基于MMP-2的MRI分子成像评价糖尿病动脉粥样硬化斑块稳定性的实验研究

The cardiovascular system is the most prominent involved target in type 2 diabetes mellitus patients with multiple organ injury. Diabetes mellitus is associated with aggressive vascular abnormalities, and atherosclerosis is regarded as the leading cause of morbidity and mortality in diabetic patients. Atherosclerotic plaques in diabetic patients are earlier onset, faster progress,higher risk of rupture in comparison to those in non-diabetic patients. In view of these risk factors, urgent evaluation of the stability of diabetic atherosclerotic plaques are necessary. In our research proposal, we intend to synthesize a collagen-targeted MRI probe (GKWHCTTKFPHHYCLY-Gd-DOTA) for detecting plaque fibrosis with type I collagen-specific peptide. Moreover, a specific matrix metalloproteinase -2 (MMP-2) antibody probe (Ab-MMP-2-SPIO) will be synthesized chemically for detecting MMP-2 in the plaque on melecular MR images. On the basis of the molecular imaging, we will analyse and determine the stability of atherosclerosis plaque in type 2 diabetes mellitus patients. Compared histopathologic findings with molecular MR imaging, the differences of stability between diabetic and non-diabetic atherosclerotic plaques will be explored. We are hopeful that the mechanisms would be clarified in regard to the vulnerability of diabetic atherosclerotic plaques based on the formation and destruction of collagen fibers. Furthermore, the study work may be potential to provide scientific evidences for early intervention diabetic atherosclerotic plaques.

2型糖尿病患者多器官损害中以心血管系统为最主要的靶器官。糖尿病大血管病变的主要病理过程是动脉粥样硬化。糖尿病动脉粥样斑块比非糖尿病患者发生更早、进展更快、更易破裂，因此对糖尿病动脉粥样硬化斑块稳定性的评价显得更为迫切。本研究拟构建能特异识别斑块中基质金属蛋白酶-2（MMP-2）和I型胶原纤维的MRI分子靶向探针（Ab-MMP-2-SPIO和GKWHCTTKFPHHYCLY-Gd-DOTA），通过MRI分子成像靶向显示斑块中I型胶原纤维和MMP-2成分，实现从分子水平评价糖尿病动脉粥样硬化斑块的稳定性；结合组织病理学结果，澄清糖尿病与非糖尿病动脉粥样硬化斑块稳定性的差异；力图从胶原纤维形成和破坏的角度去阐明糖尿病动脉粥样硬化易损性的机制；从而为临床早期干预糖尿病动脉粥样斑块提供科学依据。

本项目构建了糖尿病颈动脉斑块兔模型，采用新型锰铁纳米造影剂进行颈动脉斑块成像，并与商用钆造影剂进行成像对比，结合组织病理学结果，证实了采用新型纳米颗粒造影剂显影颈动脉斑块可行，且较传统商用造影剂显影更清晰、强化持续时间长，是一种可供选择的动脉斑块磁共振成像造影剂。此外，对糖尿病模型兔进行了心脏磁共振扫描，证实了糖尿病兔心肌发生纤维化，能检测出早期（射血分数降低前）心肌应变下降。糖尿病心血管并发症临床研究方面，研究发现增强磁共振检查可检测早期亚临床心肌功能障碍和心肌微血管灌注受损，且心肌功能障碍与冠状动脉微血管灌注受损相关。总之，研究成果为早期检测糖尿病动脉粥样斑块及心肌损伤提供有效方法，进而为临床早期干预糖尿病动脉粥样斑块提供科学依据。