Jin Qingsong, Zhao Tiantian, Lin Liangyan, Yao Xiaoyan, Teng Yaqin, Zhang Dongdong, Jin Yongjun, Yang Meizi
Department of Endocrinology and Metabolism, Yantai Affiliated Hospital of Binzhou Medical University, No. 717, Mouping District, Binzhou, 264100, Shandong Province, People's Republic of China.
Department of Pharmacology, School of Basic Medical Sciences, Binzhou Medical University, No. 522, Huanghe Third Road, Binzhou, 264003, People's Republic of China.
Hum Cell. 2023 Nov;36(6):1915-1927. doi: 10.1007/s13577-023-00952-0. Epub 2023 Aug 16.
The protein PIAS1 functions as a type of ubiquitin-protease, which is known to play an important regulatory role in various diseases, including cardiovascular diseases and cancers. Its mechanism of action primarily revolves around regulating the transcription, translation, and modification of target proteins. This study investigates role and mechanism of PIAS1 in the RUNX3/TSP-1 axis and confirms its therapeutic effects on diabetes-related complications in animal models. A diabetic vascular injury was induced in human umbilical vein endothelial cells (HUVECs) by stimulation with HO and advanced glycation end product (AGE), and a streptozotocin (STZ)-induced mouse model of diabetes was constructed, followed by detection of endogenous PIAS1 expression and SUMOylation level of RUNX3. Effects of PIAS1 concerning RUNX3 and TSP-1 on the HUVEC apoptosis and inflammation were evaluated using the ectopic expression experiments. Down-regulated PIAS1 expression and SUMOylation level of RUNX3 were identified in the HO- and AGE-induced HUVEC model of diabetic vascular injury and STZ-induced mouse models of diabetes. PIAS1 promoted the SUMOylation of RUNX3 at the K148 site of RUNX3. PIAS1-mediated SUMOylation of RUNX3 reduced RUNX3 transactivation activity, weakened the binding of RUNX3 to the promoter region of TSP-1, and caused downregulation of TSP-1 expression. PIASI decreased the expression of TSP-1 by inhibiting HO- and AGE-induced RUNX3 de-SUMOylation, thereby arresting the inflammatory response and apoptosis of HUVECs. Besides, PIAS1 reduced vascular endothelial injury and atherosclerotic plaque formation in mouse models of diabetes by inhibiting the RUNX3/TSP-1 axis. Our study proved that PIAS1 suppressed vascular endothelial injury and atherosclerotic plaque formation in mouse models of diabetes via the RUNX3/TSP-1 axis.
蛋白质PIAS1作为一种泛素蛋白酶发挥作用，已知其在包括心血管疾病和癌症在内的各种疾病中发挥重要的调节作用。其作用机制主要围绕调节靶蛋白的转录、翻译和修饰。本研究探讨了PIAS1在RUNX3/TSP-1轴中的作用和机制，并在动物模型中证实了其对糖尿病相关并发症的治疗作用。通过用HO和晚期糖基化终产物（AGE）刺激在人脐静脉内皮细胞（HUVECs）中诱导糖尿病血管损伤，并构建链脲佐菌素（STZ）诱导的糖尿病小鼠模型，随后检测内源性PIAS1表达和RUNX3的SUMO化水平。使用异位表达实验评估PIAS1对RUNX3和TSP-1的影响对HUVEC细胞凋亡和炎症的影响。在HO和AGE诱导的糖尿病血管损伤HUVEC模型和STZ诱导的糖尿病小鼠模型中，鉴定出PIAS1表达下调和RUNX3的SUMO化水平。PIAS1促进RUNX3在RUNX3的K148位点的SUMO化。PIAS1介导的RUNX3的SUMO化降低了RUNX3的反式激活活性，减弱了RUNX3与TSP-1启动子区域的结合，并导致TSP-1表达下调。PIASI通过抑制HO和AGE诱导的RUNX3去SUMO化来降低TSP-1的表达，从而阻止HUVECs的炎症反应和凋亡。此外，PIAS1通过抑制RUNX3/TSP-1轴减少糖尿病小鼠模型中的血管内皮损伤和动脉粥样硬化斑块形成。我们的研究证明，PIAS1通过RUNX3/TSP-1轴抑制糖尿病小鼠模型中的血管内皮损伤和动脉粥样硬化斑块形成。
