Small extracellular vesicles-transported lncRNA TDRKH-AS1 derived from AOPPs-treated trophoblasts initiates endothelial cells pyroptosis through PDIA4/DDIT4 axis in preeclampsia

Chen, Qian1; He, Jiexing1; Liu, Haihua1; Huang, Qiuyu1; Wang, Shuoshi4; Yin, Ailan1; Chen, Shuying5; Shen, Xinyang1; Xiao, Yanxuan1; Hu, Haoyue1; Jiang, Jiayi1; Chen, Wenqian1; Wang, Song1; Huang, Zhenqin1; Li, Jiaqi1; Peng, You1; Wang, Xiaocong1; Yang, Xinping1,2,3; Wang, Zhijian1; Zhong, Mei1

2023-07-24

10.1186/s12967-023-04346-6

JOURNAL OF TRANSLATIONAL MEDICINE   Impact Factor & Quartile

1479-5876

BackgroundSubstantial studies have demonstrated that oxidative stress placenta and endothelial injury are considered to inextricably critical events in the pathogenesis of preeclampsia (PE). Systemic inflammatory response and endothelial dysfunction are induced by the circulating factors released from oxidative stress placentae. As a novel biomarker of oxidative stress, advanced oxidation protein products (AOPPs) levels are strongly correlated with PE characteristics. Nevertheless, the molecular mechanism underlying the effect of factors is still largely unknown.MethodsWith the exponential knowledge on the importance of placenta-derived extracellular vesicles (pEVs), we carried out lncRNA transcriptome profiling on small EVs (sEVs) secreted from AOPPs-treated trophoblast cells and identified upregulated lncRNA TDRKH-AS1 as a potentially causative factor for PE. We isolated and characterized sEVs from plasma and trophoblast cells by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting. The expression and correlation of lncRNA TDRKH-AS1 were evaluated using qRT-PCR in plasmatic sEVs and placentae from patients. Pregnant mice injected with TDRKH-AS1-riched trophoblast sEVs was performed to detect the TDRKH-AS1 function in vivo. To investigate the potential effect of sEVs-derived TDRKH-AS1 on endothelial function in vitro, transcriptome sequencing, scanning electron Microscopy (SEM), immunofluorescence, ELISA and western blotting were conducted in HUVECs. RNA pulldown, mass spectrometry, RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP) and coimmunoprecipitation (Co-IP) were used to reveal the latent mechanism of TDRKH-AS1 on endothelial injury.ResultsThe expression level of TDRKH-AS1 was significantly increased in plasmatic sEVs and placentae from patients, and elevated TDRKH-AS1 in plasmatic sEVs was positively correlated with clinical severity of the patients. Moreover, pregnant mice injected with TDRKH-AS1-riched trophoblast sEVs exhibited a hallmark feature of PE with increased blood pressure and systemic inflammatory responses. Pyroptosis, an inflammatory form of programmed cell death, is involved in the development of PE. Indeed, our in vitro study indicated that sEVs-derived TDRKH-AS1 secreted from AOPPs-induced trophoblast elevated DDIT4 expression levels to trigger inflammatory response of pyroptosis in endothelial cells through interacting with PDIA4.ConclusionsHerein, results in the present study supported that TDRKH-AS1 in sEVs isolated from oxidative stress trophoblast may be implicated in the pathogenesis of PE via inducing pyroptosis and aggravating endothelial dysfunction.

Preeclampsia Advanced oxidation protein products Extracellular vesicles lncRNA TDRKH-AS1 PDIA4 DDIT4 Oxidative stress Pyroptosis

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English

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Research & Experimental Medicine

Medicine, Research & Experimental

WOS:001035769600002

BMC

Web of Science

1.Southern Med Univ, Nanfang Hosp, Dept Obstet & Gynecol, Guangzhou 510515, Peoples R China
2.Southern Med Univ, Minist Educ, Key Lab Mental Hlth, Guangzhou 510515, Peoples R China
3.Southern Med Univ, Sch Basic Med Sci, Dept Bioinformat, Guangzhou 510515, Peoples R China
4.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp, Affiliated Hosp 1,Dept Obstet,Clin Med Coll 2, Shenzhen 518020, Peoples R China
5.Shenzhen Univ, Shenzhen Peoples Hosp 2, Affiliated Hosp 1, Dept Obstet, Shenzhen 518035, Peoples R China

Chen, Qian,He, Jiexing,Liu, Haihua,et al. Small extracellular vesicles-transported lncRNA TDRKH-AS1 derived from AOPPs-treated trophoblasts initiates endothelial cells pyroptosis through PDIA4/DDIT4 axis in preeclampsia[J]. JOURNAL OF TRANSLATIONAL MEDICINE,2023,21(1).

Chen, Qian.,He, Jiexing.,Liu, Haihua.,Huang, Qiuyu.,Wang, Shuoshi.,...&Zhong, Mei.(2023).Small extracellular vesicles-transported lncRNA TDRKH-AS1 derived from AOPPs-treated trophoblasts initiates endothelial cells pyroptosis through PDIA4/DDIT4 axis in preeclampsia.JOURNAL OF TRANSLATIONAL MEDICINE,21(1).

Chen, Qian,et al."Small extracellular vesicles-transported lncRNA TDRKH-AS1 derived from AOPPs-treated trophoblasts initiates endothelial cells pyroptosis through PDIA4/DDIT4 axis in preeclampsia".JOURNAL OF TRANSLATIONAL MEDICINE 21.1(2023).