Thioredoxin system activation is associated with the progression of experimental pulmonary arterial hypertension

Zimmer, Alexsandra; Teixeira, Rayane Brinck; Constantin, Rosalia Lempk; Fernandes-Piedras, Tânia Regina Gatelli; Carraro, Cristina Campos; Türck, Patrick; Visioli, Fernanda; Baldo, Guilherme; Schenkel, Paulo Cavalheiro; Araújo, Alex Sander da Rosa

doi:10.1016/j.lfs.2021.119917

Cited by 4 publications

(5 citation statements)

References 34 publications

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“…However, there were also literatures supporting that TXNRD1 could prevent tumorigenesis ( 30 ). At present, TXNRD1 has not yet been reported in pulmonary hypertension, while the substrate of TXNRD1, thioredoxin1 (Trx1), was claimed to be increased in hypoxia-induced PASMC proliferation ( 31 ), whereas Zimmer et al observed that MCT-induced PAH animal model promoted a reduction in Trx1 ( 32 ). Potential reasons for this contradiction may arise from different stimuli or different stages of disease development.…”

Section: Discussionmentioning

confidence: 99%

Integrated Bioinformatic Analysis Reveals TXNRD1 as a Novel Biomarker and Potential Therapeutic Target in Idiopathic Pulmonary Arterial Hypertension

et al. 2022

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Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening cardiopulmonary disease lacking specific diagnostic markers and targeted therapy, and its mechanism of development remains to be elucidated. The present study aimed to explore novel diagnostic biomarkers and therapeutic targets in IPAH by integrated bioinformatics analysis. Four eligible datasets (GSE117261, GSE15197, GSE53408, GSE48149) was firstly downloaded from GEO database and subsequently integrated by Robust rank aggregation (RRA) method to screen robust differentially expressed genes (DEGs). Then functional annotation of robust DEGs was performed by GO and KEGG enrichment analysis. The protein-protein interaction (PPI) network was constructed followed by using MCODE and CytoHubba plug-in to identify hub genes. Finally, 10 hub genes were screened including ENO1, TALDO1, TXNRD1, SHMT2, IDH1, TKT, PGD, CXCL10, CXCL9, and CCL5. The GSE113439 dataset was used as a validation cohort to appraise these hub genes and TXNRD1 was selected for verification at the protein level. The experiment results confirmed that serum TXNRD1 concentration was lower in IPAH patients and the level of TXNRD1 had great predictive efficiency (AUC:0.795) as well as presents negative correlation with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR). Consistently, the expression of TXNRD1 was proved to be inhibited in animal and cellular model of PAH. In addition, GSEA analysis was performed to explore the functions of TXNRD1 and the results revealed that TXNRD1 was closely correlated with mTOR signaling pathway, MYC targets, and unfolded protein response. Finally, knockdown of TXNRD1 was shown to exacerbate proliferative disorder, migration and apoptosis resistance in PASMCs. In conclusion, our study demonstrates that TXNRD1 is a promising candidate biomarker for diagnosis of IPAH and plays an important role in PAH pathogenesis, although further research is necessary.

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Section: Discussionmentioning

confidence: 99%

Integrated Bioinformatic Analysis Reveals TXNRD1 as a Novel Biomarker and Potential Therapeutic Target in Idiopathic Pulmonary Arterial Hypertension

et al. 2022

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“…Another recent study demonstrated that miR-638 induced apoptosis through regulating STARD10 signaling, the expression of miR-638 was inversely correlated with the expression of STARD10 mRNA ( Zhao et al, 2017 ). Several previous studies have shown that apoptosis play a vital role in pulmonary arterial hypertension ( Lv et al, 2021 ; Zimmer et al, 2021 ), indicating that the association of miR-638 with PAH may be partially related to STARD10, a target gene of miR-638.…”

Section: Discussionmentioning

confidence: 99%

Effect of Xuezhikang Therapy on Expression of Pulmonary Hypertension Related miR-638 in Patients With Low HDL-C Levels

Cao¹,

Sun²,

Xu³

et al. 2021

Front. Pharmacol.

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Objective: Low plasma level of high-density lipoprotein cholesterol (HDL-C) associated with poor outcomes in several cardiovascular diseases, including pulmonary arterial hypertension (PAH). Regulation of miR-638 have been proved to be associated with PAH. The aim of this study was to evaluate the expression of miR-638 after Xuezhikang (XZK) therapy in patients with low HDL-C.Methods: Plasma levels of miR-638 were quantified by real-time polymerase chain reactions in 20 patients with PAH and 30 healthy controls. A total of 40 subjects with low HDL-C were assigned to receive an XZK therapy for 6 months. The miR-638 expression profiles were detected in PAH patients, XZK-treated subjects and lovastatin treated pulmonary arterial smooth muscle cells (PA-SMCs).Results: The relative expression level of miR-638 in the plasma was lower in the PAH patients than that in the controls (p < 0.001). An increase of 11.2% from baseline in the HDL-C level was found after XZK therapy (p < 0.001). The relative expression of miR-638 was increased after XZK treatment (p < 0.01). The changes of miR-638 were inversely associated with baseline HDL-C levels. A significantly reduction in miR-638 expression were found in PDGF-BB-treated hPA-SMCs compared to the control cells, and the pre-treatment of the cells with lovastatin significantly re-gain the expression levels in miR-638.Conclusion: In patients with low HDL-C levels, XZK therapy raised the expression of miR-638, suggesting that the potential therapeutic effect of XZK in PAH patients with low serum HDL-C levels deserves further exploration.

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“…Research showed that MCT promoted the decreased expression of Trx-1 and Nrf2. Moreover, Trx-1 is an antioxidant and regulated by Nrf2 [ 53 ]. Downregulated Nrf2, increased lipid peroxidation, and decreased antioxidant capacity were found in the lung tissue of the MCT-induced pH model.…”

Section: Nrf2-mediated Oxidative Stress and Phmentioning

confidence: 99%

Target Nuclear Factor Erythroid 2-Related Factor 2 in Pulmonary Hypertension: Molecular Insight into Application

Qin

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor involved in maintaining redox balance and activates the expression of downstream antioxidant enzymes. Nrf2 has received wide attention considering its crucial role in oxidative and electrophilic stress. Large amounts of studies have demonstrated the protective role of Nrf2 activation in various pulmonary hypertension (pH) models. Additionally, various kinds of natural phytochemicals acting as Nrf2 activators prevent the development of pH and provide a novel and promising therapeutic insight for the treatment of pH. In the current review, we give a brief introduction of Nrf2 and focus on the role and mechanism of Nrf2 in the pathophysiology of pH and then review the relevant research of Nrf2 agonists in pH in both experimental research and clinical trials.

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Thioredoxin system activation is associated with the progression of experimental pulmonary arterial hypertension

Cited by 4 publications

References 34 publications

Integrated Bioinformatic Analysis Reveals TXNRD1 as a Novel Biomarker and Potential Therapeutic Target in Idiopathic Pulmonary Arterial Hypertension

Integrated Bioinformatic Analysis Reveals TXNRD1 as a Novel Biomarker and Potential Therapeutic Target in Idiopathic Pulmonary Arterial Hypertension

Effect of Xuezhikang Therapy on Expression of Pulmonary Hypertension Related miR-638 in Patients With Low HDL-C Levels

Target Nuclear Factor Erythroid 2-Related Factor 2 in Pulmonary Hypertension: Molecular Insight into Application

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