血管微钙化在主动脉瘤/夹层发生发展中的作用与机制研究

Aortic aneurysm/dissection is a highly lethal vascular disease without up-to-date effective approach for prediction, prevention and therapy. Presently vascular calcification is being recognized as an independent risk factor for cardiovascular events. In particular, recent prospective clinical study highlights the value of microcalcification for prediction of vulnerable plaque in vessel wall. Whether vascular calcification/microcalcification involved in the pathogenesis of aortic aneurysm/dissection remains elusive. Our previous studies has identified several critical molecules regulating vascular calcification. Further preliminary studies revealed: microcalcification commonly exists in aortic aneurysm/dissection; microcalcification detected by 18F-sodium fluoride positron emission tomography in angiotensin II-infused ApoE-/- mice proceeds abdominal aortic aneurysm; angiotensin II-induced the production of inflammatory cytokines and matrix metalloproteases is inhibited by silencing the calcification mediator Runx2 in vascular smooth muscle cells. Our central hypothesis is that vascular microcalcification mediates the pathogenesis of aortic aneurysm/dissection. The present proposal aims to explore the spatio-temporal pattern of microcalcification in aortic aneurysm/dissection by a variety of animal models. Through combination of forward genetics and high through-put screening, bioinformatics analysis, in vitro and in vivo functional assay, we will try to identify the key molecules (such as Runx2, COMP, ANK et al) involved in microcalcification during aortic aneurysm/dissection formation and progression. Finally, we will explore the underlying molecular mechanism linking the two pathological processes to uncover novel therapeutic targets for aortic aneurysm/dissection.

主动脉瘤/夹层是高度致死的心血管疾病。血管钙化是心血管事件的独立危险因素，其中微钙化具有更高的预测价值。钙化/微钙化与主动脉瘤/夹层之间是否关联尚不清楚。我们前期发现了数个钙化调控关键分子。进一步预试验发现微钙化是主动脉瘤/夹层的共性病理特征；PET-CT检测的微钙化可预测小鼠腹主动脉瘤的发生；敲低钙化介质Runx2显著抑制血管紧张素II诱导的血管平滑肌产生炎症因子和MMP。由此假设：血管微钙化可能介导了主动脉瘤/夹层的发生发展。我们将在多种动物模型中研究主动脉瘤/夹层发病过程中微钙化发生的时空规律；验证Runx2、COMP、ANK等关键钙化调控分子是否参与主动脉瘤/夹层发病；筛选新的可能参与主动脉瘤/夹层发病的微钙化调控关键分子；探究平滑肌成骨样表型转换及羟磷灰石结晶这两个关键环节是否介导了微钙化促进主动脉瘤/夹层的发生；并深入挖掘其作用机制，以期发现主动脉瘤/夹层新的干预靶点。

主动脉瘤/夹层是高度致死的心血管系统疾病，但临床上目前仍缺乏针对主动脉瘤/夹层有效的早期诊断方式和治疗药物。血管钙化是心血管事件的独立危险因素，其中微钙化具有更高的预测价值，而钙化/微钙化与主动脉瘤/夹层之间是否关联尚不清楚。本研究项目旨在明确微钙化与主动脉瘤/夹层出现的时空规律，探究微钙化及钙化调控关键分子在主动脉瘤/夹层发病中的作用及机制，并筛选出靶向血管钙化及主动脉瘤/夹层的潜在治疗药物。自项目开展以来，我们已按研究计划完成系列实验和相关工作，取得多项成果，主要包括：1. 利用临床使用的[18F]-NaF放射性探针和小动物PET-CT平台，在血管紧张素II诱导的腹主动脉瘤模型中选取不同时间点检测微钙化，并进行分子机制探究，揭示了微钙化为腹主动脉瘤新的病理特征和致病因素；2. 找到多个血管钙化和主动脉瘤/夹层的共同关键调控分子，包括钙化关键转录因子Runx2、细胞外基质蛋白COMP、内质网应激分子非剪切型XBP1、基底膜蛋白Nidogen-2、焦磷酸盐转运体ANK等，并充分探讨其在钙化和主动脉瘤/夹层中的作用机制，为疾病治疗提供新的靶点；3. 明确了筛选药物柚皮素对主动脉瘤/夹层的抑制作用，发现柚皮素可激活溶酶体生物合成关键转录因子TFEB，并通过靶向14-3-3-TFEB结合面治疗主动脉瘤。本项目从分子影像、动物模型、关键调控分子筛查和验证、药物筛选等多个维度深入探究血管微钙化在主动脉瘤/夹层发生发展的作用，拓展了领域内对主动脉瘤/夹层发病机制的认识；为主动脉瘤/夹层的发生发展和风险评估提供新的临床诊断策略；并为研发主动脉瘤/夹层防治药物提供新的思路。