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.

Therapeutic Strategies in Pulmonary Arterial Hypertension

2012 ◽  
Vol 8 (3) ◽  
pp. 198
Author(s):  
Carmine Dario Vizza ◽  
Roberto Badagliacca ◽  
Roberto Poscia ◽  
Mario Mezzapesa ◽  
Martina Nocioni ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Treatment Options ◽  
First Line Therapy ◽  
Specialist Centre ◽  
Threatening Condition ◽  
Poor Treatment ◽  
Life Threatening ◽  
Pulmonary Arterial ◽  
Endothelial Receptor

Pulmonary arterial hypertension (PAH) is a serious and life-threatening condition for which the prognosis remains poor. Treatment options include endothelial receptor antagonists, phosphodiesterase (PDE5) inhibitors and prostanoids. Despite all demonstrating good short-term efficacy, none of the currently available drug therapies are curative. Treatment with prostanoids is complex and requires careful monitoring and management through a specialist centre. Furthermore, clinical efficacy is dependent on adequate up-titration of the drug. Treatment should be individualised and modified according to clinical response, with the addition of other therapies if required. The importance of monitoring and modifying therapeutic regimes is discussed. There appears to be reluctance among patients and physicians to employ prostanoid therapy, though an aggressive first-line therapy may be appropriate in advanced cases.

Beta3-adrenergic stimulation restores endothelial mitochondrial dynamics and prevents pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Oliver ◽  
S.F Rocha ◽  
M Spaczynska ◽  
D.V Lalama ◽  
M Gomez ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Therapeutic Strategy ◽  
Mitochondrial Dynamics ◽  
Systolic Pressure ◽  
Funding Source ◽  
Pulmonary Arterial

Abstract Background Endothelial dysfunction is one of the most important hallmarks of pulmonary arterial hypertension (PAH). This leads to anomalous production of vasoactive mediators that are responsible for a higher vascular tone and a subsequent increase in pulmonary artery pressure (PAP), and to an increased vascular permeability that favors perivascular inflammation and remodeling, thus worsening the disease. Therefore, preservation of the endothelial barrier could become a relevant therapeutic strategy. Purpose In previous studies, others and we have suggested the pharmacological activation of the β3-adrenergic receptor (AR) as a potential therapeutic strategy for pulmonary hypertension (PH) due to left heart disease. However, its potential use in other forms of PH remain unclear. The aim of the present study was to elucidate whether the β3-AR agonist mirabegron could preserve pulmonary endothelium function and be a potential new therapy in PAH. Methods For this purpose, we have evaluated the effect of mirabegron (2 and 10 mg/kg·day) in different animal models, including the monocrotaline and the hypoxia-induced PAH models in rats and mice, respectively. Additionally, we have used a transgenic mouse model with endothelial overexpression of human β3-AR in a knockout background, and performed in vitro experiments with human pulmonary artery endothelial cells (HPAECs) for mechanistic experiments. Results Our results show a dose dependent effect of mirabegron in reducing mean PAP and Right Ventricular Systolic Pressure in both mice and rats. In addition, the use of transgenic mice has allowed us to determine that pulmonary endothelial cells are key mediators of the beneficial role of β3-AR pathway in ameliorating PAH. Mechanistically, we have shown in vitro that activation of β3-AR with mirabegron protects HPAECs from hypoxia-induced ROS production and mitochondrial fragmentation by restoring mitochondrial fission/fusion dynamics. Conclusions This protective effect of mirabegron would lead to endothelium integrity and preserved pulmonary endothelial function, which are necessary for a correct vasodilation, avoiding increased permeability and remodeling. Altogether, the current study demonstrates a beneficial effect of the β3-AR agonist mirabegron that could open new therapeutic avenues in PAH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Programa de Atracciόn de Talento, Comunidad de Madrid

DESIGN DEVELOPMENT AND OPTIMIZATION OF A SUSTAINED RELEASE TABLET OF BOSENTAN MONOHYDRATE FOR PULMONARY ARTERIAL HYPERTENSION

INDIAN DRUGS ◽  
2019 ◽  
Vol 56 (03) ◽  
pp. 61-67
Author(s):  
P. P Dighe ◽  
H. M Tank ◽  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Sustained Release ◽  
Arterial Hypertension ◽  
In Vitro Release ◽  
Design Development ◽  
23 Factorial Design ◽  
Sustained Release Tablet ◽  
Pulmonary Arterial ◽  
Release Tablet

