Targeting inflammation and immunity in pulmonary arterial hypertension: any easier after the CANTOS proof‐of‐concept that anti‐inflammation cuts cardiovascular events?

Gerges, Christian; Lang, Irene M.

doi:10.1177/2045893218754855

Cited by 2 publications

(2 citation statements)

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“…PAH is linked to pulmonary vascular in ammation and immune dysregulation, both of which are in uenced by TLR4 signaling pathways. [30]. One study also showed that PAH patients have TLR3 de ciency [31].TLR1 and TLR4, which we identi ed as hub genes in our study that play important roles in TLR signaling, con rmed by previous studies.…”

Section: Discussionsupporting

confidence: 87%

In Silico Analysis of Pulmonary Arterial Hypertension to İdentify Key Biomarkers at Protein and RNA Levels

Akçay

2022

Preprint

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Background Pulmonary arterial hypertension (PAH) is a chronic cardiopulmonary disorder marked by a raised hypertension in the pulmonary arteries. There is no remedy for PAH, existing medications can help to reduce the disease’s progression. The goal of this research was to investigate potential protein and RNA biomarkers of PAH by bioinformatic analysis. Methods Two PAH datasets accessed from the publicly available Gene Expression Omnibus (GEO) database were utilized to discover differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for common DEGs were conducted by the DAVID tool. Cytoscape was used to create the protein-protein interaction (PPI) and pick the top 10 hub genes. The transcription factors (TFs) and microRNAs (miRNAs) that target DEGs and hub genes were investigated using the JASPAR database. Potential therapeutics that target the top hub genes have been discovered. Results Ten hub genes were discovered to be linked to the pathogenesis of PAH (CCL5, TLR4, TLR1, SPP1, CYBB, HGF, IGF1, SELL, CD163 and POSTN). “Positive regulation of tumor necrosis factor biosynthetic process” and a “toll-like receptor signaling pathway” are the most enriched GO term and KEGG pathway, respectively. “hsa-mir-26b-5p, hsa-mir-146a-5p, hsa-mir-335-5p” and FOXC1, YY1, GATA2 are the top TFs targeting hub genes. 21 drugs targeting ten hub genes have been discovered. Conclusions Our results would help to discover the pathogenesis of PAH and hub genes, miRNAs and 10 TFs that might serve as potential therapeutic targets at protein and RNA levels for PAH patients.

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Section: Discussionsupporting

confidence: 87%

In Silico Analysis of Pulmonary Arterial Hypertension to İdentify Key Biomarkers at Protein and RNA Levels

Akçay

2022

Preprint

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“…Pulmonary vascular remodelling, through pulmonary arterial (PA) smooth muscle cell (PASMC) proliferation and fibrosis, plays a critical role in PH development and involves a chronic imbalance in vasoactive substances. Pulmonary arterial hypertension (PAH), in which small pulmonary arteries progressively narrow, leading to increases in pulmonary vascular resistance and pressure, right heart failure and ultimately death, is strongly associated with dysregulated immunity and pulmonary vascular inflammation largely regulated through TLR4 signalling pathways (Gerges and Lang, 2018). In response to local injury (acute lung injury) or stress (hypoxia; cold exposure), TLR4 stimulation causes PA ECs to produce and secrete fractalkine (CX3CL1), a chemokine that attracts immune cells (Amsellem et al, 2017;Florentin and Dutta, 2017).…”

Section: Pulmonary Hypertensionmentioning

confidence: 99%

Targeting toll‐like receptor 4 signalling pathways: can therapeutics pay the toll for hypertension?

Nunes

Oliveira

Mowry

et al. 2018

British J Pharmacology

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The immune system plays a prominent role in the initiation and maintenance of hypertension. The innate immune system, via toll-like receptors (TLRs), identifies distinct signatures of invading microbes and damage-associated molecular patterns and triggers a chain of downstream signalling cascades, leading to secretion of pro-inflammatory cytokines and shaping the adaptive immune response. Over the past decade, a dysfunctional TLR-mediated response, particularly via TLR4, has been suggested to support a chronic inflammatory state in hypertension, inducing deleterious local and systemic effects in host cells and tissues and contributing to disease progression. While the underlying mechanisms triggering TLR4 need further research, evidence suggests that sustained elevations in BP disrupt homeostasis, releasing endogenous TLR4 ligands in hypertension. In this review, we discuss the emerging role of TLR4 in the pathogenesis of hypertension and whether targeting this receptor and its signalling pathways could offer a therapeutic strategy for management of this multifaceted disease.

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Targeting inflammation and immunity in pulmonary arterial hypertension: any easier after the CANTOS proof‐of‐concept that anti‐inflammation cuts cardiovascular events?

Cited by 2 publications

References 10 publications

In Silico Analysis of Pulmonary Arterial Hypertension to İdentify Key Biomarkers at Protein and RNA Levels

In Silico Analysis of Pulmonary Arterial Hypertension to İdentify Key Biomarkers at Protein and RNA Levels

Targeting toll‐like receptor 4 signalling pathways: can therapeutics pay the toll for hypertension?

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