Is there a role for prostanoid-mediated inhibition of IL-6<i>trans</i>-signalling in the management of pulmonary arterial hypertension?

Durham, Gillian A.; Palmer, Timothy M.

doi:10.1042/bst20190046

Cited by 10 publications

(7 citation statements)

References 118 publications

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“…SOCS3 inhibits the activation of JAK/STAT induced by IL-6 by directly inhibiting JAK kinase activity, thereby preventing the binding of the substrate and ATP Kershaw et al [ 24 ]. Durham and Palmer found that IL-6 activates JAK-STAT signaling to induce the transcription of proinflammatory and proantigen genes, and SOCS3 restricts IL-6 signaling, which resists the progression of pulmonary arterial hypertension (PAH) Durham & Palmer [ 25 ]. Damage to endothelial function and vascular inflammation are key factors in the onset of hypertension.…”

Section: Discussionmentioning

confidence: 99%

[Retracted] SOCS3 Gene Polymorphism and Hypertension Susceptibility in Chinese Population: A Two‐Center Case‐Control Study

Kuang

Dong

Liu³

et al. 2021

BioMed Research International

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Endothelial inflammation and vascular damage are essential risk factors contributing to hypertension. Suppressor of cytokine signaling 3 (SOCS3) is involved in the regulation of multiple inflammatory pathways. A large number of studies have shown that the anti-inflammatory effect of SOCS3 in hypertension, obesity, and allergic reactions has brought more insights into the inhibition of inflammation. Therefore, we selected a tagSNP of SOCS3 (rs8064821) to investigate whether they are contributing to the risk of hypertension in the Chinese population. In total, 532 patients with hypertension and 569 healthy controls were enrolled for two central of China. SOCS3 rs8064821 C>A polymorphism was genotyped using TaqMan assay. SOCS3 rs8064821 CA genotype was associated with an increased risk of hypertension ( OR = 1.821 , 95 % CI = 1.276 -2.600, P = 0.001 ). Rs8064821 A allele was associated with higher SOCS3 mRNA level in PBMCs from healthy donors. SOCS3 rs8064821 C>A polymorphism may contribute to the risk of hypertension in the Chinese population by regulating the expression of SOCS3.

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Section: Discussionmentioning

confidence: 99%

[Retracted] SOCS3 Gene Polymorphism and Hypertension Susceptibility in Chinese Population: A Two‐Center Case‐Control Study

Kuang

Dong

Liu³

et al. 2021

BioMed Research International

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“…Distal pulmonary arterioles isolated from the lung tissue of patients with iPAH displayed increased levels of membrane-bound IL-6R in the smooth muscle layer compared with control arteries [ 29 ]. Patients with iPAH exhibit increased IL-6 serum levels, which correlate with their prognoses [ 25 , 30 , 31 ].…”

Section: Jak/stat Activatorsmentioning

confidence: 99%

The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

Roger

Milara

Montero

et al. 2021

IJMS

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Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

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“…It is reported that IL-6 may affect the homeostasis of energy and glucose in obese mice through activating IL-6 trans-signaling in central nervous system [ 38 ], and thus IL-6 may be a potential therapeutic target in treatment of obesity [ 39 ]. Inflammation can function as an essential role in development of pulmonary arterial hypertension, including IL-6 [ 40 ]. Therefore, IL-6 may be a promising therapeutic target for pulmonary arterial hypertension via regulation of intracellular IL-6 signaling [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Uncovering antiobesity-related hypertension targets and mechanisms of metformin, an antidiabetic medication

Yang

Xiao

et al. 2021

Bioengineered

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Metformin, a common clinical drug used to treat diabetes mellitus, is found with potential antiobese actions as reported in increasing evidences. However, the detailed mechanisms of metformin-antiobesity-related hypertension remain unrevealed. We have utilized the bioinformatics strategy, including network pharmacology and molecular docking analyses, to uncover pharmacological targets and molecular pathways of bioactive compounds against clinical disorders, such as cancers, coronavirus disease 2019. In this report, the in-silico approaches using network pharmacology and molecular docking was utilized to identify the core targets, pharmacological functions and mechanisms of metformin against obesity-related hypertension. The networking analysis identified 154 differentially expressed genes of obesity and hypertension, and 21 interaction genes, 6 core genes of metformin treating obesity-related hypertension. As results, molecular docking findings indicated the binding capability of metformin with key proteins, including interleukin 6 (IL-6) and chemokine (C-C motif) Ligand 2 (CCL2) expressed in obesity-and hypertension-dependent tissues. Metformin-exerted antihypertension/obesity actions involved in metabolic regulation, inflammatory suppression. And antihypertension/obesity mechanisms of metformin were revealed, including regulation of inflammatory and immunological signaling pathways for ameliorating microenvironmental homeostasis in targeting tissues. In conclusion, our current bioinformatics findings have uncovered all pharmacological targets, biological functions and signaling pathways of metformin treating obesity-related hypertension, thus promoting its clinical application in future.

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Is there a role for prostanoid-mediated inhibition of IL-6trans-signalling in the management of pulmonary arterial hypertension?

Cited by 10 publications

References 118 publications

[Retracted] SOCS3 Gene Polymorphism and Hypertension Susceptibility in Chinese Population: A Two‐Center Case‐Control Study

[Retracted] SOCS3 Gene Polymorphism and Hypertension Susceptibility in Chinese Population: A Two‐Center Case‐Control Study

The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

Uncovering antiobesity-related hypertension targets and mechanisms of metformin, an antidiabetic medication

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