Pulmonary arterial hypertension (PAH) means high blood pressure in the lungs caused by obstruction in the small arteries of the lungs.The current study involves the fabrication of oral matrix sustained release tablet of bosentan monohydrate, a dual endothelin receptor antagonist, the optimisation of its in vitro release and characterisation. Methocel K4M PremiumDC2, a directly compressible HPMC grade, has been used as the sustained release polymer. Pregelatinised starch is used as a diluent and release modifier and sodium lauryl sulphate as a solubiliser. The influence of the above variables on drug release is measured using a 23 factorial design using design expert software. Surface response plots show significant interaction among the formulation variables, thus aiding in optimization of bilayer tablet.

Trapping of BMP receptors in distinct membrane domains inhibits their function in pulmonary arterial hypertension

2011 ◽  
Vol 301 (2) ◽  
pp. L218-L227 ◽  
Author(s):  
Yaxin Jiang ◽  
Anja Nohe ◽  
Beth Bragdon ◽  
Chunhong Tian ◽  
Nung Rudarakanchana ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Skeletal Development ◽  
Treatment Options ◽  
Bmp Signaling ◽  
Membrane Domains ◽  
Coated Pits ◽  
Smad Signaling ◽  
Bmp Receptors ◽  
Pulmonary Arterial

Bone morphogenetic proteins (BMPs) are pleiotrophic growth factors that influence diverse processes such as skeletal development, hematopoiesis, and neurogenesis. They play crucial roles in diseases such as pulmonary arterial hypertension (PAH). In PAH, mutants of the BMP type II receptors (BMPR2) were detected, and their functions were impaired during BMP signaling. It is thought that expression levels of these receptors determine the fate of BMP signaling, with low levels of expression leading to decreased Smad activation in PAH. However, our studies demonstrate, for the first time, that the localization of receptors on the plasma membrane, in this case BMPR2, was misdirected. Three BMPR2 mutants, D485G, N519K, and R899X, which are known to be involved in PAH, were chosen as our model system. Our results show that all three BMPR2 mutants decreased BMP-dependent Smad phosphorylation and Smad signaling. Although the three mutants reached the cell membrane and their expression was lower than that of BMPR2, they formed smaller clusters and associated differently with membrane domains, such as caveolae and clathrin-coated pits. The disruption of these domains restored the Smad signaling of D485G and N519K to the level of wild-type BMPR2, showing that these mutants were trapped in the domains, rather than just expressed at a lower level on the surface. Therefore, new treatment options for PAH should also target receptor localization, rather than just expression level.

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.

Abstract 18446: Identification of a Novel Cellular Actor Participating in Vascular Remodeling During Pulmonary Arterial Hypertension : the PW1+ Progenitor Cells

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
France Dierick
Keyword(s):  
Bone Marrow ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Bone Marrow Cells ◽  
Mouse Lung ◽  
Pulmonary Vessels ◽  
Pulmonary Arterial ◽  
Lung Vessels

AIM: PW1+ progenitors were identified in various adult tissues and can differentiate in smooth muscle cells (SMC) in vitro. Our hypothesis is that PW1+ progenitors are recruited to participate in the vascular remodeling during pulmonary arterial hypertension (PAH). METHODS: PW1IRESnLacZ+/- mice express the β-galactosidase as a reporter gene for PW1 expression allowing to follow the lineage of PW1+ cells during a few days. These mice were exposed to chronic hypoxia (CH) to induce PAH, lung vessels neomuscularisation and SMC proliferation. PW1+ and β-Gal+ cells were studied by FACS and by immunofluorescence. RESULTS: PW1+ cells are localized in the lung parenchyma and in the perivascular zone in rodent and human lung. Two PW1+ populations were identified by flow cytometry in the mouse lung 1/ a Sca-1high/CD34high/PDGFR-α+ population which differentiates into calponin+ or α-SMA+ SMC and into vWF+ endothelial cell and 2/ a CD34-/CD146+ population expressing pericyte markers. After 2-4 days of CH, the number of lung PW1+ cells is increased (x3.5, p<0.01) and, in small pulmonary vessels media, the proportion of β-Gal+ SMC derived from PW1+ cells is increased (64±6% vs 35±3%, p<0.05) suggesting a recruitment and differentiation of PW1+ cells into lung vascular SMC. Moreover WT mice irradiated and engrafted with GFP+/β-Gal+ bone marrow cells do not show any increase in GFP+ SMC in lung vessels and do not show any β-Gal+ cells in the lung indicating that the lung PW1+ progenitors are not derived from bone marrow . Moreover, in the human PAH lung, PW1+ cells were observed in remodeled vascular structures: in the media of remodeled vessel and in plexiform lesions. CONCLUSION: These results suggest that lung resident PW1+ progenitors are recruited to participate in the vascular remodeling of small pulmonary vessels in experimental and human PAH. These progenitors show characteristics of pericytes and of vascular progenitors.

