Essential Genes and MiRNA–mRNA Network Contributing to the Pathogenesis of Idiopathic Pulmonary Arterial Hypertension

Hao, Shengyu; Jiang, Pan; Xie, Liang; Xiang, Guiling; Liu, Zilong; Hu, Weiping; Wu, Qiao; Jiang, Liyan; Xiao, Yi; Li, Shanqun

doi:10.3389/fcvm.2021.627873

Cited by 8 publications

(4 citation statements)

References 40 publications

(45 reference statements)

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“…Inflammation, including macrophages recruited early in PAH and activities of various cytokines or chemokines, is being deemed as a major contributor to the pathogenesis of PAH (3). Several researchers have indicated that a wide variety of chemokine systems comprising the CCL2-CCR2, CX3CL1-CX3CR1 and CCL5-CCR5 axis involved in macrophage recruitment and pulmonary vascular remodeling (6)(7)(8). Even several chemokines, for example, CCL2 and CXCL10, have emerged as potential biomarkers of PAH due to the elevating trend in disease setting and their correlation with disease severity in different forms of PAH (9,10).…”

Section: Introductionmentioning

confidence: 99%

Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension

Jiang,

Wu,

Liu

et al. 2023

Front. Immunol.

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ObjectiveInflammation is recognized as a contributor in the development of pulmonary arterial hypertension (PAH), and the recruitment and functional capacity of immune cells are well-orchestrated by chemokines and their receptors. This study is aimed at identification of critical chemokines in the progression of PAH via transcriptomic analysis.MethodsDifferentially expressed genes (DEGs) from lungs of PAH patients were achieved compared to controls based on Gene Expression Omnibus (GEO) database. Gene set enrichment analysis (GSEA) was applied for functional annotation and pathway enrichement. The abundance of immune cells was estimated by the xCell algorithm. Weighted correlation network analysis (WGCNA) was used to construct a gene expression network, based on which a diagnostic model was generated to determine its accuracy to distinguish PAH from control subjects. Target genes were then validated in lung of hypoxia-induce pulmonary hypertension (PH) mouse model.ResultsACKR4 (atypical chemokine receptor 4) was downregulated in PAH lung tissues in multiple datasets. PAH relevant biological functions and pathways were enriched in patients with low-ACKR4 level according to GSEA enrichment analysis. Immuno-infiltration analysis revealed a negative correlation of activated dendritic cells, Th1 and macrophage infiltration with ACKR4 expression. Three gene modules were associated with PAH via WGCNA analysis, and a model for PAH diagnosis was generated using CXCL12, COL18A1 and TSHZ2, all of which correlated with ACKR4. The ACKR4 expression was also downregulated in lung tissues of our experimental PH mice compared to that of controls.ConclusionsThe reduction of ACKR4 in lung tissues of human PAH based on transcriptomic data is consistent with the alteration observed in our rodent PH. The correlation with immune cell infiltration and functional annotation indicated that ACKR4 might serve as a protective immune checkpoint for PAH.

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Section: Introductionmentioning

confidence: 99%

Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension

Jiang,

Wu,

Liu

et al. 2023

Front. Immunol.

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“…MicroRNA-mRNA network contributes to the pathogenesis of idiopathic pulmonary arterial hypertension [ 28 ]. In this study, bioinformatics analysis indicated that NOS1 might be a direct downstream target of miR-4640-5p.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of miR-4640-5p alleviates pulmonary hypertension in chronic obstructive pulmonary disease patients by regulating nitric oxide synthase 1

