Department of Cardiology, The First Medical Center of Chinese PLA General Hospital & Medical School of Chinese PLA, Beijing, China.
Department of Cardiology, The Eighth Medical Center of Chinese PLA General Hospital, Beijing, China.
FASEB J. 2020 Aug;34(8):10835-10849. doi: 10.1096/fj.202000734R. Epub 2020 Jun 27.
Exposure to microgravity results in vascular remodeling and cardiovascular dysfunction. To elucidate the mechanism involved in this condition, we investigated whether endoplasmic reticulum (ER) stress during simulated microgravity induced endothelial inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs). Microgravity was simulated by clinorotation in the current study. We examined markers of ER stress, inducible nitric oxide (NO) synthase (iNOS)/NO content, proinflammatory cytokine production, nuclear factor kappa B (NF-κB)/IκB signaling, NLRP3 inflammasome, and detected apoptosis in HUVECs. We found that the levels of C/EBP homologous protein and glucose-regulated protein 78, pro-inflammatory cytokines (IL-6, TNF-α, IL-8, and IL-1β), and iNOS/NO content were upregulated by clinorotation. ER stress inhibition with tauroursodeoxycholic acid or 4-phenylbutyric acid and iNOS inhibition with 1400 W dramatically suppressed activation of the NF-κB/IκB pathway and the NLRP3 inflammasome, and decreased the production of pro-inflammatory cytokines. The increase of apoptosis in HUVECs during clinorotation was significantly suppressed by inhibiting ER stress, iNOS activity, NF-κB/IκB, and the NLRP3 inflammasome signaling pathway. Therefore, simulated microgravity causes ER stress in HUVECs, and subsequently activates iNOS/NO-NF-κB/IκB and the NLRP3 inflammasome signaling pathway, which have key roles in the induction of endothelial inflammation and apoptosis.
暴露于微重力会导致血管重塑和心血管功能障碍。为了阐明涉及这种情况的机制，我们研究了模拟微重力期间内质网（ER）应激是否会诱导人脐静脉内皮细胞（HUVEC）中的内皮炎症和细胞凋亡。在本研究中，通过回旋培养来模拟微重力。我们检查了 ER 应激标志物、诱导型一氧化氮合酶（iNOS）/NO 含量、促炎细胞因子产生、核因子 kappa B（NF-κB）/IκB 信号转导、NLRP3 炎性体，并检测了 HUVEC 中的细胞凋亡。我们发现，回旋培养会上调 C/EBP 同源蛋白和葡萄糖调节蛋白 78、促炎细胞因子（IL-6、TNF-α、IL-8 和 IL-1β）以及 iNOS/NO 含量。使用牛磺熊去氧胆酸或 4-苯基丁酸抑制 ER 应激和使用 1400W 抑制 iNOS，可显著抑制 NF-κB/IκB 通路和 NLRP3 炎性体的激活，并减少促炎细胞因子的产生。通过抑制 ER 应激、iNOS 活性、NF-κB/IκB 和 NLRP3 炎性体信号通路，显著抑制了回旋培养过程中 HUVEC 中细胞凋亡的增加。因此，模拟微重力会导致 HUVEC 中的 ER 应激，随后激活 iNOS/NO-NF-κB/IκB 和 NLRP3 炎性体信号通路，这些通路在诱导内皮炎症和凋亡中起关键作用。
