Upregulation of miR-335-3p by NF-κB Transcriptional Regulation Contributes to the Induction of Pulmonary Arterial Hypertension via APJ during Hypoxia

Fan, Junming; Fan, Xiaofang; Guang, Hui; Shan, Xiaoqiong; Tian, Qiuyun; Zhang, Fukun; Chen, Ran; Ye, Fangzhou; Quan, Hui; Zhang, Haizeng; Ding, Liang; Zhang, Gan; Xue, Feng; Wang, Yongyu; Mao, Sun‐Zhong; Hu, Liang-Gang; Gong, Yongsheng

doi:10.7150/ijbs.34517

Cited by 23 publications

(23 citation statements)

References 49 publications

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“…Chronic normobaric hypoxia stimulated PAH and also increased the level of miR-335-3p in the mouse lung [91]. The inhibition of miR-335-3p resulted in the attenuation of chronic normobaric hypoxia-induced vascular remodeling and PAH in mice [91]. A significant increase in miR-30a-5p level in the plasma of PAH patients was recently reported [92].…”

Section: Pahmentioning

confidence: 82%

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miRNAs in Lung Development and Diseases

Boateng

Krauss‐Etschmann

2020

IJMS

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The development of the lung involves a diverse group of molecules that regulate cellular processes, organ formation, and maturation. The various stages of lung development are marked by accumulation of small RNAs that promote or repress underlying mechanisms, depending on the physiological environment in utero and postnatally. To some extent, the pathogenesis of various lung diseases is regulated by small RNAs. In this review, we discussed miRNAs regulation of lung development and diseases, that is, COPD, asthma, pulmonary fibrosis, and pulmonary arterial hypertension, and also highlighted possible connotations for human lung health.After fertilization in the mouse, total miRNA in the two-cell-stage embryo was demonstrated to be significantly lower than the levels in one-cell zygote [15]. Notably, total miRNA in the four-cell-stage embryo was higher than the levels in the two-cell-stage embryo [15]. In the early mouse embryo, miR-127 was upregulated at E6.5 and E7.5 [16]. Overexpression of miR-127 in mouse embryonic stem cells, which differentiated into embryoid bodies, increased the mRNA levels of Gsc, Foxa2, and Brachyury (mesendoderm markers), but elicited no change in Pax6 and Otx2 (ectoderm markers) three days after transfection. Inhibition of miR-127 showed opposite regulation of Gsc, Foxa2, and Brachyury. miR-127, moreover, was suggested to control mesendoderm differentiation [16]. miR-326 regulated sonic hedgehog signaling by targeting Smo and Gli2 [17]. The inhibition of smoothened in cultured explanted E12 mouse lung resulted in the expansion of distal epithelium, and disruption of normal branching pattern and mesenchymal integrity [17]. Another study described the functional role of miR-142-3p in the mouse embryonic lung mesenchyme. The miRNA was shown to regulate adenomatous polyposis coli to further modulate Wnt signaling [18]. Taken together, miR-142-3p regulated the proliferation and differentiation of mesenchymal progenitors in the mouse embryonic lung [18].In the developing mouse lung, the level of miR-17 was stable (E11.5-E16.5), predominantly at the pseudoglandular stage, with higher epithelial levels at E12.5 [19]. Simultaneous knockdown of miR-17 and its paralogs, miR-20a and miR-106b, for 72 h in epithelial lung explants altered branching, even in FGF10-treated condition [19]. In the human fetal lung, miR-449a was upregulated at 18-20 weeks (canalicular stage), and in the mouse embryonic lung, miR-449a level was increased from E15.5 to E18.5 [20]. The inhibition of miR-449a in E16.5 mouse lung culture (end of pseudoglandular stage) increased the mRNA levels of Mycn and Sox9, and the protein levels of Ki-67 and SOX9 particularly in the distal epithelial region [20].Knockout of miR-26a-1/miR-26a-2 in the mouse promoted the formation of dilated lumens and aerated regions at the beginning of the canalicular stage (E16.5) of lung development [21]. Results at the saccular stage (E18.5) also indicated large lamellar bodies, and increased SP-A, SP-B, and SP-C protein levels in miR-26a knockout mice....

