Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs?

2007 ◽  
Vol 293 (1) ◽  
pp. H77-H85 ◽  
Author(s):  
Pravin B. Sehgal ◽  
Somshuvra Mukhopadhyay
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Membrane Trafficking ◽  
Experimental Models ◽  
Electron Microscopic ◽  
Surface Receptors ◽  
Arterial Lesions ◽  
Microscopic Studies ◽  
Pulmonary Arterial ◽  
Membrane Tethers

Histological and electron microscopic studies over the past four decades have highlighted “plump,” “enlarged” endothelial, smooth muscle, and fibroblastic cellular elements with increased endoplasmic reticulum, Golgi stacks, and vacuolation in pulmonary arterial lesions in human and in experimental (hypoxia and monocrotaline) pulmonary arterial hypertension. However, the contribution of disrupted intracellular membrane trafficking in the pathobiology of this disease has received insufficient attention. Recent studies suggest a pathogenetic role of the disruption of intracellular trafficking of vasorelevant proteins and cell-surface receptors in the development of this disease. The purpose of this essay is to highlight the molecular regulation of vesicular trafficking by membrane tethers, SNAREs and SNAPs, and to suggest how their dysfunction, directly and/or indirectly, might contribute to development of pulmonary arterial hypertension in experimental models and in humans, including that due to mutations in bone morphogenetic receptor type 2.

Role of survivin in experimental models of pulmonary arterial hypertension

2016 ◽  
Author(s):  
Isabel Blanco ◽  
Elisabet Ferrer ◽  
Susana Maqueda ◽  
Tanja Paul ◽  
Neus Luque ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Experimental Models ◽  
Pulmonary Arterial

scholarly journals New and Emerging Therapies for Pulmonary Arterial Hypertension

2019 ◽  
Vol 70 (1) ◽  
pp. 45-59 ◽  
Author(s):  
Edda Spiekerkoetter ◽  
Steven M. Kawut ◽  
Vinicio A. de Jesus Perez
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular Dysfunction ◽  
Experimental Models ◽  
Metabolic Dysfunction ◽  
Alternative Pathways ◽  
Exercise Limitation ◽  
Emerging Therapies ◽  
New Findings ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that causes right ventricular dysfunction and exercise limitation and progresses to death. New findings from translational studies have suggested alternative pathways for treatment. These avenues include sex hormones, genetic abnormalities and DNA damage, elastase inhibition, metabolic dysfunction, cellular therapies, and anti-inflammatory approaches. Both novel and repurposed compounds with rationale from preclinical experimental models and human cells are now in clinical trials in patients with PAH. Findings from these studies will elucidate the pathobiology of PAH and may result in clinically important improvements in outcome.

scholarly journals The BMP Receptor 2 in Pulmonary Arterial Hypertension: When and Where the Animal Model Matches the Patient

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1422 ◽  
Author(s):  
Chris Happé ◽  
Kondababu Kurakula ◽  
Xiao-Qing Sun ◽  
Denielli da Silva Goncalves Bos ◽  
Nina Rol ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Arterial Hypertension ◽  
Transforming Growth Factor ◽  
Experimental Models ◽  
Receptor Expression ◽  
Rat Models ◽  
Downstream Signaling ◽  
Pulmonary Arterial ◽  
Expression And Activity

