端激酶（JNK）是参与AAA形成的几种酶（包括基质金属蛋白酶（MMP））的重要上游调节因子。本研究的目的是确定在AAA形成过程中，男性和女性在JNK方面是否存在性别差异。
雄性和雌性C57/B6小鼠接受弹性蛋白酶或热灭活弹性蛋白酶的主动脉灌注，在第3天和第14天采集主动脉用于表型测定、逆转录聚合酶链反应（RT-PCR）、蛋白质印迹法和酶谱分析。此外，进行了使用小干扰RNA（siRNA）的体外实验，以确定JNK对基质金属蛋白酶（MMP）的调节作用。采用t检验进行组间比较。
与雌性相比，雄性在第14天形成的AAA更大（P < 0.001），JNK1蛋白、前MMP9、前MMP2和活性MMP2的水平显著更高。在第3天，雄性具有更多的JNK1信使核糖核酸（mRNA）、蛋白质和MMP活性。体外敲低JNK 1或2可降低MMP活性，而同时敲低JNK 1和2则可阻断所有MMP活性。
性别之间JNK的改变部分导致了实验性AAA形成速率的差异，可能是通过对MMP的不同调节实现的。
