scholarly journals BMPR2 mutations and endothelial dysfunction in pulmonary arterial hypertension (2017 Grover Conference Series)

2018 ◽  
Vol 8 (2) ◽  
pp. 204589401876584 ◽  
Author(s):  
Andrea Frump ◽  
Allison Prewitt ◽  
Mark P. de Caestecker
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Endothelial Function ◽  
Arterial Hypertension ◽  
Experimental Models ◽  
Vascular Pathology ◽  
Pulmonary Vasculature ◽  
Tissue Samples ◽  
Established Disease ◽  
Pulmonary Arterial ◽  
The Many

Despite the discovery more than 15 years ago that patients with hereditary pulmonary arterial hypertension (HPAH) inherit BMP type 2 receptor ( BMPR2) mutations, it is still unclear how these mutations cause disease. In part, this is attributable to the rarity of HPAH and difficulty obtaining tissue samples from patients with early disease. However, in addition, limitations to the approaches used to study the effects of BMPR2 mutations on the pulmonary vasculature have restricted our ability to determine how individual mutations give rise to progressive pulmonary vascular pathology in HPAH. The importance of understanding the mechanisms by which BMPR2 mutations cause disease in patients with HPAH is underscored by evidence that there is reduced BMPR2 expression in patients with other, more common, non-hereditary form of PAH, and that restoration of BMPR2 expression reverses established disease in experimental models of pulmonary hypertension. In this paper, we focus on the effects on endothelial function. We discuss some of the controversies and challenges that have faced investigators exploring the role of BMPR2 mutations in HPAH, focusing specifically on the effects different BMPR2 mutation have on endothelial function, and whether there are qualitative differences between different BMPR2 mutations. We discuss evidence that BMPR2 signaling regulates a number of responses that may account for endothelial abnormalities in HPAH and summarize limitations of the models that are used to study these effects. Finally, we discuss evidence that BMPR2-dependent effects on endothelial metabolism provides a unifying explanation for the many of the BMPR2 mutation-dependent effects that have been described in patients with HPAH.

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 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.

scholarly journals Restoration of Vitamin D Levels Improves Endothelial Function and Increases TASK-Like K+ Currents in Pulmonary Arterial Hypertension Associated with Vitamin D Deficiency

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 795
Author(s):  
Maria Callejo ◽  
Daniel Morales-Cano ◽  
Gema Mondejar-Parreño ◽  
Bianca Barreira ◽  
Sergio Esquivel-Ruiz ◽  
...  
Keyword(s):  
Vitamin D ◽  
Pulmonary Arterial Hypertension ◽  
Endothelial Function ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Standard Diet ◽  
Pulmonary Vascular Remodeling ◽  
Vitamin D Levels ◽  
Pulmonary Arterial ◽  
K Currents

Background: Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We hypothesize that recovering optimal levels of vitD in an animal model of PAH previously depleted of vitD improves the hemodynamics, the endothelial dysfunction and the ionic remodeling. Methods: Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O2) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and randomly divided into two groups: (a) continued on vitD-free diet or (b) received an oral dose of 100,000 IU/Kg of vitD plus standard diet for three weeks. Hemodynamics, pulmonary vascular remodeling, pulmonary arterial contractility, and K+ currents were analyzed. Results: Recovering optimal levels of vitD improved endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the activity of TASK-1 potassium channels. However, vitD supplementation did not reduce pulmonary pressure and did not ameliorate pulmonary vascular remodeling and right ventricle hypertrophy. Conclusions: Altogether, these data suggest that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH.

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 18587: Downregulation of Pulmonary Artery Endothelial Catechol-o-methyltransferase Activity by Aldosterone Increases Norepinephrine Levels in Pulmonary Arterial Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Samantha Torquato ◽  
Kiyotake Ishikawa ◽  
Jaume Aguerro ◽  
Bradley A Maron ◽  
Joseph Loscalzo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Therapeutic Interventions ◽  
Pulmonary Vasculature ◽  
Methyltransferase Activity ◽  
Comt Activity ◽  
Pulmonary Arterial

Elevated levels of norepinephrine (NE) occur in pulmonary arterial hypertension (PAH) and are determined, in part, by the activity of catechol- O -methyltransferase (COMT). COMT degrades catecholamines, is negatively regulated by calcium, and is expressed by pulmonary artery endothelial cells (PAEC). As hyperaldosteronism occurs in PAH and aldosterone (ALDO) influences calcium levels, we hypothesized that ALDO decreases COMT activity to increase NE levels in PAH. Accordingly, human PAEC were treated with ALDO (10 -7 mol/L), a level that is achieved clinically in PAH, for up to 72 h. Compared to vehicle-treated PAEC, ALDO decreased COMT activity by 59.2 ± 6.2% (p<0.01) to increase NE levels in the medium (122.4 ± 11.8 vs. 210.7 ± 15.5 pg/mL/mg protein, p<0.01). This occurred as a result of an ALDO-mediated decrease in COMT protein expression by 52.6 ± 9.3% (p<0.01) as well as an increase in intracellular calcium levels (102.9 ± 21.0 vs. 167.7 ± 17.8 nmol/L, p<0.05) to inhibit activity. These effects were abrogated by coincubation with spironolactone. To determine the in vivo relevance of these findings, COMT was examined in the rat monocrotaline model of PAH with confirmed hyperALDO. COMT was decreased (47.6 ± 10.2 %control, p<0.05) in remodeled pulmonary arterioles with a concomitant increase in lung NE levels (432.8 ± 44.5 vs. 899.7 ± 34.2 pg/mL, p<0.01) compared to control rats. In the porcine pulmonary vein banding model of pulmonary hypertension (PH-pigs) with elevated mean pulmonary artery pressure (15[13-15] vs. 35[27-43], p<0.01) and pulmonary vascular resistance (PVR) index (1.97[1.74-2.28] vs. 5.78[2.61-8.75], p <0.05), ALDO levels were also increased (27.1 ± 5.1 vs. 60.8 ± 10.6 pg/mL, p<0.03) in advance of right heart failure as compared to sham controls. PH-pigs demonstrated a 48.3 ± 9.9% (p<0.02) decrease in pulmonary vascular COMT expression and an increase in NE levels (114.6 ± 20.2 vs. 1,622.6 ± 489.2 pg/mL, p<0.02) that correlated positively with ALDO levels (R 2 =0.58, p<0.02). These findings were confirmed in patients with PAH. Together, these data indicate that there is crosstalk in the pulmonary vasculature between ALDO and the sympathetic nervous system to regulate NE levels in PAH, and thus, have implications for therapeutic interventions.

