Department of Radiology, Bichat Hospital, Paris, France.
Invest Radiol. 2010 Oct;45(10):662-8. doi: 10.1097/RLI.0b013e3181ee5bbf.
Abdominal aortic aneurysm (AAA) rupture is a devastating event, and development of noninvasive methods to detect AAA at risk is needed. Matrix metalloproteinases (MMPs) play a major role in AAA growth and their subsequent rupture. This study was aimed to evaluate the ability of P947, a recently developed magnetic resonance imaging (MRI) contrast agent, to target MMPs in vivo in expanding experimental AAAs.
AAAs were induced in Wistar rats (n = 18) by perfusion of a segment of the abdominal aorta with porcine elastase. After 5 or 6 days of elastase perfusion, when the aortic segment was expanding and showed inflammation with high MMP levels, rats were injected either with P947 (n = 6), P1135, a scramble form of P947 (n = 6), or with the reference contrast agent Gadolinium-DOTA (Gd-DOTA) (n = 3). Sham-operated rats (n = 3) were injected with P947 as controls. Imaging was performed on the animals using a 1.5T MRI scanner before and at different times after injection of contrast agents (100 μmol/kg). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gelatin zymography of culture media conditioned by incubation with perfused aortic segment or control TA from elastase-perfused rats (n = 3) was performed to determine levels of MMP2 and MMP9. In addition, in situ gelatin zymography was used to localize these active MMPs on frozen histologic sections.
The normalized signal enhancement determined on MRI images was higher in the perfused aortic segment of rats injected with P947 (162%) than in rats injected with P1135 (100%) or Gd-DOTA (117%) (P < 0.01 using the Friedman test) from 5 to 125 minutes after injection. The area of contrast enhancement on MRI images colocalized with the fluorescence generated by MMPs in the AAA inflammatory area, as detected by in situ zymography on histologic sections.
Our data showed that MRI using P947 allows detection of MMP activity within the inflammatory wall of experimental AAAs, thus representing a potential noninvasive method to detect AAAs with a high risk of rupture.
腹主动脉瘤（AAA）破裂是一种破坏性事件，需要开发非侵入性方法来检测有风险的 AAA。基质金属蛋白酶（MMPs）在 AAA 的生长及其随后的破裂中起主要作用。本研究旨在评估最近开发的磁共振成像（MRI）造影剂 P947 在体内靶向 MMP 的能力，以检测扩张性实验性 AAA。
通过向猪弹性蛋白酶灌注一段腹主动脉，在 Wistar 大鼠中诱导 AAA（n = 18）。在用弹性蛋白酶灌注 5 或 6 天后，当主动脉段扩张并显示出具有高 MMP 水平的炎症时，将大鼠分别注射 P947（n = 6）、P1135（P947 的乱序形式，n = 6）或参考造影剂钆-DOTA（Gd-DOTA）（n = 3）。假手术大鼠（n = 3）作为对照注射 P947。在注射造影剂前和不同时间（100μmol/kg），使用 1.5T MRI 扫描仪对动物进行成像。对孵育灌注主动脉段或弹性蛋白酶灌注大鼠的对照 TA 后的培养物进行十二烷基硫酸钠-聚丙烯酰胺凝胶电泳（SDS-PAGE）明胶酶谱分析，以确定 MMP2 和 MMP9 的水平。此外，还使用原位明胶酶谱法在冷冻组织切片上定位这些活性 MMP。
在注射 P947 的大鼠灌注主动脉段的 MRI 图像上确定的归一化信号增强（162%）高于注射 P1135（100%）或 Gd-DOTA（117%）的大鼠（使用 Friedman 检验，P < 0.01）。从注射后 5 到 125 分钟。MRI 图像上的对比增强区域与 MMP 在炎症区 AAA 中产生的荧光共定位，如在组织学切片上的原位酶谱法检测到的。
我们的数据表明，使用 P947 的 MRI 允许检测实验性 AAA 炎症壁内的 MMP 活性，因此代表了一种潜在的非侵入性方法，可以检测破裂风险高的 AAA。
