scholarly journals The Molecular Genetics and Cellular Mechanisms Underlying Pulmonary Arterial Hypertension

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
Author(s):  
Rajiv D. Machado
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Treatment Options ◽  
Molecular Genetic ◽  
Pulmonary Arteries ◽  
Rapid Identification ◽  
Cellular Mechanisms ◽  
Systemic Involvement ◽  
Pulmonary Arterial ◽  
The Impact

Pulmonary arterial hypertension (PAH) is an incurable disorder clinically characterised by a sustained elevation of mean arterial pressure in the absence of systemic involvement. As the adult circulation is a low pressure, low resistance system, PAH represents a reversal to a foetal state. The small pulmonary arteries of patients exhibit luminal occlusion resultant from the uncontrolled growth of endothelial and smooth muscle cells. This vascular remodelling is comprised of hallmark defects, most notably the plexiform lesion. PAH may be familial in nature but the majority of patients present with spontaneous disease or PAH associated with other complications. In this paper, the molecular genetic basis of the disorder is discussed in detail ranging from the original identification of the major genetic contributant to PAH and moving on to current next-generation technologies that have led to the rapid identification of additional genetic risk factors. The impact of identified mutations on the cell is examined, particularly, the determination of pathways disrupted in disease and critical to pulmonary vascular maintenance. Finally, the application of research in this area to the design and development of novel treatment options for patients is addressed along with the future directions PAH research is progressing towards.

scholarly journals Molecular and Genetic Profiling for Precision Medicines in Pulmonary Arterial Hypertension

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 638
Author(s):  
Shahood Fazal ◽  
Malik Bisserier ◽  
Lahouaria Hadri
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Genetic Variants ◽  
High Throughput Sequencing ◽  
Molecular Genetic ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Common Genetic Variants ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling is, in part, responsible for high pulmonary vascular resistance and the mean pulmonary arterial pressure, increasing the transpulmonary gradient and the right ventricular “pressure overload”, which may result in right ventricular (RV) dysfunction and failure. Current technological advances in multi-omics approaches, high-throughput sequencing, and computational methods have provided valuable tools in molecular profiling and led to the identification of numerous genetic variants in PAH patients. In this review, we summarized the pathogenesis, classification, and current treatments of the PAH disease. Additionally, we outlined the latest next-generation sequencing technologies and the consequences of common genetic variants underlying PAH susceptibility and disease progression. Finally, we discuss the importance of molecular genetic testing for precision medicine in PAH and the future of genomic medicines, including gene-editing technologies and gene therapies, as emerging alternative approaches to overcome genetic disorders in PAH.

scholarly journals Sex Dimorphism in Pulmonary Hypertension: The Role of the Sex Chromosomes

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 779
Author(s):  
Daria S. Kostyunina ◽  
Paul McLoughlin
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Sex Chromosomes ◽  
Bone Morphogenetic Protein 2 ◽  
Sex Dimorphism ◽  
Pulmonary Arterial ◽  
The Impact

Pulmonary hypertension (PH) is a condition characterised by an abnormal elevation of pulmonary artery pressure caused by an increased pulmonary vascular resistance, frequently leading to right ventricular failure and reduced survival. Marked sexual dimorphism is observed in patients with pulmonary arterial hypertension, a form of pulmonary hypertension with a particularly severe clinical course. The incidence in females is 2–4 times greater than in males, although the disease is less severe in females. We review the contribution of the sex chromosomes to this sex dimorphism highlighting the impact of proteins, microRNAs and long non-coding RNAs encoded on the X and Y chromosomes. These genes are centrally involved in the cellular pathways that cause increased pulmonary vascular resistance including the production of reactive oxygen species, altered metabolism, apoptosis, inflammation, vasoconstriction and vascular remodelling. The interaction with genetic mutations on autosomal genes that cause heritable pulmonary arterial hypertension such as bone morphogenetic protein 2 (BMPR2) are examined. The mechanisms that can lead to differences in the expression of genes located on the X chromosomes between females and males are also reviewed. A better understanding of the mechanisms of sex dimorphism in this disease will contribute to the development of more effective therapies for both women and men.

scholarly journals Symptoms, impacts, and suitability of the Pulmonary Arterial Hypertension – Symptoms and Impact (PAH-SYMPACT™) questionnaire in patients with chronic thromboembolic pulmonary hypertension (CTEPH): a qualitative interview study

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Brooke Currie ◽  
Evan Davies ◽  
Amélie Beaudet ◽  
Larissa Stassek ◽  
Leah Kleinman
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Shortness Of Breath ◽  
Response Options ◽  
Qualitative Interview Study ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
The Impact