Abstract 3570: A Critical and Novel Role of Nogo (Neurite Outgrowth Inhibitor) in Pulmonary Arterial Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Gopinath Sutendra ◽  
Sebastien Bonnet ◽  
Paulette Wright ◽  
Peter Dromparis ◽  
Alois Haromy ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Nuclear Translocation ◽  
Pulmonary Arteries ◽  
Over Expression ◽  
Nfat Activation ◽  
Pulmonary Arterial ◽  
Systemic Arteries

Nogo was first identified as an inhibitor of neuronal axonal regeneration. Recently, Nogo-B was implicated in the proliferative and anti-apoptotic remodeling in systemic arteries; reduced Nogo-B expression was seen in remodeled mouse femoral arteries following injury. Pulmonary arterial hypertension (PAH) is also characterized by proliferative/anti-apoptotic remodeling in pulmonary arteries (PA), sparing systemic vessels. PAH PA smooth muscle cells (PASMC) are characterized by mitochondrial hyperpolarization (increased ΔΨm), decreased production of reactive oxygen species (ROS) (suppressing mitochondria-dependent apoptosis), down-regulation of Kv1.5 and activation of the transcription factor NFAT (promoting contraction and proliferation). We found that in contrast to systemic vessels, Nogo-B expression is significantly increased in vivo and in vitro in PAs and PASMCs from patients (n=6) and mice (n=42) with PAH, compared to normals. We hypothesized that Nogo is involved in the pathogenesis of PAH . Nogo −/− mice (n=7) had a normal phenotype and, in contrast to Nogo +/+ , did not develop chronic hypoxia (CH)-induced PAH assessed invasively (catheterization, RV/LV+Septum) and non-invasively (pulmonary artery acceleration time and treadmill performance) (n=7, Table ). CH- Nogo +/+ PASMC had the expected increase in ΔΨm (measured by TMRM), decreased ROS (MitoSOX), increased [Ca ++ ] i (FLUO3), decreased Kv1.5 (immunohistochemistry) and NFAT activation (nuclear translocation). None of these changes occurred in CH- Nogo −/− PASMC while all were induced in normoxic Nogo +/+ PASMC by adenoviral over-expression of Nogo-B . Heterozygote CH- Nogo +/− (n=7) values were between Nogo −/− and Nogo +/+ suggesting a gene dose-dependent effect. Nogo is over-expressed in human and rodent PAH and induces critical features of the PAH phenotype. Nogo targeting might represent a novel and selective therapeutic strategy for PAH. Table

Recent Updates in Both the Diagnosis and Treatment Options that Impact the Clinical Treatment of Pulmonary Arterial Hypertension

2010 ◽  
Vol 2 ◽  
pp. CMT.S4192
Author(s):  
Charles D. Burger
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Treatment Plan ◽  
Treatment Options ◽  
Pharmaceutical Formulations ◽  
World Health ◽  
New Agents ◽  
Pulmonary Arterial ◽  
New Treatment ◽  
Health Organization

The evaluation and management of pulmonary arterial hypertension (PAH) is a rapidly evolving area of subspecialty medicine requiring regular clinical updates. Most notably are changes in the World Health Organization diagnostic scheme whereby the clinician categorizes the correct type of pulmonary hypertension in order direct the most specific evaluation and treatment plan. In addition, there have been several changes in both the FDA-approved pharmaceutical formulations and new agents for the treatment of PAH. This review will provide an update in these areas and more importantly, guidance to the clinician on the most appropriate utilization of these new treatment options.

