Hypoxia-Induced Pulmonary Arterial Hypertension: The Role of TLR4

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1146-1146
Author(s):  
Liping Ma ◽  
Jianxing Chang ◽  
Hui Wu ◽  
Yabing Chen
Keyword(s):  
Reactive Oxygen Species ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Wall Thickness ◽  
Arterial Wall ◽  
Pulmonary Vasculature ◽  
Oxygen Species ◽  
Arterial Wall Thickness ◽  
Pulmonary Arterial

Abstract Abstract 1146 Pulmonary arterial hypertension (PAH) is often as a result of COPD and contributes to morbidity and mortality of chronic cor pulmonale. Hypoxemia is its main clinical features. The toll-like receptors are a group of type I transmembrane proteins that play a central role in specific recognition of pathagen-associated molecular patterns and are critical for the induction of innate immunity and inflammation. Expression of these innate immune receptors, especially TLR4 in healthy and pathological arteries has implicated its role in the homeostasis of vasculature. Chronic hypoxia-induced PAH is mediated by increased production of reactive oxygen species (ROS). ROS have been linked to activation of toll-like receptor 4 (TLR4) signaling. The present studies investigated the role of TLR4 in the pathogenesis PAH and the underlying mechanisms. In vitro, pulmonary arterial smooth muscle cells (PASMC) derived from TLR4−/− mice exhibited increased production of intracellular reactive oxygen species (ROS). Furthermore, under hypoxia, the expression of TLR4 in PASMC from WT mice was decreased, ROS production in PASMC from WT mice were increased, suggesting down-regulation of TLR4 may contribute to hypoxia-induced PAH. Using a hypoxia-induced PAH model, we found that hypoxia induced PAH and increased pulmonary arterial wall thickness in wild type (WT) mice. In contrast, mice deficient in TLR4 spontaneously developed PAH and increased pulmonary arterial wall thickness, which were not further enhanced by hypoxia. Consistent with the development of PAH in TLR4−/− mice, echocardiography confirmed right ventricular hypertrophy and decreased pulmonary arterial acceleration time compared to WT mice. Above results suggest that TLR4 plays an important role in maintaining normal pulmonary vasculature, and that hypoxia induces PAH via TLR4. In short, these studies demonstrate an important role of TLR4 in maintaining normal pulmonary vasculature and in the development of hypoxia-induced PAH. Genetic ablation of TLR4 and inhibition of TLR4 expression by hypoxia induces PASMC proliferation and vascular remodeling, in association with redox signaling in the pathogenesis of PAH. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension

2020 ◽  
pp. 1902061
Author(s):  
David Macias ◽  
Stephen Moore ◽  
Alexi Crosby ◽  
Mark Southwood ◽  
Xinlin Du ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Target Genes ◽  
Right Heart Failure ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
The Impact

Pulmonary Arterial Hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant HIF2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from IPAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyper-proliferative phenotype and over-active arginase activity in blood outgrowth endothelial cells from IPAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.

scholarly journals Smouldering fire or conflagration? An illustrated update on the concept of inflammation in pulmonary arterial hypertension

2021 ◽  
Vol 30 (162) ◽  
pp. 210161
Author(s):  
Frédéric Perros ◽  
Marc Humbert ◽  
Peter Dorfmüller
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Rare Condition ◽  
Progressive Increase ◽  
Pulmonary Vasculature ◽  
Ventricular Failure ◽  
Myocardial Remodelling ◽  
Pulmonary Arterial ◽  
The Right

Pulmonary arterial hypertension (PAH) is a rare condition that is characterised by a progressive increase of pulmonary vascular resistances that leads to right ventricular failure and death, if untreated. The underlying narrowing of the pulmonary vasculature relies on several independent and interdependent biological pathways, such as genetic predisposition and epigenetic changes, imbalance of vasodilating and vasoconstrictive mediators, as well as dysimmunity and inflammation that will trigger endothelial dysfunction, smooth muscle cell proliferation, fibroblast activation and collagen deposition. Progressive constriction of the pulmonary vasculature, in turn, initiates and sustains hypertrophic and maladaptive myocardial remodelling of the right ventricle. In this review, we focus on the role of inflammation and dysimmunity in PAH which is generally accepted today, although existing PAH-specific medical therapies still lack targeted immune-modulating approaches.

