Key result
Elevated sEV-derived TDRKH-AS1 in preeclampsia induces endothelial cell pyroptosis and preeclampsia-like features in vivo.
Why the study?
The molecular mechanism underlying how circulating factors released from oxidative stress placentae induce endothelial dysfunction and systemic inflammation in preeclampsia was largely unknown.
TDRKH-AS1 in sEVs from oxidative stress trophoblasts may drive preeclampsia pathogenesis by inducing endothelial pyroptosis, presenting a potential novel biomarker and therapeutic target.
Answers are grounded in this paper and cite their sources.
sEVs-derived TDRKH-AS1 may promote preeclampsia via endothelial pyroptosis; hypothesis-generating and leaves open biomarker or therapeutic roles pending validation.
BACKGROUND: Substantial 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. METHODS: With 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. RESULTS: The 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. CONCLUSIONS: Herein, 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.
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Chen et al. (2023) studied Preeclampsia (n=60). sEVs-derived TDRKH-AS1 vs. Normal pregnancy controls was evaluated on Relative expression of TDRKH-AS1 in plasmatic small extracellular vesicles (p=<0.01). Expression of sEVs-derived TDRKH-AS1 was significantly elevated in preeclampsia patients and was shown to induce endothelial cell pyroptosis and preeclampsia-like features in vivo.
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