scholarly journals Schistosomiasis-associated pulmonary arterial hypertension: a systematic review

2020 ◽  
Vol 29 (155) ◽  
pp. 190089 ◽  
Author(s):  
Daniela Knafl ◽  
Christian Gerges ◽  
Charles H. King ◽  
Marc Humbert ◽  
Amaya L. Bustinduy
Keyword(s):  
Systematic Review ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transforming Growth Factor ◽  
Meta Analysis ◽  
Signalling Pathway ◽  
Pathophysiological Mechanisms ◽  
Clinical Registries ◽  
Life Threatening ◽  
Pulmonary Arterial

Schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) is a life-threatening complication of chronic hepatosplenic schistosomiasis. It is suggested to be the leading cause of pulmonary arterial hypertension (PAH) worldwide. However, pathophysiological data on Sch-PAH are scarce. We examined the hypothesis that there are pronounced similarities in pathophysiology, haemodynamics, and survival of Sch-PAH and idiopathic PAH (iPAH).This systematic review and meta-analysis was registered in the PROSPERO database (identifier CRD42018104066). A systematic search and review of the literature was performed according to PRISMA guidelines for studies published between 01 January 1990 and 29 June 2018.For Sch-PAH, 18 studies evaluating pathophysiological mechanisms, eight studies on haemodynamics (n=277), and three studies on survival (n=191) were identified. 16 clinical registries reporting data on haemodynamics and survival including a total of 5792 patients with iPAH were included for comparison. Proinflammatory molecular pathways are involved in both Sch-PAH and iPAH. The transforming growth factor (TGF)-β signalling pathway is upregulated in Sch-PAH and iPAH. While there was no difference in mean pulmonary artery pressure (54±17 mmHg versus 55±15 mmHg, p=0.29), cardiac output (4.4±1.3 L·min−1versus 4.1±1.4 L·min−1, p=0.046), and cardiac index (2.6±0.7 L·min−1·m−2versus 2.3±0.8 L·min−1·m−2, p<0.001) were significantly higher in Sch-PAH compared to iPAH, resulting in a lower pulmonary vascular resistance in Sch-PAH (10±6 Woods units versus 13±7 Woods units, p<0.001). 1- and 3-year survival were significantly better in the Sch-PAH group (p<0.001).Sch-PAH and iPAH share common pathophysiological mechanisms related to inflammation and the TGF-β signalling pathway. Patients with Sch-PAH show a significantly better haemodynamic profile and survival than patients with iPAH.

scholarly journals Effects of Different Types of Exercise Training on Pulmonary Arterial Hypertension: A Systematic Review

2020 ◽  
Vol 9 (6) ◽  
pp. 1689 ◽  
Author(s):  
Lena Waller ◽  
Karsten Krüger ◽  
Kerstin Conrad ◽  
Astrid Weiss ◽  
Katharina Alack
Keyword(s):  
Physical Activity ◽  
Pulmonary Arterial Hypertension ◽  
Exercise Training ◽  
Arterial Hypertension ◽  
Treatment Options ◽  
Human Studies ◽  
Respiratory Muscle Training ◽  
Exercise Interventions ◽  
Different Types ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) represents a chronic progressive disease characterized by high blood pressure in the pulmonary arteries leading to right heart failure. The disease has been a focus of medical research for many years due to its worse prognosis and limited treatment options. The aim of this study was to systematically assess the effects of different types of exercise interventions on PAH. Electronic databases were searched until July 2019. MEDLINE database was used as the predominant source for this paper. Studies with regards to chronic physical activity in adult PAH patients are compared on retrieving evidence on cellular, physiological, and psychological alterations in the PAH setting. Twenty human studies and 12 rat trials were identified. Amongst all studies, a total of 628 human subjects and 614 rats were examined. Regular physical activity affects the production of nitric oxygen and attenuates right ventricular hypertrophy. A combination of aerobic, anaerobic, and respiratory muscle training induces the strongest improvement in functional capacity indicated by an increase of 6 MWD and VO2 peak. In human studies, an increase of quality of life was found. Exercise training has an overall positive effect on the physiological and psychological components of PAH. Consequently, PAH patients should be encouraged to take part in regular exercise training programs.

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