Endothelial cell pyroptosis is a novel cause of endothelial dysfunction in sepsis. Reticulocalbin-2 (RCN2) is involved in regulating vascular inflammation and plays an important role in the cardiovascular system. However, the role of RCN2 in inflammation-induced endothelial cell pyroptosis remains to be explored. Here, we found that RCN2 was upregulated after lipopolysaccharide (LPS) treatment in a concentration‐ and time-dependent manner. RCN2 knockdown resulted in a significant decrease in pyroptosis, reduced LDH and IL-1β release and ROS production and inhibited the expression of pyroptosis‐related proteins (NLRP3, cleaved caspase-1, and cleaved GSDMD) (all p < 0.05). N‐acetyl‐L‐cysteine (NAC) counteracted the effects of RCN2 on pyroptosis (all p < 0.01). The silencing of RCN2 antagonized the inhibitory effect of LPS on the phosphorylation of eNOS (p < 0.05). We predicted and confirmed that specificity protein-1(SP1) could directly bind to the RCN2 promoter and regulate RCN2. RCN2 overexpression rescued the inhibitory effect of SP1 inhibitor on HUVEC pyroptosis induced by LPS (all p < 0.05). These findings suggested that the activation of the SP1/RCN2/ROS signaling pathway could promote LPS-induced endothelial cell pyroptosis.

内皮细胞焦亡是脓毒症内皮功能障碍的新原因。Reticulocalbin-2 (RCN2) 参与调节血管炎症并在心血管系统中发挥重要作用。然而，RCN2 在炎症诱导的内皮细胞焦亡中的作用仍有待探索。在这里，我们发现脂多糖 (LPS) 处理后 RCN2 以浓度和时间依赖性方式上调。RCN2 敲低导致焦亡显着减少，LDH 和 IL-1β 释放减少以及 ROS 产生减少，并抑制焦亡相关蛋白（NLRP3、cleaved caspase-1 和 cleaved GSDMD）的表达（所有 p < 0.05）。N-乙酰-L-半胱氨酸（NAC）抵消了 RCN2 对细胞焦亡的影响（所有 p < 0.01）。RCN2 的沉默拮抗 LPS 对 eNOS 磷酸化的抑制作用 (p < 0.05)。我们预测并证实了特异性蛋白-1(SP1) 可以直接与 RCN2 启动子结合并调节 RCN2。RCN2 过表达挽救了 SP1 抑制剂对 LPS 诱导的 HUVEC 细胞焦亡的抑制作用（所有 p < 0.05）。这些发现表明 SP1/RCN2/ROS 信号通路的激活可以促进 LPS 诱导的内皮细胞焦亡。