Ikonomidis John S, Gibson William C, Butler Jessica E, McClister David M, Sweterlitsch Sarah E, Thompson Robert P, Mukherjee Rupak, Spinale Francis G
Assistant Professor of Surgery, Division of Cardiothoracic Surgery, Medical University of South Carolina, Suite 409 CSB, 96 Jonathan Lucas Street, Charleston, SC 29425, USA.
Circulation. 2004 Sep 14;110(11 Suppl 1):II268-73. doi: 10.1161/01.CIR.0000138384.68947.20.
The cause of thoracic aortic aneurysms (TAAs) is poorly understood. Previous work has suggested an association between development of aortic aneurysms and matrix metalloproteinase (MMP) activity. We hypothesized that removal of the primary endogenous aortic MMP inhibitor (TIMP) through TIMP-1 gene deletion will increase TAA progression.
The descending thoracic aortas of wild-type 129 SvE and TIMP-1 gene knockout (TIMP-1-/-) mice were exposed to 0.5 mol/L CaCl2 for 15 minutes, with terminal studies performed at 4 or 8 weeks. TAA lumen diameter was measured using confocal microscopy and normalized to the ascending aorta. In addition, sections were studied with in situ zymography and immunohistochemistry staining for MMP-9. Both wild-type [TAA/ascending ratio (mean+/-SEM): control, 0.85+/-0.02 (n=14); 4 weeks, 1.00+/-0.03 (n=13); 8 weeks, 1.05+/-0.10 (n=9)] and TIMP-1-/- [control, 0.98+/-0.04 (n=11); 4 weeks, 1.10+/-0.03 (n =21); 8 weeks, 1.22+/-0.09 (n=10)] groups developed aneurysms at 4 and 8 weeks compared with their respective controls (P<0.05). TIMP-1-/- animals developed larger aneurysms than the corresponding wild-type group (P<0.05). Aneurysms in the TIMP-1-/- group were larger at 8 weeks than at 4 weeks (P<0.05), which was not seen in the wild-type aneurysm groups. Both groups showed presence of MMP-9 in 4 and 8 weeks, most prominently in the adventitia and outer media. In situ zymographic activity was increased in the 8-week TIMP-1-/- group compared with wild-type.
Deletion of the TIMP-1 gene results in increased and continued progression of aneurysm formation compared with wild-type mice in a unique TAA model caused at least in part by an alteration in the balance between gelatinase activity and its endogenous inhibition. Therapeutic strategies aimed at modifying MMP activity may reduce or prevent the progression of TAAs.
胸主动脉瘤（TAA）的病因尚不清楚。先前的研究表明主动脉瘤的发生与基质金属蛋白酶（MMP）活性之间存在关联。我们推测通过缺失TIMP-1基因去除内源性主动脉MMP主要抑制剂会加速TAA的进展。
将野生型129 SvE和TIMP-1基因敲除（TIMP-1-/-）小鼠的降主动脉暴露于0.5 mol/L氯化钙中15分钟，并在4周或8周时进行终末研究。使用共聚焦显微镜测量TAA管腔直径，并将其与升主动脉进行标准化。此外，采用原位酶谱法和MMP-9免疫组织化学染色对切片进行研究。野生型组[TAA/升主动脉比值（均值±标准误）：对照组，0.85±0.02（n = 14）；4周时，1.00±0.03（n = 13）；8周时，1.05±0.10（n = 9）]和TIMP-1-/-组[对照组，0.98±0.04（n = 11）；4周时，1.10±0.03（n = 21）；8周时，1.22±0.09（n = 10）]在4周和8周时与各自对照组相比均出现了动脉瘤（P<0.05）。TIMP-1-/-组动物形成的动脉瘤比相应野生型组更大（P<0.05）。TIMP-1-/-组8周时的动脉瘤比4周时更大（P<0.05），而野生型动脉瘤组未出现这种情况。两组在4周和8周时均显示有MMP-9存在，最明显的是在外膜和外中膜。与野生型相比，8周时TIMP-1-/-组的原位酶谱活性增加。
在一种至少部分由明胶酶活性及其内源性抑制之间平衡改变引起的独特TAA模型中，与野生型小鼠相比，TIMP-1基因缺失导致动脉瘤形成增加且持续进展。旨在调节MMP活性的治疗策略可能会减少或预防TAA的进展。
