SFRP5通过WNT/β-catenin信号通路对动脉硬化进程的影响及其机制研究

Arteriosclerosis and vascular aging play an important role in the mechanism of hypertension and target organ damage. It is known that the underlying mechanism of arteriosclerosis is the chronic vascular inflammation derived from mitochondrial oxidative stress in smooth muscle cell. As indicated in our previous studies, with advancing age, elastic arteries get stiffening, while muscular arteries remain unaltered. However, the mechanism is unclear. Recent study indicated that, SFRP5 derived from adipose tissue, as a novel anti-inflammatory adipokine, could affect mitochondrial oxidative stress in adipocyte via WNT/β-catenin signal pathway. Our preliminary experiment revealed that SFRP5 was expressed in the adipose tissue around femoral artery and aorta, whereas the amount in the former was significantly higher than that in the latter. Hence, we hypothesized that, via WNT/β-catenin signal pathway, adipocyte derived SFRP5 would have an impact on the chronic vascular inflammation derived from mitochondrial oxidative stress in smooth muscle cell. Furthermore, the discrepancy in the development of vascular aging in the elastic and muscular arteries would be mainly attributable to the amount of SFRP5 secreted by the adipose tissue. The present study would be conducted at population and animal levels to investigate the association of SFRP5 with vascular inflmation and arterial stiffness, as well as to investigate the influence of SFRP5 on the vascular inflammation derived from mitochondrial oxidative stress in smooth muscle cell. The present study would provide new theoretical basis and therapeutic target to the development of the novel de-stiffening and antihypertensive agents.

动脉硬化及老化是高血压与靶器官损害的重要原因之一，其核心机制为平滑肌细胞线粒体应激所介导的动脉内慢性炎症反应。我们研究证实：随年龄增长，弹性动脉僵硬度逐渐增加，而肌性动脉则基本不变，但其机制不明。新近研究发现：脂肪细胞来源的SFRP5作为一种新的抗炎因子，能通过WNT/β-catenin通路影响脂肪细胞线粒体应激水平。我们发现：SFRP5在肌性动脉周围脂肪中的分泌量显著高于弹性动脉。据此，我们推测：动脉周围脂肪分泌的SFRP5能通过WNT/β-catenin通路影响平滑肌细胞线粒体应激水平进而调节动脉炎症反应，而SFRP5在肌性及弹性动脉周围的分泌差异是这两种动脉硬化进程不同步的关键。本项目拟从动物水平研究SFRP5与动脉炎症及硬化之间的关系，并分析SFRP5对动脉硬化的影响机制是否与平滑肌细胞内线粒体氧化应激水平及其介导的炎症反应有关，从而为抗动脉硬化药物的研发提供理论依据及治疗靶点。

动脉硬化及老化是高血压与靶器官损害的重要原因之一，其核心机制为平滑肌细胞线粒体应激所介导的动脉内慢性炎症反应。我们前期研究已证实：随年龄增长，弹性动脉僵硬度逐渐增加，而肌性动脉则基本不变，但其机制不明。新近研究发现：脂肪细胞来源的SFRP5作为一种新的抗炎因子，能通过WNT/β-catenin通路影响脂肪细胞线粒体应激水平。我们前期发现：SFRP5在肌性动脉周围脂肪中的分泌量显著高于弹性动脉。而且，我们通过本课题研究证明：1.动脉周围脂肪分泌的SFRP5能通过WNT/β-catenin通路显著促进平滑肌细胞的增值、迁移。2.SFRP5在动脉硬化及其相关靶器官损害方面发挥了重要的调节作用。3.降压药物在降压及降低血压变异性机制方面的差异部分与SFRP5的影响有关。在此工作基础上，我们还在人群水平（n=1745）建立了血清水平SFRP5与动脉硬化相关性靶器官损害的关系，在动物水平制备了SFRP5 KO小鼠，并成功获得了国家自然科学基金面上项目（81670377）资助，以深入SFRP5对动脉硬化及其相关靶器官损害的机制。通过本课题的研究，将为抗动脉硬化药物开发及保护动脉硬化相关性靶器官损害提供新的理论依据及治疗靶点