抗氧化应激转录因子Nrf2在抑制血管钙化发生中的作用及机制研究

Vascular calcification (VC) has long been considered as one of the main characteristics of vascular aging and a predictive risk factor of cardiovascular events and plaque burden, but there is still no fully effective treatment or cure for this condition until today. Previous works from our group and other groups have shown that activation of nuclear factor erythroid-2-related factor (Nrf2), a major antioxidant and anti-inflammatory transcription factor, could significantly postpone initiation and development of VC, but the exact mechanisms remain poorly understood. We have previously specifically knocked down expression of Nrf2 in vascular smooth muscle cells (VSMCs) of mice. In this work, we are planning to use this mouse model to investigate the involvement of Nrf2 in all stages of VC including primary cellular response to environmental change of inflammatory and oxidative stress; secondary response of signaling network promoting differentiation of VSMC towards an osteoblast-like phenotype and apoptosis; and the final stage marked by initiation of deposition and growth of hydroxyapatite crystal within the vascular wall. The goal of our investigation is to understand the role of Nrf2 along the whole process of VC and to explore the possibility to inhibit this process after deepened understanding of the mechanism of VC. The outcome of our research could serve as a solid base for prevention and treatment of VC in the future.

血管钙化是血管衰老的重要标记以及临床心脑血管事件的危险因子，目前尚无有效的抑制其发生的药物。我们前期的研究以及最新的文献均表明激活Nrf2的表达可明显抑制血管钙化的发生，但其抑制血管钙化的具体分子机制目前尚未完全揭示。Nrf2是机体中重要的抗氧化应激的核转录因子，同时与血管钙化发生发展的各环节均存在着紧密的联系。本课题组已成功构建离体和在体血管钙化模型，同时将特别构建在血管平滑肌细胞内特异性敲除Nrf2的转基因小鼠，以此为基础系统研究Nrf2对血管钙化的发生和发展的各个环节的作用，包括炎症和氧化应激水平的改变，参与血管钙化的信号通路的变化，细胞的成骨样分化的改变，以及最终导致的钙化的发生程度的差异，由此阐释Nrf2抑制血管钙化的具体机制。同时我们也将在本课题中研究不同的Nrf2激活剂对血管钙化的抑制效果，为未来临床上预防和延缓血管钙化寻找新的治疗靶点和针对性措施提供理论基础。

为了评估 Nrf2及其激活剂在血管中膜钙化发生发展中的作用，本研究在离体水平敲除和过表达血管平滑肌细胞内的Nrf2，明确了Nrf2对高磷诱导的血管平滑肌细胞钙化有抑制作用，并证明了Nrf2激活剂对血管钙化的抑制作用及其对氧化应激、成骨样蛋白表达和凋亡的调控作用。在体水平，本研究使用平滑肌特异性敲除Nrf2的转基因小鼠，证明了Nrf2对高磷诱导的主动脉环钙化及高嘌呤饮食诱导的血管钙化均有明显抑制作用。本研究还通过自然衰老模型明确了血管平滑肌组织年龄相关性Nrf2功能失调，证明了年龄加速血管钙化的发生且Nrf2激活剂可改善年龄引起的血管钙化加剧。血管钙化是血管衰老的重要标记，也是临床心脑血管事件的危险因子，目前尚无抑制其发生的有效药物。本课题研究Nrf2在血管钙化和血管衰老中的作用，为弄清血管钙化和血管衰老间的分子信号联系提供新思路。本课题还通过研究不同的Nrf2激活剂对血管钙化的抑制效果，为未来临床上预防和延缓血管钙化寻找新的治疗靶点和针对性措施提供理论基础。