PSA通过抑制平滑肌细胞增殖迁移减轻血管再狭窄的作用及机制

Prostate-specific antigen (PSA), also known as kallikrein 3 (KLK3), is a serine protease with a molecular weight of 28741Da, which is involved in acute inflammatory reactions, production of antimicrobial peptides, regulation of systemic arterial blood pressure, proteolysis, and inhibition of angiogenesis and other biological processes. The current research reports that PSA anti-angiogenic properties mainly inhibit the formation, proliferation and migration of endothelial cells, but the specific mechanism of PSA exerting anti-angiogenic effects is still unclear. Based on previous studies, we found that PSA can inhibit the proliferation and migration of smooth muscle cells in a dose-dependent manner, and can alleviate the proliferation and activation of smooth muscle cells after carotid balloon injury in rats, increase the lumen area of blood vessels, and PSA can reduce the level of pSTAT3 in a dose-dependent manner. Therefore, we hypothesized that PSA can inhibit vascular restenosis by inhibiting the activity of smooth muscle cells by inhibiting the JAK2/STAT3 pathway. In this study, the effects of PSA on smooth muscle cells and blood vessels and related mechanisms were determined by cell, animal, molecular experiments and clinical population analysis. By further improving the function of PSA, it provides a theoretical basis for clinical application of PSA to prevent restenosis after vascular injury.

前列腺特异性抗原（PSA）也称激肽释放酶3（KLK3），是1个相对分子质量28741Da的丝氨酸蛋白酶，参与体内急性炎症反应，抗菌肽的生产，调节全身动脉血压，蛋白水解，抑制血管生成等生物学过程。目前的研究报道PSA抗血管生成特性主要为抑制内皮细胞的成管、增殖、迁移活动，但PSA发挥抗血管生成作用的具体机制尚不明确。申请人基于前期研究发现PSA可呈剂量依赖型抑制平滑肌细胞的增殖和迁移，且可减轻大鼠颈动脉球囊损伤后平滑肌细胞增殖和活化，增加血管内腔面积，PSA可呈剂量依赖型降低pSTAT3的水平，因此提出假设：PSA通过抑制JAK2/STAT3通路抑制平滑肌细胞的活动进而可减轻血管再狭窄。本研究通过细胞、动物、分子实验和临床人群分析明确PSA对平滑肌细胞及血管的作用和相关机制，通过进一步完善PSA的功能，为临床应用PSA防治血管损伤后再狭窄提供理论基础。

前列腺特异性抗原（PSA）为一丝氨酸蛋白酶，参与体内急性炎症反应，调节全身动脉血压，蛋白水解，抑制血管生成等生物学过程。既往研究报道PSA抗血管生成特性主要为抑制内皮细胞的成管、增殖、迁移活动，但PSA发挥抗血管生成作用的具体机制尚不明确。本研究明确PSA对血管平滑肌和尿路平滑肌细胞的增殖、迁移、凋亡的影响，在大鼠血管平滑肌细胞中完成PSA对JAK2/STAT3通路调控关系研究，证实PSA可通过抑制JAK2/STAT3信号通路抑制平滑肌细胞增殖和活化进而减轻血管损伤后再狭窄，同时通过PSA 对于尿路平滑肌细胞的功能研究为输尿管狭窄的治疗提供新的方向。课题过分析了多组前列腺癌ADT治疗前后组织样本肿瘤微环境中免疫特征变化，发现JUNB可以作为指示ADT治疗预后及免疫特征变化的关键分子之一，同时初步探讨转移性去势抵抗性前列腺癌（mCRPC）患者双极雄激素（BAT）治疗序贯免疫检查点抑制剂治疗的疗效和安全性，为晚期前列腺患者的治疗提供新的思路。