Apoptosis, inflammation, and fibrosis contribute to vascular remodeling and injury. Elabela (ELA) serves as a crucial regulator to maintain vascular function and has been implicated in the pathogenesis of hypertensive vascular remodeling. This study aims to explore regulatory roles and underlying mechanisms of ELA in rat aortic adventitial fibroblasts (AFs) in response to angiotensin II (ATII). In cultured AFs, exposure to ATII resulted in marked decreases in mRNA and protein levels of ELA, fibroblast growth factor 21 (FGF21), and angiotensin-converting enzyme 2 (ACE2) as well as increases in apoptosis, inflammation, oxidative stress, and cellular migration, which were partially blocked by the exogenous replenishment of ELA and recombinant FGF21, respectively. Moreover, treatment with ELA strikingly reversed ATII-mediated the loss of FGF21 and ACE2 levels in rat aortic AFs. FGF21 knockdown with small interfering RNA (siRNA) significantly counterbalanced protective effects of ELA on ATII-mediated the promotion of cell migration, apoptosis, inflammatory, and oxidative injury in rat aortic AFs. More importantly, pretreatment with recombinant FGF21 strikingly inhibited ATII-mediated the loss of ACE2 and the augmentation of cell apoptosis, oxidative stress, and inflammatory injury in rat aortic AFs, which were partially prevented by the knockdown of ACE2 with siRNA. In summary, ELA exerts its anti-apoptotic, anti-inflammatory, and anti-oxidant effects in rat aortic AFs via activation of the FGF21–ACE2 signaling. ELA may represent a potential candidate to predict vascular damage and targeting the FGF21–ACE2 signaling may be a promising therapeutic intervention for vascular adventitial remodeling and related disorders.

细胞凋亡、炎症和纤维化导致血管重塑和损伤。 Elabela (ELA) 是维持血管功能的关键调节因子，并与高血压血管重塑的发病机制有关。本研究旨在探讨 ELA 在大鼠主动脉外膜成纤维细胞 (AF) 中对血管紧张素 II (ATII) 反应的调节作用和潜在机制。在培养的 AF 中，暴露于 ATII 会导致 ELA、成纤维细胞生长因子 21 (FGF21) 和血管紧张素转换酶 2 (ACE2) 的 mRNA 和蛋白质水平显着降低，并且细胞凋亡、炎症、氧化应激和细胞因子增加。迁移，分别被 ELA 和重组 FGF21 的外源补充部分阻断。此外，ELA 治疗显着逆转了 ATII 介导的大鼠主动脉 AF 中 FGF21 和 ACE2 水平的丧失。使用小干扰 RNA (siRNA) 敲低 FGF21 可以显着平衡 ELA 对 ATII 介导的大鼠主动脉 AF 细胞迁移、凋亡、炎症和氧化损伤的保护作用。更重要的是，重组 FGF21 预处理显着抑制了 ATII 介导的 ACE2 丢失以及大鼠主动脉 AF 中细胞凋亡、氧化应激和炎症损伤的增加，而用 siRNA 敲低 ACE2 可以部分阻止这些作用。总之，ELA 通过激活 FGF21-ACE2 信号传导在大鼠主动脉 AF 中发挥抗凋亡、抗炎和抗氧化作用。 ELA 可能代表预测血管损伤的潜在候选者，并且靶向 FGF21-ACE2 信号传导可能是血管外膜重塑和相关疾病的有前途的治疗干预措施。