Multimodality Imaging Reveals a Gradual Increase in Matrix Metalloproteinase Activity at Aneurysmal Lesions in Live Fibulin-4 Mice
Multimodality Imaging Reveals a Gradual Increase in Matrix Metalloproteinase Activity at Aneurysmal Lesions in Live Fibulin-4 Mice
复制标题
DOI：
10.1161/circimaging.109.933093
复制
发表时间：
2010-09-01
影响因子：
7.5
通讯作者：
Essers, Jeroen
中科院分区：
文献类型：
--
作者：
Kaijzel, Eric L.;van Heijningen, Paula M.;Essers, Jeroen
背景--我们使用可激活的近红外荧光探头，对动脉瘤形成过程中上调的基质金属蛋白酶(MMPs)的酶活性进行了成像。我们使用我们的转基因fiblin-4小鼠动脉瘤形成模型，测试了这些可激活的酶传感器是否可以直接报告动脉瘤中关键生物标记物的体内活性。携带纤蛋白-4低表达等位基因(纤蛋白-4(R/R))的纯合子小鼠表现为升主动脉扩张，以及由松散的弹性纤维网络引起的扭曲、僵硬的主动脉。值得注意的是，即使在纤维蛋白-4(+/R)杂合子小鼠中纤维蛋白-4的表达适度减少，偶尔也会导致适度的动脉瘤形成。方法和结果-通过对纤维蛋白-4(+/R)和纤维蛋白-4(R/R)动物的主动脉转录组和蛋白质表达分析，发现过度的转化生长因子-β信号在动脉瘤形成的发病机制中是关键事件。为了确定受扰的弹性蛋白板层结构是否源于转化生长因子-β调节的基质金属蛋白酶的诱导，我们进行了明胶酶谱分析，并使用可激活的近红外荧光探针，利用不同的体内光学成像模块，以及荧光信号与同一动物的CT图像的共同配准，来监测和定量动物中的基质金属蛋白酶的上调。明胶酶谱分析显示，在腓肠肌蛋白-4(R/R)小鼠的主动脉弓中，活性形式的基质金属蛋白酶-9的存在显著增加。利用近红外荧光探针和随后的等表面浓度图从重建的纤蛋白-4(+/R)和纤蛋白-4(R/R)小鼠重建的断层图像中进行体内分析，显示动脉瘤病变中MMPs的激活程度增加。结论-我们的目标是开发分子成像程序，以便更快、更早、更容易地识别主动脉瘤。我们发现，通过非侵入性断层成像方法在体内共同记录基质金属蛋白酶活性可以检测到基质金属蛋白酶活性增加，甚至在动脉瘤实际形成之前就可以检测到。(中国心脏血管成像学会。2010；3：567-577。)
Background-We imaged the protease activity of matrix metalloproteinases (MMPs) upregulated during aneurysm formation, using protease-activatable near-infrared fluorescence probes. We tested whether these protease-activatable sensors can directly report the in vivo activity of the key biomarkers in aneurysm, using our genetically modified fibulin-4 mouse models for aneurysm formation. Mice homozygous for the fibulin-4 reduced-expression allele (fibulin-4(R/R)) show dilatation of the ascending aorta and a tortuous, stiffened aorta resulting from disorganized elastic fiber networks. Strikingly, even a moderate reduction in expression of fibulin-4 in the heterozygous fibulin-4(+/R) mice occasionally results in modest aneurysm formation.Methods and Results-Aorta transcriptome and protein expression analysis of fibulin-4(+/R) and fibulin-4(R/R) animals identified excessive transforming growth factor-beta signaling as the critical event in the pathogenesis of aneurysm formation. To determine whether a perturbed elastin lamellar structure arose from induction of transforming growth factor-beta-regulated MMPs, we performed gelatin zymography and used a protease-activatable near-infrared fluorescence probe to monitor and quantify MMP upregulation in animals, using various in vivo optical imaging modules and coregistration of the fluorescence signal with CT images of the same animals. Gelatin zymography demonstrated a significant increase in the presence of the active form of MMP-9 in the aortic arch of fibulin-4(R/R) mice. In vivo analysis of MMP upregulation using the near-infrared fluorescence probe and subsequent isosurface concentration mapping from reconstructed tomographic images from fibulin-4(+/R) and fibulin-4(R/R) mice revealed a graded increase in activation of MMPs within the aneurysmal lesions.Conclusions-We aimed to develop molecular imaging procedures for faster, earlier, and easier recognition of aortic aneurysms. We show that in vivo coregistration of MMP activity by noninvasive tomographic imaging methods allows the detection of increased MMP activity, even before the aneurysm has actually formed. (Circ Cardiovasc Imaging. 2010;3:567-577.)