Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China.
Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China.
J Transl Med. 2024 Nov 28;22(1):1080. doi: 10.1186/s12967-024-05887-0.
Excessive oxidative stress is known to cause endothelial dysfunction and drive cardiovascular diseases (CVD). While telomerase reverse transcriptase (TERT) shows protective effects against oxidative stress in rodents and is associated to human flow-mediated dilation in CVD, its regulatory mechanisms in human vascular systems under pathological oxidative stress require further investigation.
Human induced pluripotent stem cells (hiPSCs) were used to create vascular organoids (VOs). These VOs and human umbilical vein endothelial cells (HUVECs) were subjected to oxidative stress through both hydrogen peroxide (HO) and oxidized low-density lipoprotein (oxLDL) models. The effects of TERT overexpression by inhibition of the ubiquitin protein ligase E3 component N-recognin 5 (UBR5) on reactive oxygen species (ROS)-induced vascular injury and cellular senescence were assessed using neovascular sprouting assays, senescence-associated β-galactosidase (SA-β-Gal) staining, and senescence-associated secretory phenotype (SASP) assays.
ROS significantly impaired VO development and endothelial progenitor cell (EPC) angiogenesis, evidenced by reduced neovascular sprouting and increased senescence markers, including elevated SA-β-Gal activity and SASP-related cytokine levels. Overexpression of TERT counteracted these effects, restoring VO development and EPC function. Immunoprecipitation-mass spectrometry identified UBR5 as a critical TERT regulator, facilitating its degradation. Inhibition of UBR5 stabilized TERT, improving VO angiogenic capacity, and reducing SA-β-Gal activity and SASP cytokine levels.
Inhibiting UBR5 stabilizes TERT, which preserves EPC angiogenic capacity, reduces VO impairment, and delays endothelial cell senescence under oxidative stress. These findings highlight the potential of targeting UBR5 to enhance vascular health in oxidative stress-related conditions.
已知过度氧化应激会导致内皮功能障碍并引发心血管疾病（CVD）。端粒酶逆转录酶（TERT）在啮齿动物中显示出对氧化应激的保护作用，并与 CVD 中的人体血流介导的扩张有关，但在病理性氧化应激下其在人体血管系统中的调节机制仍需进一步研究。
利用人诱导多能干细胞（hiPSC）构建血管类器官（VO）。通过过氧化氢（HO）和氧化型低密度脂蛋白（oxLDL）模型，使这些 VO 和人脐静脉内皮细胞（HUVEC）产生氧化应激。通过新生血管形成试验、衰老相关β-半乳糖苷酶（SA-β-Gal）染色和衰老相关分泌表型（SASP）试验，评估通过抑制泛素蛋白连接酶 E3 成分 N-识别受体 5（UBR5）抑制 TERT 过表达对 ROS 诱导的血管损伤和细胞衰老的影响。
ROS 显著损害了 VO 的发育和内皮祖细胞（EPC）的血管生成，表现为新生血管形成减少和衰老标志物增加，包括 SA-β-Gal 活性升高和 SASP 相关细胞因子水平升高。TERT 的过表达逆转了这些作用，恢复了 VO 的发育和 EPC 的功能。免疫沉淀-质谱分析鉴定 UBR5 是 TERT 的关键调节因子，促进其降解。抑制 UBR5 可稳定 TERT，改善 VO 的血管生成能力，并降低 SA-β-Gal 活性和 SASP 细胞因子水平。
抑制 UBR5 可稳定 TERT，从而维持 EPC 的血管生成能力，减少 VO 损伤，并在氧化应激下延缓内皮细胞衰老。这些发现强调了靶向 UBR5 以增强与氧化应激相关条件下血管健康的潜力。
