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

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.

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

Circulation ◽

10.1161/circ.130.suppl_2.18587 ◽

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.

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.382 ◽

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.

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

Pulmonary Circulation ◽

10.1177/20458940211021036 ◽

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.

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Vascular Remodeling in Pulmonary Arterial Hypertension: The Potential Involvement of Innate and Adaptive Immunity

Frontiers in Medicine ◽

10.3389/fmed.2021.806899 ◽

2021 ◽

Vol 8 ◽

Author(s):

Rachid Tobal ◽

Judith Potjewijd ◽

Vanessa P. M. van Empel ◽

Renee Ysermans ◽

Leon J. Schurgers ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Immune Cells ◽

Vascular Remodeling ◽

Pulmonary Vasculature ◽

M2 Macrophage ◽

High Morbidity ◽

Vascular Cells ◽

Immunological Mechanisms ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a severe disease with high morbidity and mortality. Current therapies are mainly focused on vasodilative agents to improve prognosis. However, recent literature has shown the important interaction between immune cells and stromal vascular cells in the pathogenic modifications of the pulmonary vasculature. The immunological pathogenesis of PAH is known as a complex interplay between immune cells and vascular stromal cells, via direct contacts and/or their production of extra-cellular/diffusible factors such as cytokines, chemokines, and growth factors. These include, the B-cell—mast-cell axis, endothelium mediated fibroblast activation and subsequent M2 macrophage polarization, anti-endothelial cell antibodies and the versatile role of IL-6 on vascular cells. This review aims to outline the major pathophysiological changes in vascular cells caused by immunological mechanisms, leading to vascular remodeling, increased pulmonary vascular resistance and eventually PAH. Considering the underlying immunological mechanisms, these mechanisms may be key to halt progression of disease.

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00559.2020 ◽

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.

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Clinical Trials Targeting Metabolism in Pulmonary Arterial Hypertension

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-17.3.110 ◽

2018 ◽

Vol 17 (3) ◽

pp. 110-114 ◽

Cited By ~ 1

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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The estrogen paradox in pulmonary arterial hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00057.2010 ◽

2010 ◽

Vol 299 (4) ◽

pp. L435-L438 ◽

Cited By ~ 12

Author(s):

Seiichiro Sakao ◽

Nobuhiro Tanabe ◽

Koichiro Tatsumi

Keyword(s):

Gender Differences ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Therapeutic Interventions ◽

Pulmonary Vasculature ◽

Target Cells ◽

Beneficial Effects ◽

Estrogen Exposure ◽

Increased Risk ◽

Pulmonary Arterial

Idiopathic pulmonary arterial hypertension (PAH) is a disabling condition characterized by PA vasoconstriction and remodeling as well as in situ thrombosis and eventual right heart failure. Idiopathic PAH occurs more frequently in females than in males. The female:male ratio is 1.64 ∼ 3.88:1. Although endogenous sex hormones including estrogen have been suggested to account for the observed gender differences in PAH, a precise pathobiology for the gender differences remains uncertain. Recent studies demonstrated that estrogen exerts beneficial effects on the pulmonary vasculature. However, it seems to contradict the female predominance that is observed in idiopathic PAH. Moreover, Sweeney and Voelkel (Sweeney L and Voelkel NF. Eur J Med Res 14: 433–442, 2009) showed that early and long-term estrogen exposure might be correlated with an increased risk of the development of PAH. Here we ask the question: Is estrogen a friend or a foe? According to accumulating evidence, we postulate that the different effects of estrogens on different target cells could account for this paradox, i.e., estrogens may exert beneficial effects only on the increased muscularization of vessel walls, but not on phenotypically altered endothelial cells. The effects of estrogens on the pulmonary vasculature are potent and complex, yet not fully understood. A better mechanistic understanding may allow for future therapeutic interventions in patients with PAH.

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

Pulmonary Circulation ◽

10.1177/2045894018765840 ◽

2018 ◽

Vol 8 (2) ◽

pp. 204589401876584 ◽

Cited By ~ 11

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.

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