Trophoblastic mitochondrial DNA induces endothelial dysfunction and NLRP3 inflammasome activation: Implications for preeclampsia

作者全名："Lv, Zi; Lv, Ding-Yi; Meng, Jia-Yu; Sha, Xiao-Yan; Qian, Xue-Ya; Chen, Yun-Shan; Pan, Xiu-Yu; Yu, Guang-Yuan; Liu, Hui-Shu"

作者地址："[Lv, Zi; Sha, Xiao-Yan; Qian, Xue-Ya; Chen, Yun-Shan; Pan, Xiu-Yu; Liu, Hui-Shu] Jinan Univ, Affiliated Hosp 1, Dept Obstet, 9 Jinsui Rd, Guangzhou, Peoples R China; [Lv, Zi; Sha, Xiao-Yan; Qian, Xue-Ya; Chen, Yun-Shan; Pan, Xiu-Yu; Liu, Hui-Shu] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Dept Obstet, 9 Jinsui Rd, Guangzhou, Peoples R China; [Lv, Ding-Yi] Chongqing Med Univ, Affiliated Hosp 1, Dept Cardiol, Chongqing 400016, Peoples R China; [Meng, Jia-Yu] Chongqing Med Univ, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Yu, Guang-Yuan] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Dept Pediat, Guangzhou, Peoples R China"

通信作者："Yu, GY (通讯作者)，Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Dept Pediat, Guangzhou, Peoples R China."

来源：INTERNATIONAL IMMUNOPHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000992230700001

JCR分区：Q1

影响因子：4.8

年份：2023

卷号：114

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Endothelial dysfunction; NLRP3 inflammasome; Mitochondrial DNA; Inflammation; Preeclampsia

摘要："Aims: Preeclampsia (PE) is characterised by systemic vascular endothelium dysfunction. Circulating trophoblastic secretions contribute to endothelial dysfunction, resulting in PE; however, the underlying mechanisms remain unclear. Herein, we aimed to determine the potential correlation between the release of trophoblastic mitochondrial deoxyribonucleic acid (DNA) (mtDNA) and endothelium damage in PE. Materials and methods: Umbilical cord sera and tissues from patients with PE were investigated for inflammasome activation. Following this, trophoblastic mitochondria were isolated from HTR-8/SVneo trophoblasts under 21 % oxygen (O2) or hypoxic conditions (1 % O2 for 48 h) for subsequent treatments. Primary human umbilical vein endothelial cells (HUVECs) were isolated from the human umbilical cord and then exposed to a vehicle (phosphate-buffered saline [PBS]), mtDNA, hypo-mtDNA, or hypo-mtDNA with INF39 (nucleotide oligomerisation domain-like receptor family pyrin domain containing 3 [NLRP3]-specific inhibitor) for 12 h before flow cytometry and immunoblotting. The effects of trophoblastic mtDNA on the endothelium were further analysed in vivo using enzyme-linked immunosorbent assay (ELISA) and vascular reactivity assay. The effects of mtDNA on vascular phenotypes were also tested on NLRP3 knockout mice. Results: Elevated interleukin (IL)-1 beta in PE sera was accompanied by NLRP3 inflammasome activation in cord tissues. In vitro and in vivo experiments revealed that the release of trophoblastic mtDNA could damage the endothelium via NLRP3 activation, resulting in the overexpression of NLRP3, caspase-1 p20, IL-1 beta p17, and gasdermin D (GSDMD); reduced endothelial nitric oxide synthase (eNOS) levels; and impaired vascular relaxation. Flow cytometric analysis confirmed that extensive cell death was induced by mtDNA, and simultaneously, a more pronounced pro-apoptotic effect was caused by hypoxia-treated trophoblastic mtDNA. The NLRP3 knockout or pharmacologic NLRP3 inhibition partially reversed tumour necrosis factor-alpha (TNF-alpha) and IL-1 beta levels and endothelium-dependent vasodilation in mice. Conclusion: These findings demonstrate that trophoblastic mtDNA induced NLRP3/caspase-1/IL-1 beta signalling activation, eNOS-related endothelial injury, and vasodilation dysfunction in PE."

基金机构："High-tech Major Featured Technology Program of Guangzhou Municipal Health Commission [2019GX07]; National Nature Science Foundation of China [81701456]; Research Foundation of Guangzhou Women and Children's Medical Center for Clinical Doctors [2021BS050, 2020BS004]"

基金资助正文："This work was funded by High-tech Major Featured Technology Program of Guangzhou Municipal Health Commission (number: 2019GX07, recipient: HS. L.) , the National Nature Science Foundation of China (number: 81701456, the recipient: XY. S.) , and the Research Foundation of Guangzhou Women and Children's Medical Center for Clinical Doctors (number: 2021BS050, the recipient: Z. L.; number: 2020BS004, the recipient: GY. Y.) ."