Background: Mutations in bone morphogenetic protein receptor type II (BMPR2) are leading to the development of hereditary pulmonary arterial hypertension (PAH). In non-hereditary forms of PAH, perturbations in the transforming growth factor-β (TGF-β)/BMP-axis are believed to cause deficient BMPR2 signaling by changes in receptor expression, the activity of the receptor and/or downstream signaling. To date, BMPR2 expression and its activity in the lungs of patients with non-hereditary PAH is poorly characterized. In recent decades, different animal models have been used to understand the role of BMPR2 signaling in PAH pathophysiology. Specifically, the monocrotaline (MCT) and Sugen–Hypoxia (SuHx) models are extensively used in interventional studies to examine if restoring BMPR2 signaling results in PAH disease reversal. While PAH is assumed to develop in patients over months or years, pulmonary hypertension in experimental animal models develops in days or weeks. It is therefore likely that modifications in BMP and TGF-β signaling in these models do not fully recapitulate those in patients. In order to determine the translational potential of the MCT and SuHx models, we analyzed the BMPR2 expression and activity in the lungs of rats with experimentally induced PAH and compared this to the BMPR2 expression and activity in the lungs of PAH patients. Methods: the BMPR2 expression was analyzed by Western blot analysis and immunofluorescence (IF) microscopy to determine the quantity and localization of the receptor in the lung tissue from normal control subjects and patients with hereditary or idiopathic PAH, as well as in the lungs of control rats and rats with MCT or SuHx-induced PAH. The activation of the BMP pathway was analyzed by determining the level and localization of phosphorylated Smad1/5/8 (pSmad 1/5/8), a downstream mediator of canonical BMPR2 signaling. Results: While BMPR2 and pSmad 1/5/8 expression levels were unaltered in whole lung lysates/homogenates from patients with hereditary and idiopathic PAH, IF analysis showed that BMPR2 and pSmad 1/5/8 levels were markedly decreased in the pulmonary vessels of both PAH patient groups. Whole lung BMPR2 expression was variable in the two PAH rat models, while in both experimental models the expression of BMPR2 in the lung vasculature was increased. However, in the human PAH lungs, the expression of pSmad 1/5/8 was downregulated in the lung vasculature of both experimental models. Conclusion: BMPR2 receptor expression and downstream signaling is reduced in the lung vasculature of patients with idiopathic and hereditary PAH, which cannot be appreciated when using human whole lung lysates. Despite increased BMPR2 expression in the lung vasculature, the MCT and SuHx rat models did develop PAH and impaired downstream BMPR2-Smad signaling similar to our findings in the human lung.

scholarly journals Novel Approaches to Treat Experimental Pulmonary Arterial Hypertension: A Review

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
S. Umar ◽  
P. Steendijk ◽  
D. L. Ypey ◽  
D. E. Atsma ◽  
E. E. van der Wall ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Treatment Options ◽  
Experimental Models ◽  
Homogeneous Groups ◽  
Emerging Trends ◽  
Animal Data ◽  
Life Threatening ◽  
Pulmonary Arterial

Background. Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by an increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure, and ultimately death. Current treatments can improve symptoms and reduce severity of the hemodynamic disorder but gradual deterioration in their condition often necessitates a lung transplant.Methods and Results. In experimental models of PAH, particularly the model of monocrotaline-induced pulmonary hypertension, efficacious treatment options tested so far include a spectrum of pharmacologic agents with actions such as anti-mitogenic, proendothelial function, proangiogenic, antiinflammatory and antioxidative. Emerging trends in PAH treatment are gene and cell therapy and their combination, like (progenitor) cells enriched with eNOS or VEGF gene. More animal data should be collected to investigate optimal cell type, in vitro cell transduction, route of administration, and number of cells to inject. Several recently discovered and experimentally tested interventions bear potential for therapeutic purposes in humans or have been shown already to be effective in PAH patients leading to improved life expectation and better quality of life.Conclusion. Since many patients remain symptomatic despite therapy, we should encourage research in animal models of PAH and implement promising treatments in homogeneous groups of PAH patients.

Role of Redox Homeostasis and Inflammation in the Pathogenesis of Pulmonary Arterial Hypertension

2018 ◽  
Vol 25 (11) ◽  
pp. 1340-1351 ◽  
Author(s):  
Adriane Bello-Klein ◽  
Daniele Mancardi ◽  
Alex S. Araujo ◽  
Paulo C. Schenkel ◽  
Patrick Turck ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Redox Homeostasis ◽  
Experimental Studies ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Pulmonary Vasculature ◽  
High Morbidity ◽  
Pulmonary Arterial

This review addresses pulmonary arterial hypertension (PAH), an incurable disease, which determines high morbidity and mortality. Definition of the disease, its characteristics, classification, and epidemiology are discussed. A difficulty in the diagnosis of PAH due to the lack of symptoms specificity is highlighted. Echocardiographic analysis and electrocardiogram of patients help in the diagnosis and in the follow up of the disease. Nevertheless, right ventricle (RV) catheterization constitutes the gold standard for diagnosing PAH. Oxidative stress and inflammation, in an interactive manner, play a major role in the development of pulmonary vascular remodeling and consequent increase of pulmonary pressure. The latter results in an increase in RV afterload, culminating with RV hypertrophy, which may progress to failure. Both clinical and experimental studies have shown increased oxidative stress and inflammation, not only in lungs and pulmonary vasculature but also in RV. The use of experimental models, such as the monocrotaline-induced PAH, has helped in the understanding of the pathophysiology of PAH, as well as in the development of new therapeutic strategies. In addition to the traditional therapeutics, the use of therapeutic interventions capable of modulating oxidative stress and inflammation may offer newer strategies in the prevention as well as management of this disease.