Abstract 382: Cyclophilin A (CypA) is a Pathogenic Mediator of Pulmonary Arterial Hypertension

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Chao Xue
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Specific Inhibitor ◽  
Cyclophilin A ◽  
Pulmonary Vasculature ◽  
Tunel Staining ◽  
Mesenchymal Transition ◽  
Pulmonary Arterial

Rationale: Pulmonary arterial hypertension (PAH) is a devastating disease in which oxidative stress has been proposed to mediate pathological changes to the pulmonary vasculature such as endothelial cell (EC) apoptosis, endothelial to mesenchymal transition (EndMT), vascular smooth muscle cell (VSMC) proliferation, and inflammation. Our previous study showed that cyclophilin A (CypA) was secreted from EC and VSMC in response to oxidative stress, and much of the secreted CypA was acetylated (AcK-CypA). Furthermore, CypA was increased in the plasma of patients with PAH. Objective: To evaluate the cell- s pecific role of CypA in PAH and compare the relative effects of AcK-CypA and CypA on EC apoptosis, development of an inflammatory EC phenotype and EndMT. Methods and Results: Transgenic overexpression of CypA in EC, but not SMC, caused a PAH phenotype including increased pulmonary artery pressure, α-smooth muscle actin expression in small arteries, and CD45 positive cells in the lungs. Mechanistic analysis using cultured mouse lung microvascular EC showed that CypA and AcK-CypA increased apoptosis measured by caspase 3 cleavage and TUNEL staining. MM284, a specific inhibitor of extracellular CypA, prevented EC apoptosis. In addition, CypA and AcK-CypA promoted an EC inflammatory phenotype assessed by increased VCAM1 and ICAM1 expression, phosphorylation of p65, and degradation of IkB. Furthermore, CypA and AcK-CypA promoted EndMT assayed by change in cell morphology, increased mesenchymal markers and EndMT related transcription factors. At all concentrations, AcK-CypA stimulated greater increases in apoptosis, inflammation and EndMT than CypA. Conclusions: EC-derived CypA (especially AcK-CypA) causes PAH by a presumptive mechanism involving increased EC apoptosis, inflammation and EndMT. Our results suggest that inhibiting extracellular secreted CypA is a novel therapeutic approach for PAH.

scholarly journals Novel Therapeutic Approaches of Pulmonary Arterial Hypertension

2019 ◽  
Vol 28 (02) ◽  
pp. 112-117
Author(s):  
Sanjay Tyagi ◽  
Vishal Batra
Keyword(s):  
Nitric Oxide ◽  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Endothelin Receptors ◽  
Pulmonary Vasculature ◽  
Therapeutic Approaches ◽  
Uncommon Disease ◽  
Pulmonary Arterial ◽  
Novel Therapeutic

AbstractPulmonary arterial hypertension (PAH) is an uncommon disease characterized progressive remodeling of pulmonary vasculature. Although treatment for PAH have improved in last two decades but the outcome remains fatal. Currently, the therapies for PAH target three well-established pathways the nitric oxide (NO) pathway, endothelin receptors, and prostanoids. There are multiple potential targets for development of newer drugs in PAH which requires meticulous research and clinical trials.

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.

Pulmonary vasculature

2017 ◽  
Author(s):  
Sophie Vergnaud ◽  
David Dobarro ◽  
John Wort
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Treatment Strategies ◽  
Symptomatic Improvement ◽  
Pulmonary Vasculature ◽  
History Of ◽  
Diffuse Cutaneous Systemic Sclerosis ◽  
Pulmonary Arterial ◽  
Phosphodiesterase 5 ◽  
Haemodynamic Improvement

A 16-year-old girl with a diagnosis of diffuse cutaneous systemic sclerosis is referred to a specialist pulmonary hypertension centre with a history of progressive breathlessness, reduced exercise tolerance, and raised pulmonary pressures on transthoracic echocardiogram. She is found to have pulmonary arterial hypertension on right cardiac catheterization and is started on sildenafil, a phosphodiesterase-5 inhibitor, which stabilizes her condition. An endothelin receptor antagonist is added, which provides some initial symptomatic improvement. She continues to deteriorate over a period of 5 years, ultimately requiring intravenous prostanoids, the only treatment to provide a real symptomatic and haemodynamic improvement. This chapter explores the physiology and pathophysiology of pulmonary arterial hypertension, its classification, the means of investigation and diagnosis, who to refer to specialist centres, and the concepts behind current and future treatment strategies.

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