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare form of pulmonary hypertension caused by blood clots and scar tissue in the blood vessels of the lungs. Health-related quality of life is often significantly impaired in patients with CTEPH. However, a better understanding of how CTEPH symptoms affect patients’ lives is needed to optimally assess the impact of the disease and treatment. Objectives This qualitative study aimed to better understand the symptoms of CTEPH and how they affect patients’ lives, as well as to determine the appropriateness of the Pulmonary Arterial Hypertension – Symptoms and Impact (PAH-SYMPACT™) questionnaire for use in this patient population. Methods Adults diagnosed with CTEPH, recruited from two clinical sites in the US, participated in one-to-one qualitative telephone interviews. They described their experience of CTEPH symptoms and the impact these symptoms have on their lives. They also provided feedback on the comprehensibility and relevance of the PAH-SYMPACT™‘s instructions, items, and response options. Results Participants (N = 12) had a mean age of 62.5 years. Two thirds were female and most (83%) had undergone pulmonary endarterectomy and/or balloon pulmonary angioplasty. The most frequently endorsed symptoms were shortness of breath (endorsed by all 12 participants), fatigue (11 participants), and lightheadedness (10 participants). All participants identified shortness of breath as an “extremely important” symptom, and seven participants rated fatigue as “extremely important.” The most frequent impacts of CTEPH were on ability to walk quickly (endorsed by all 12 participants), ability to walk up inclines or stairs (11 participants), and ability to carry things (11 participants). The PAH-SYMPACT™ items were relevant to most participants and reflected their experience of CTEPH. All participants indicated that no important CTEPH symptoms were missing from the PAH-SYMPACT™. Overall, the instructions, items, and response options of the PAH-SYMPACT™ were clear and easy to understand. Conclusions The symptoms and impacts experienced by patients with CTEPH align with items included in the PAH-SYMPACT™. The PAH-SYMPACT™ appears to be fit for purpose for assessing disease status in patients with CTEPH.

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.

scholarly journals The striated muscles in pulmonary arterial hypertension: adaptations beyond the right ventricle

2015 ◽  
Vol 46 (3) ◽  
pp. 832-842 ◽  
Author(s):  
Emmy Manders ◽  
Silvia Rain ◽  
Harm-Jan Bogaard ◽  
M. Louis Handoko ◽  
Ger J.M. Stienen ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Exercise Intolerance ◽  
Muscle Dysfunction ◽  
Striated Muscles ◽  
Pulmonary Arterial ◽  
The Right ◽  
The Impact

Pulmonary arterial hypertension (PAH) is a fatal lung disease characterised by progressive remodelling of the small pulmonary vessels. The daily-life activities of patients with PAH are severely limited by exertional fatigue and dyspnoea. Typically, these symptoms have been explained by right heart failure. However, an increasing number of studies reveal that the impact of the PAH reaches further than the pulmonary circulation. Striated muscles other than the right ventricle are affected in PAH, such as the left ventricle, the diaphragm and peripheral skeletal muscles. Alterations in these striated muscles are associated with exercise intolerance and reduced quality of life. In this Back to Basics article on striated muscle function in PAH, we provide insight into the pathophysiological mechanisms causing muscle dysfunction in PAH and discuss potential new therapeutic strategies to restore muscle dysfunction.

scholarly journals A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension

2018 ◽  
Vol 51 (6) ◽  
pp. 1702638 ◽  
Author(s):  
Anna R. Hemnes ◽  
Anandharajan Rathinasabapathy ◽  
Eric A. Austin ◽  
Evan L. Brittain ◽  
Erica J. Carrier ◽  
...  
Keyword(s):  
Pilot Study ◽  
Pulmonary Arterial Hypertension ◽  
Angiotensin Converting Enzyme ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
Converting Enzyme ◽  
Open Label ◽  
Angiotensin Converting Enzyme 2 ◽  
Markers Of Inflammation ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1–7) (Ang-(1–7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1–7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg−1 intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2–4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

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

Abstract 15120: Nanoparticle-Mediated Delivery of Pitavastatin into Small Pulmonary Arteies by Intravenous Administration Attenuated the Progression of Already Established Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kenzo Ichimura ◽  
Tetsuya Matoba ◽  
Ryoji Nagahama ◽  
Kaku Nakano ◽  
Kenji Sunagawa ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Intravenous Administration ◽  
Pulmonary Arteries ◽  
Intratracheal Instillation ◽  
Poly Lactic Acid ◽  
Bolus Administration ◽  
Sprague Dawley ◽  
Pulmonary Arterial

Background: Pulmonary arterial hypertension (PAH) is an intractable disease of small pulmonary artery in which multiple pathogenetic factors are involved. We have previously reported that poly(lactic acid/glycolic acid) (PLGA) nanoparticle (NP)-mediated targeting of pitavastatin into lungs by intratracheal instillation attenuated the development of PAH. In the present study we examined the effects of intravenous treatment with pitavastatin-NPs on the progression of already established PAH induced by monocrotaline (MCT). Methods and Results: Male Sprague-Dawley rats (200 to 230 g) were injected subcutaneously with 60 mg/kg MCT to induce PAH. At day 17 after MCT injection when PAH had been already established, animals were randomly divided into 4 groups, which treated with intravenous daily bolus administration of the following drugs for consecutive 4 days from 17 to 20 days after MCT injection; 1) vehicle, 2) FITC-NPs, 3) pitavastatin alone (1, 3, 10 or 30 mg/kg), or 4) pitavastatin-NPs (containing 1 or 3 mg/kg pitavastatin). Treatment with pitavastatin-NPs, but not with pitavastatin alone attenuated the progression of established PAH (Fig. A) associated with the reduction of inflammation and small pulmonary artery remodeling (stenosis and obstruction of pulmonary arterial branches) (Fig. B). In trace experiments, intravenous administration of FITC-NPs revealed the targeting of FITC-NPs into small pulmonary artery in rats with MCT-induced PAH, but not in normal animals. Importantly, in a separate protocol, treatment with pitavastatin-NPs improved the survival rate at day 35 (30% in pitavastatin-NP group vs. 61% in FITC-NP group, P<0.05 by Kaplan-Meier). Conclusion: A novel NP-mediated targeting of pitavastatin into small pulmonary arteries by intravenous administration attenuated the progression of established PAH and improved survival associated with anti-inflammatory and anti-remodeling effects in a rat model of MCT-induced PAH.

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 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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