Divergent Roles of Matrix Metalloproteinase 2 in Pathogenesis of Thoracic Aortic Aneurysm
Divergent Roles of Matrix Metalloproteinase 2 in Pathogenesis of Thoracic Aortic Aneurysm
复制标题
DOI：
10.1161/atvbaha.114.305115
复制
发表时间：
2015-04-01
影响因子：
8.7
通讯作者：
Kassiri, Zamaneh
中科院分区：
文献类型：
--
作者：
Shen, Mengcheng;Lee, Jiwon;Kassiri, Zamaneh
目的：主动脉动脉瘤，即主动脉局部扩张，由主动脉细胞外基质（ECM）完整性受损引起。基质金属蛋白酶（MMPs）传统上被称为ecm降解酶。在患者和动物模型中，MMP2与动脉瘤有关。我们通过2种主动脉重构和动脉瘤模型研究了MMP2在胸主动脉瘤中的作用。方法与结果：雄性10周龄MMP2缺陷（MMP2(-/-)）小鼠和野生型小鼠分别给予血管紧张素II （Ang II, 1.5 mg/kg/day）或生理盐水（Alzet泵）治疗4周。尽管两种基因型小鼠在注入Ang II后均表现出升主动脉扩张，但MMP2（-/-）小鼠的胸主动脉和胸主动脉瘤扩张更为严重。在MMP2（-/-）胸主动脉和平滑肌细胞中，Ang II诱导的弹性蛋白和胶原蛋白（mRNA和蛋白）的增加被明显抑制，而在MMP2(-/-) -Ang II腹主动脉中，只有mRNA水平降低。与MMP2缺失一致，与野生型angii胸腹主动脉相比，MMP2(-/-)- ang II的蛋白水解活性较低。体内和体外mmp2缺乏抑制了潜在转化生长因子-a和Smad2/3通路的激活。有趣的是，MMP2（-/-）小鼠对cacl2诱导的胸主动脉瘤有保护作用，cacl2诱导的胸主动脉瘤会引发ECM降解，但不会合成。结论：本研究揭示了MMP2在ECM降解和ECM合成中的双重作用。此外，与腹主动脉对异常ECM降解的易感性相比，胸主动脉对ECM合成受损的易感性更大，这为主动脉对动脉瘤发展的区域易感性提供了见解。
Objective-Aortic aneurysm, focal dilation of the aorta, results from impaired integrity of aortic extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are traditionally known as ECM-degrading enzymes. MMP2 has been associated with aneurysm in patients and in animal models. We investigated the role of MMP2 in thoracic aortic aneurysm using 2 models of aortic remodeling and aneurysm.Approach and Results-Male 10-week-old MMP2-deficient (MMP2(-/-)) and wild-type mice received angiotensin II (Ang II, 1.5 mg/kg/day) or saline (Alzet pump) for 4 weeks. Although both genotypes exhibited dilation of the ascending aorta after Ang II infusion, MMP2(-/-) mice showed more severe dilation of the thoracic aorta and thoracic aortic aneurysm. The Ang II-induced increase in elastin and collagen (mRNA and protein) was markedly suppressed in MMP2(-/-) thoracic aorta and smooth muscle cells, whereas only mRNA levels were reduced in MMP2(-/-) -Ang II abdominal aorta. Consistent with the absence of MMP2, proteolytic activities were lower in MMP2(-/-)-Ang II compared with wild-type-Ang II thoracic and abdominal aorta. MMP2-deficiency suppressed the activation of latent transforming growth factor-a and the Smad2/3 pathway in vivo and in vitro. Intriguingly, MMP2(-/-)mice were protected against CaCl 2 -induced thoracic aortic aneurysm, which triggered ECM degradation but not synthesis.Conclusions-This study reveals the dual role of MMP2 in ECM degradation, as well as ECM synthesis. Moreover, the greater susceptibility of the thoracic aorta to impaired ECM synthesis, compared with vulnerability of the abdominal aorta to aberrant ECM degradation, provides an insight into the regional susceptibility of the aorta to aneurysm development.