PEDF/SIRT1关键信号调控胸主动脉瘤血管重构的分子机制研究

The depletion of smooth muscle cells caused by cell pyroptosis and pathological angiogenesis are the main pathological changes of vascular remodeling of aortic aneurysm, however, the detailed underlying mechanisms are not clear. Our previous studies showed that silent information regulator of transcription 1 (SIRT1) is a fundamental signaling pathway that controls the regenerative, reparative and remodeling processes after cardiovascular injuries, and that pigment epithelium-derived factor (PEDF) is a highly effective inhibitor of angiogenesis. We first verified that PEDF could effectively ameliorate thoracic aortic aneurysm in mice, accompanied by the significant upregulation of SIRT1 expression, however, the downstream effector molecules remain to be elucidated. Hypoxia inducible factor-1α (HIF-1α) is an important proangiogenic factor and a crucial effector of vascular remodeling of aortic aneurysm. Besides, HIF-1α could activate the Caspase-1 signaling pathway, which is the executive signaling pathway of pyroptosis. Notably, both PEDF and SIRT1 could improve vascular remodeling in tumor tissues via inhibiting HIF-1α. Therefore, we speculate that the PEDF/SIRT1 signaling pathway may retard the formation and progression of thoracic aortic aneurysm through regulating vascular remodeling via inhibiting HIF-1α. The human aortic aneurysm specimens, gene knockout mice, adeno-associated viruses, siRNA interference and other techniques will be used to illuminate the novel mechanisms of vascular remodeling in thoracic aortic aneurysm both in vivo and in vitro. In this way, we may find novel potential therapeutic targets for the prevention and treatment of thoracic aortic aneurysm.

细胞焦亡所致的平滑肌细胞丢失和病理性新生血管生成是主动脉瘤血管重构的主要病理改变，但具体信号调控机制不清。我们系列研究证实，SIRT1是调控心血管组织再生、修复及重构的基本信号通路，PEDF是一种强效血管生成抑制因子。我们发现，外源性补充PEDF可明显改善小鼠胸主动脉瘤，并激活SIRT1信号通路，但具体下游效应分子不明。HIF-1α是主动脉瘤血管重构重要效应分子，是体内重要的促新生血管生成因子之一，且能够激活细胞焦亡关键信号Caspase-1。研究发现，PEDF、SIRT1均可通过抑制HIF-1α改善肿瘤组织血管重构。由此，我们提出科学假说：PEDF-SIRT1关键信号通过抑制HIF-1α效应因子改善血管重构调控胸主动脉瘤形成进展。本项目拟利用已建成的临床标本库，采用基因敲除、腺相关病毒、siRNA等技术，通过在体、离体水平研究阐明上述科学假说，为胸主动脉瘤防治寻找潜在分子标志和干预靶点。

主动脉瘤是最凶险的危重症心血管疾病之一，随着病情进展，患者可突发破裂猝死，病情凶险，对人体生命健康威胁极大。主动脉瘤的主要病理特征是中膜层平滑肌细胞凋亡和细胞外基质降解等，引起主动脉壁中膜层渐进性退化。目前，尚无有效的药物可以延缓或是限制主动脉瘤/夹层的发展，因此，深入研究主动脉瘤/夹层的发病机制，寻找新的治疗靶点对于主动脉瘤/夹层的防治具有重要的临床价值和社会意义。色素上皮衍生因子（PEDF）是一种具有营养和保护神经、抑制肿瘤、抑制血栓形成、抗氧化、抗炎和抑制新生血管生成等特性的多功能蛋白质。本课题组前期研究发现：来源于衰老小鼠的骨髓基质干细胞体外表达、分泌PEDF显著增高，而且衰老小鼠骨髓基质干细胞分泌的PEDF增加影响了衰老骨髓基质干细胞移植治疗心肌梗死的疗效。在课题的资助下，我们进一步发现1．PEDF在人主动脉中膜表达，且在胸主动脉瘤/夹层主动脉中膜表达显著增加，PEDF表达增加显著延长胸主动脉瘤/夹层患者术后住院时间。2．PEDF及其受体LR在胸主动脉瘤/夹层主动脉中膜平滑肌细胞上显著增加，PEDF表达增加促进炎症因子诱导的中膜平滑肌细胞凋亡。3．PEDF促中膜平滑肌细胞凋亡的机制是通过与其受体LR结合，激活PPARγ信号通路，上调凋亡蛋白p53和caspase3。证实PEDF可能在主动脉瘤/夹层形成过程中发挥重要作用，为临床上防治主动脉瘤/夹层提供了新的治疗靶点和方案。