scholarly journals Detecting thromboxane signaling abnormalities in experimental models of pulmonary arterial hypertension

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Neil D Detweiler ◽  
Dinesh K Hirenallur-S ◽  
Steven T Haworth ◽  
John B Gordon ◽  
Nancy J Rusch
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Experimental Models ◽  
Pulmonary Arterial

Pulmonary arterial hypertension associated with interferon beta treatment for multiple sclerosis: a case report

2009 ◽  
Vol 15 (7) ◽  
pp. 885-886 ◽  
Author(s):  
AH Ledinek ◽  
SŠ Jazbec ◽  
I Drinovec ◽  
U Rot
Keyword(s):  
Multiple Sclerosis ◽  
Case Report ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Respiratory Symptoms ◽  
Interferon Beta ◽  
Experimental Models ◽  
Interferon Treatment ◽  
Pulmonary Arterial ◽  
Stimulation Of

A 23-year-old woman with multiple sclerosis developed respiratory symptoms 3 years after introduction of interferon beta-1b. The diagnosis of pulmonary arterial hypertension (PAH) was established. The patient partially responded to sildenafil and bosetan treatment. This is the first report of PAH, associated with interferon beta therapy. As shown in experimental models, interferon treatment can induce PAH by stimulation of thromboxane cascade and secretion of various inflammatory mediators.

scholarly journals New insights into the pathobiological and pharmacological basis of the sex-disparity in patients with pulmonary arterial hypertension

2021 ◽  
Author(s):  
Tanvirul Hye ◽  
Pankaj Dwivedi ◽  
Wei Li ◽  
Tim Lahm ◽  
Eva S. Nozik ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Sex Hormones ◽  
Pulmonary Arteries ◽  
Experimental Models ◽  
New Drugs ◽  
Therapeutic Interventions ◽  
Disease Etiology ◽  
Pulmonary Arterial ◽  
Sex Disparity

Pulmonary arterial hypertension (PAH) affects more women than men, although affected females tend to survive longer than affected males. This sex-disparity in PAH is postulated to stem from the diverse roles of sex hormones in disease etiology. In animal models, estrogens appear to be implicated not only in pathologic remodeling of pulmonary arteries, but also in protection against right ventricular (RV) hypertrophy. In contrast, the male sex hormone testosterone is associated with reduced survival in male animals, where it is associated with increased RV mass, volume, and fibrosis. However, it also has a vasodilatory effect on pulmonary arteries. Further, patients of both sexes show varying degrees of response to current therapies for PAH. As such, there are many gaps and contradictions regarding PAH development, progression, and therapeutic interventions in male versus female patients. Many of these questions remain unanswered, which may be due in part to lack of effective experimental models that can consistently reproduce PAH pulmonary microenvironments in their sex-specific forms. This review article summarizes the roles of estrogens and related sex hormones, immunological and genetical differences, and the benefits and limitations of existing experimental tools to fill in gaps in our understanding of the sex-based variation in PAH development and progression. Finally, we highlight the potential of a new tissue-chip-based model mimicking PAH-afflicted male and female pulmonary arteries to study the sex-based differences in PAH and to develop personalized therapies based on patient sex and responsiveness to existing and new drugs.

scholarly journals Clinical Trials Targeting Metabolism in Pulmonary Arterial Hypertension

2018 ◽  
Vol 17 (3) ◽  
pp. 110-114 ◽  
Author(s):  
Evan L. Brittain
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Aerobic Glycolysis ◽  
Experimental Models ◽  
Pulmonary Vasculature ◽  
Acid Oxidation ◽  
Metabolic Dysfunction ◽  
Metabolic Derangement ◽  
Pulmonary Arterial

Metabolic derangement is a pathologic feature of pulmonary arterial hypertension (PAH).1 Metabolic abnormalities such as aerobic glycolysis and impaired fatty acid oxidation are consistently observed across different animal models of PAH. Importantly, altered metabolism in human PAH and experimental models is not restricted to the pulmonary vasculature, raising the possibility that PAH is a systemic metabolic disease.2 For example, lipid accumulation is present in the myocardium and skeletal muscle of humans with PAH and the right ventricle exhibits increased glucose uptake compared with matched controls. As a result of these observations, targeting metabolic dysfunction has emerged as an important therapeutic approach for patients with PAH.3 This article will review key aspects of metabolism in PAH, existing metabolic data in humans, and will describe completed and ongoing clinical trials targeting metabolic dysfunction in patients with PAH.

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