scholarly journals EXPRESS: Platelets, extracellular vesicles & coagulation in pulmonary arterial hypertension

2021 ◽  
pp. 204589402110210
Author(s):  
Sarah Cullivan ◽  
Claire A Murphy ◽  
Luisa Weiss ◽  
Shane P Comer ◽  
Barry Kevane ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Therapeutic Interventions ◽  
Pulmonary Vasculature ◽  
Future Research ◽  
Regulatory Pathways ◽  
Paracrine Signalling ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary vasculature, characterised pathologically by proliferation, remodelling and thrombosis in situ. Unfortunately, existing therapeutic interventions do not reverse these findings and the disease continues to result in significant morbidity and premature mortality. A number of haematological derangements have been described in PAH which may provide insights into the pathobiology of the disease and also provide opportunities to target new therapeutic pathways. These include quantitative and qualitative platelet abnormalities, such as thrombocytopaenia, increased mean platelet volume (MPV) and altered platelet bioenergetics. Furthermore, a hypercoagulable state and aberrant negative regulatory pathways can be observed, which could contribute to thrombosis in situ in distal pulmonary arteries and arterioles. Finally, there is increasing interest in the role of extracellular vesicle (EV) autocrine and paracrine signalling in PAH, and their potential utility as biomarkers and novel therapeutic targets. This review focuses on the potential role of platelets, EVs and coagulation pathways in the pathobiology of PAH. We highlight important unanswered clinical questions and the implications of these observations for future research and PAH directed therapies.

scholarly journals Echocardiography in Pulmonary Arterial Hypertension: Is It Time to Reconsider Its Prognostic Utility?

2021 ◽  
Vol 10 (13) ◽  
pp. 2826
Author(s):  
Ioannis T. Farmakis ◽  
Eftychia Demerouti ◽  
Panagiotis Karyofyllis ◽  
George Karatasakis ◽  
Maria Stratinaki ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Pulmonary Vasculature ◽  
Right Heart ◽  
Prognostic Utility ◽  
Pulmonary Arterial ◽  
Prognostic Implications ◽  
The Right

Pulmonary arterial hypertension (PAH) is characterized by an insult in the pulmonary vasculature, with subsequent right ventricular (RV) adaptation to the increased afterload that ultimately leads to RV failure. The awareness of the importance of RV function in PAH has increased considerably because right heart failure is the predominant cause of death in PAH patients. Given its wide availability and reduced cost, echocardiography is of paramount importance in the evaluation of the right heart in PAH. Several echocardiographic parameters have been shown to have prognostic implications in PAH; however, the role of echocardiography in the risk assessment of the PAH patient is limited under the current guidelines. This review discusses the echocardiographic evaluation of the RV in PAH and during therapy, and its prognostic implications, as well as the potential significant role of repeated echocardiographic assessment in the follow-up of patients with PAH.

scholarly journals The pathophysiological role of novel pulmonary arterial hypertension gene SOX17

2021 ◽  
pp. 2004172
Author(s):  
Yukyee Wu ◽  
John Wharton ◽  
Rachel Walters ◽  
Eleni Vasilaki ◽  
Jurjan Aman ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Dominant Mode ◽  
Pulmonary Vasculature ◽  
Incomplete Penetrance ◽  
Pathophysiological Role ◽  
Sequencing Studies ◽  
Pulmonary Arterial ◽  
The Right

Pulmonary arterial hypertension (PAH) is a progressive disease predominantly targeting pre-capillary blood vessels. Adverse structural re-modelling and increased pulmonary vascular resistance result in cardiac hypertrophy and ultimately failure of the right ventricle. Recent whole genome and exome sequencing studies have identified SOX17 as a novel risk gene in PAH, with a dominant mode of inheritance and incomplete penetrance. Rare deleterious variants in the gene and more common variants in upstream enhancer sites have both been associated with the disease and a deficiency of SOX17 expression may predispose to PAH. This review aims to consolidate the evidence linking genetic variants in SOX17 to PAH and explores the numerous targets and effects of the transcription factor, focussing on the pulmonary vasculature and the pathobiology of PAH.

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