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Section: Pahmentioning

confidence: 82%

“…Moreover, miR-27a targeted SMAD5 to promote hypoxia-induced endothelial to mesenchymal transition [90]. Chronic normobaric hypoxia stimulated PAH and also increased the level of miR-335-3p in the mouse lung [91]. The inhibition of miR-335-3p resulted in the attenuation of chronic normobaric hypoxia-induced vascular remodeling and PAH in mice [91].…”

Section: Pahmentioning

confidence: 99%

miRNAs in Lung Development and Diseases

Boateng

Krauss‐Etschmann

2020

IJMS

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“…It has been reported that inflammation of vascular smooth muscle cells played a key role in various vascular disorders, including PAH, restenosis and atherosclerosis [13]. In terms of PAH research, a recent study noted that the up‐regulation of miR‐335‐3p mediated by NF‐κB contributes to the inhibition of apelin receptor and development of PAH [14]. Moreover, Li et al [15] found that NF‐κB‐mediated miR‐130a modulation might play a critical role in excessive lung vascular remodeling, which is a major cause of the increased pulmonary vascular resistance.…”

Section: Discussionmentioning

confidence: 99%

CCR7 and its related molecules may be potential biomarkers of pulmonary arterial hypertension

Cai

Dong

et al. 2021

FEBS Open Bio

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Pulmonary arterial hypertension (PAH) is a chronic progressive cardiovascular disease characterized by vascular remodeling and leading to right heart failure. The purpose of this research was to further study the pathogenesis of PAH and to detect potential prognostic signatures. Differentially expressed genes (DEGs) selected from GSE38267 were mostly enriched in inflammation-related pathways, suggesting inflammation may be involved in the occurrence and development of PAH. Through the prediction and verification of related miRNAs and lncRNAs using online databases and GEO datasets, CCR7 and its related molecules, including hsa-let-7e-5p and SNHG12, were identified as possible targets. The expression levels of CCR7, hsa-let-7e-5p and SNHG12 were then verified by qRT-PCR in vivo and in vitro. Further study showed that silencing of SNHG12 decreased the expression of CCR7 under hypoxia treatment in vitro. Dual-luciferase reporter assays were utilized to verify the relationship between hsa-let-7e-5p and SNHG12. Collectively, our research reveals that a lncRNA/miRNA/mRNA interaction network may be involved in the pathogenesis of PAH, and suggest SNHG12, hsa-let-7e-5p and CCR7 as potential biomarkers for PAH.

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“…We report the discovery of potentially pathogenic variants in TNIP2 and TRAF2, two genes associated with inflammation and immunity whose role in PAH has not been previously documented. Through the use of patient-derived cells and in vitro gene knockdown studies, we show that TNIP2 and TRAF2 act by suppressing the activation of NF-κB, a transcription complex that controls the expression of inflammatory cytokines and genes associated with cell proliferation in PAH (18)(19)(20)(21). We conclude that TNIP2 and TRAF2 pathogenic variants could increase PAH susceptibility through their capacity to alter cellular immune responses and drive abnormal cellular proliferation in the pulmonary vasculature.…”

Section: Introductionmentioning

confidence: 93%

Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension

et al. 2021

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Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling and right heart failure. Specific genetic variants increase the incidence of PAH in carriers with a family history of PAH, those who suffer from certain medical conditions, and even those with no apparent risk factors. Inflammation and immune dysregulation are related to vascular remodeling in PAH, but whether genetic susceptibility modifies the PAH immune response is unclear. TNIP2 and TRAF2 encode for immunomodulatory proteins that regulate NF-κB activation, a transcription factor complex associated with inflammation and vascular remodeling in PAH.Methods: Two unrelated families with PAH cases underwent whole-exome sequencing (WES). A custom pipeline for variant prioritization was carried out to obtain candidate variants. To determine the impact of TNIP2 and TRAF2 in cell proliferation, we performed an MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay on healthy lung pericytes transfected with siRNA specific for each gene. To measure the effect of loss of TNIP2 and TRAF2 on NF-kappa-beta (NF-κB) activity, we measured levels of Phospho-p65-NF-κB in siRNA-transfected pericytes using western immunoblotting.Results: We discovered a novel missense variant in the TNIP2 gene in two affected individuals from the same family. The two patients had a complex form of PAH with interatrial communication and scleroderma. In the second family, WES of the proband with PAH and primary biliary cirrhosis revealed a de novo protein-truncating variant in the TRAF2. The knockdown of TNIP2 and TRAF2 increased NF-κB activity in healthy lung pericytes, which correlated with a significant increase in proliferation over 24 h.Conclusions: We have identified two rare novel variants in TNIP2 and TRAF2 using WES. We speculate that loss of function in these genes promotes pulmonary vascular remodeling by allowing overactivation of the NF-κB signaling activity. Our findings support a role for WES in helping identify novel genetic variants associated with dysfunctional immune response in PAH.

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Upregulation of miR-335-3p by NF-κB Transcriptional Regulation Contributes to the Induction of Pulmonary Arterial Hypertension via APJ during Hypoxia

Cited by 23 publications

References 49 publications

miRNAs in Lung Development and Diseases

miRNAs in Lung Development and Diseases

CCR7 and its related molecules may be potential biomarkers of pulmonary arterial hypertension

Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension

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