To determine the roles of nuclear localization of pro-caspase-1 in human aortic endothelial cells (HAECs) activated by proatherogenic lipid lysophosphatidylcholine (LPC), we examined cytosolic and nuclear localization of pro-caspase-1, identified nuclear export signal (NES) in pro-caspase-1 and sequenced RNAs. We made the following findings: 1) LPC increases nuclear localization of procaspase-1 in HAECs. 2) Nuclear pro-caspase-1 exports back to the cytosol, which is facilitated by a leptomycin B-inhibited mechanism. 3) Increased nuclear localization of pro-caspase-1 by a new NES peptide inhibitor upregulates inflammatory genes in oxidative stress and Th17 pathways; and SUMO activator N106 enhances nuclear localization of pro-caspase-1 and caspase-1 activation (p20) in the nucleus. 4) LPC plus caspase-1 enzymatic inhibitor upregulates inflammatory genes with hypercytokinemia/hyperchemokinemia and interferon pathways, suggesting a novel capsase-1 enzyme-independent inflammatory mechanism. 5) LPC in combination with NES inhibitor and caspase-1 inhibitor upregulate inflammatory gene expression that regulate Th17 activation, endotheli-1 signaling, p38-, and ERK- MAPK pathways. To examine two hallmarks of endothelial activation such as secretomes and membrane protein signaling, LPC plus NES inhibitor upregulate 57 canonical secretomic genes and 76 exosome secretomic genes, respectively, promoting four pathways including Th17, IL-17 promoted cytokines, interferon signaling and cholesterol biosynthesis. LPC with NES inhibitor also promote inflammation via upregulating ROS promoter CYP1B1 and 11 clusters of differentiation (CD) membrane protein pathways. Mechanistically, all the LPC plus NES inhibitor-induced genes are significantly downregulated in CYP1B1-deficient microarray, suggesting that nuclear caspase-1-induced CYP1B1 promotes strong inflammation. These transcriptomic results provide novel insights on the roles of nuclear caspase-1 in sensing DAMPs, inducing ROS promoter CYP1B1 and in regulating a large number of genes that mediate HAEC activation and inflammation. These findings will lead to future development of novel therapeutics for cardiovascular diseases (CVD), inflammations, infections, transplantation, autoimmune disease and cancers. (total words: 284).

为了确定 pro-caspase-1 在由致动脉粥样硬化脂质溶血磷脂酰胆碱 (LPC) 激活的人主动脉内皮细胞 (HAEC) 中的核定位作用，我们检查了 pro-caspase-1 的细胞溶质和核定位，确定了核输出信号 (NES)在 pro-caspase-1 和测序的 RNA 中。我们取得了以下发现：1） LPC 增加了 HAEC 中 procaspase-1 的核定位。2)核 pro-caspase-1 输出回胞质溶胶，这是由细霉素 B 抑制机制促进的。3)一种新的 NES 肽抑制剂增加了 pro-caspase-1 的核定位，上调了氧化应激和 Th17 通路中的炎症基因；SUMO 激活剂 N106 增强细胞核中 pro-caspase-1 和 caspase-1 激活 (p20) 的核定位。4) LPC 加 caspase-1 酶抑制剂通过高细胞因子血症/高趋化因子血症和干扰素途径上调炎症基因，提示一种新的 capsase-1 酶非依赖性炎症机制。5)LPC 与 NES 抑制剂和 caspase-1 抑制剂联合上调调节 Th17 激活、内皮细胞 1 信号、p38 和 ERK-MAPK 通路的炎症基因表达。为了检查内皮激活的两个标志，如分泌物和膜蛋白信号，LPC 加 NES 抑制剂分别上调 57 个经典分泌基因和 76 个外泌体分泌基因，促进 Th17、IL-17 促进细胞因子、干扰素信号和胆固醇生物合成等四种途径。带有 NES 抑制剂的 LPC 还通过上调 ROS 启动子 CYP1B1 和 11 个分化簇 (CD) 膜蛋白途径来促进炎症。机制上，所有 LPC 加 NES 抑制剂诱导的基因在 CYP1B1 缺陷型微阵列中显着下调，表明核 caspase-1 诱导的 CYP1B1 促进了强烈的炎症。这些转录组学结果为核 caspase-1 在感知 DAMP、诱导 ROS 启动子 CYP1B1 和调节大量介导 HAEC 激活和炎症的基因中的作用提供了新的见解。这些发现将导致心血管疾病（CVD）、炎症、感染、移植、自身免疫性疾病和癌症的新疗法的未来发展。（总字数：284）。感染、移植、自身免疫性疾病和癌症。（总字数：284）。感染、移植、自身免疫性疾病和癌症。（总字数：284）。