Zhao

Yan

et al. 2023

Respir Res

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Background Pulmonary hypertension (PH) is a devastating disease characterized by vasoconstriction and vascular remodeling, leading to right ventricular failure and death. PH is a common complication of chronic obstructive pulmonary disease (COPD). Accumulating evidence demonstrate that microRNAs participate in the pathobiology of PH in COPD patients. In this study, we aimed to evaluate the expression and function of microRNA-4640-5p (miR-4640-5p) in PH. Methods The mRNA and protein levels were determined by quantitative polymerase chain reaction (qPCR) and western blot, separately. Functional assays and western blot were performed to determine the effects of miR-4640-5p and NOS1 on cell growth, migration. Besides, the dual-luciferase reporter assays were used to validate miR-4640-5p and NOS1 interactions. Results We found that miR-4640-5p expression was significantly higher in the lung tissues of COPD-PH patients than in the healthy controls while higher expression of miR-4640-5p was correlated with more severe COPD-PH. By using pulmonary artery smooth muscle cell (PASMC) in in vitro assays, we demonstrated that inhibition of miR-4640-5p suppressed cell proliferation and migration of PASMC via regulating mTOR/S6 signaling. Bioinformatics analysis and validation experiments revealed that nitric oxide synthase 1 (NOS1) was a direct downstream target of miR-4640-5p. Overexpression of NOS1 partially antagonized the effect of miR-4640-5p in regulating PASMC cell proliferation and migration. In addition, our findings suggested that miR-4640-5p/NOS1 axis regulated mitochondrial dynamics in PASMCs. Furthermore, in the hypoxia-induced PH rat model, inhibition of miR-4640-5p ameliorated PH with reduced right ventricular systolic pressure and Fulton index. Conclusions miR-4640-5p regulates PH via targeting NOS1, which provides a potential diagnostic biomarker and therapeutic target for COPD-PH patients.

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“…A previous study showed a connection between idiopathic pulmonary arterial hypertension (IPAH) and and miR-34b-5p, which was associated with most of the declinable target differentially expressed genes, cell multiplication, and adhesion-independent growth [ 68 ]. The target genes of miR-34b-5p are basically related to immune and inflammatory reactions, for instance, neutrophil chemotaxis and migration, integrin binding, and Toll-like receptor binding [ 69 , 70 ]. Besides, they are also involved in inflammation pathways such as the IL-17 signaling pathway, indicating that miR-34b-5p might play crucial roles in the pathogenesis of IPAH through enhanced inflammatory response [ 71 ].…”

Section: Mir-34b-5p In Injurymentioning

confidence: 99%

Role of microRNA-34b-5p in cancer and injury: how does it work?

Bai

Zheng

et al. 2022

Cancer Cell Int

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MicroRNAs (miRNAs or miRs) are a class of noncoding single-stranded RNAs that can regulate gene expression by binding to the untranslated sequences at the 3 ' end of messenger RNAs. The microRNA-34 family is dysregulated in various human diseases. It is considered as a tumor-suppressive microRNA because of its synergistic effect with the well-known tumor suppressor p53. As a member of the miRNA-34 family, miR-34b-5p serves as a powerful regulator of a suite of cellular activities, including cell growth, multiplication, development, differentiation, and apoptosis. It promotes or represses disease occurrence and progression by participating in some important signaling pathways. This review aimed to provide an overview and update on the differential expression and function of miR-34b-5p in pathophysiologic processes, especially cancer and injury. Additionally, miR-34b-5p‐mediated clinical trials have indicated promising consequences for the therapies of carcinomatosis and injury. With the application of the first tumor-targeted microRNA drug based on miR-34a mimics, it can be inferred that miR-34b-5p may become a crucial factor in the therapy of various diseases. However, further studies on miR-34b-5p should shed light on its involvement in disease pathogenesis and treatment options.

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Essential Genes and MiRNA–mRNA Network Contributing to the Pathogenesis of Idiopathic Pulmonary Arterial Hypertension

Cited by 8 publications

References 40 publications

Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension

Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension

Inhibition of miR-4640-5p alleviates pulmonary hypertension in chronic obstructive pulmonary disease patients by regulating nitric oxide synthase 1

Role of microRNA-34b-5p in cancer and injury: how does it work?

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