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Pathophysiology and Treatment of Pulmonary Arterial Hypertension
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Pathophysiology and Treatment of Pulmonary Arterial Hypertension

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 19910

Special Issue Editor

Dr. Yoshihiro Fukumoto

E-Mail Website
Guest Editor
Department of Internal Medicine, Cardiovascular Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
Interests: atherosclerosis; heart failure; pulmonary hypertension; onco-cardiology; cardiac rehabilitation

Special Issue Information

Dear Colleagues,

Pulmonary arterial hypertension is a rare and devastating condition, characterized by the remodeling and the obstruction of pulmonary microvessels and resulting in increased pulmonary vascular resistance, elevated pulmonary arterial pressures, and right ventricular failure. When PAH occurs in a hereditary context, germline mutations in various genes have been identified. The pathophysiological process of PAH is an intricate process that involves vasoconstriction, vascular remodeling, endothelial dysfunction, inflammation, and thrombosis.

This Special Issue aims to provide comprehensible knowledge regarding recently identified mechanisms of the cellular pathogenesis of pulmonary arterial hypertension, which could open future and innovative treatment options and strategies.

Dr. Yoshihiro Fukumoto
Guest Editor

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 157 KiB  
Editorial
Pathophysiology and Treatment of Pulmonary Arterial Hypertension
by Yoshihiro Fukumoto
Int. J. Mol. Sci. 2024, 25(2), 1166; https://doi.org/10.3390/ijms25021166 - 18 Jan 2024
Cited by 2 | Viewed by 1464
Abstract
Pulmonary hypertension (PH) is recognized as a pathophysiological disorder encompassing a wide spectrum of clinical conditions related to various cardiovascular and respiratory diseases [...] Full article
(This article belongs to the Special Issue Pathophysiology and Treatment of Pulmonary Arterial Hypertension)

Research

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16 pages, 2280 KiB  
Article
Effects of the Oral Angiotensin II Type 2 Receptor Agonist C21 in Sugen-Hypoxia Induced Pulmonary Hypertension in Rats
by Göran Tornling, Rohit Batta, Dan Salvail, Johan Raud and Christopher P. Denton
Int. J. Mol. Sci. 2023, 24(8), 7478; https://doi.org/10.3390/ijms24087478 - 19 Apr 2023
Cited by 7 | Viewed by 2219
Abstract
Substantial evidence supports the involvement of the renin-angiotensin system in pulmonary hypertension (PH), and the angiotensin II type 2 receptor (AT2R) is known to exert tissue protective actions. The effect of the selective AT2R agonist C21 (also known as [...] Read more.
Substantial evidence supports the involvement of the renin-angiotensin system in pulmonary hypertension (PH), and the angiotensin II type 2 receptor (AT2R) is known to exert tissue protective actions. The effect of the selective AT2R agonist C21 (also known as Compound 21 or buloxibutid) was evaluated in the rat Sugen-hypoxia PH model. After a single injection of Sugen 5416 and hypoxia for 21 days, C21 (2 or 20 mg/kg) or vehicle was administered perorally twice daily from Day 21 to Day 55. On Day 56, hemodynamic assessments were performed, and lung and heart tissue were prepared for quantification of cardiac and vascular remodeling and fibrosis. Treatment with C21 20 mg/kg improved cardiac output and stroke volume and decreased right ventricular hypertrophy (all p < 0.05). Treatment with C21 2 mg/kg significantly decreased vessel wall and muscular layer thickness and increased the luminal opening in vessels >100 μm (all p < 0.05). There were no significant differences between the two C21 doses on any parameter, and post hoc analyses comparing the merged C21 groups with the vehicle group showed that C21 treatment reduced vascular remodeling (reduced endothelial proliferation and thickening of the vascular wall) in vessels of all sizes; moreover, the diastolic pulmonary artery pressure and right ventricular pressure were reduced along with reduction of right ventricular hypertrophy. Sugen 5416 and hypoxia increased pulmonary collagen deposition, which was counteracted by C21 20 mg/kg. In conclusion, the effects of C21 on vascular remodeling, hemodynamic alterations, and fibrosis suggest that AT2R agonists may have a role in Group 1 and 3 PH treatment. Full article
(This article belongs to the Special Issue Pathophysiology and Treatment of Pulmonary Arterial Hypertension)
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12 pages, 3350 KiB  
Article
Egln1Tie2Cre Mice Exhibit Similar Therapeutic Responses to Sildenafil, Ambrisentan, and Treprostinil as Pulmonary Arterial Hypertension (PAH) Patients, Supporting Egln1Tie2Cre Mice as a Useful PAH Model
by Yi Peng, Jingbo Dai and You-Yang Zhao
Int. J. Mol. Sci. 2023, 24(3), 2391; https://doi.org/10.3390/ijms24032391 - 25 Jan 2023
Cited by 4 | Viewed by 2691
Abstract
Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not [...] Read more.
Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not develop severe PH and occlusive vascular remodeling. Egln1Tie2Cre mice with Tie2Cre-mediated deletion of Egln1, which encodes hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2), is the only mouse model with severe PAH, progressive occlusive pulmonary vascular remodeling, and right-sided heart failure leading to 50–80% mortality from the age of 3–6 months, indicating that the Egln1Tie2Cre mice model is a long-sought-after murine PAH model. However, it is unknown if Egln1Tie2Cre mice respond to FDA-approved PAH drugs in a way similar to PAH patients. Here, we tested the therapeutic effects of the three vasodilators: sildenafil (targeting nitric oxide signaling), ambrisentan (endothelin receptor antagonist), and treprostinil (prostacyclin analog) on Egln1Tie2Cre mice. All of them attenuated right ventricular systolic pressure (RVSP) in Egln1Tie2Cre mice consistent with their role as vasodilators. However, these drugs have no beneficial effects on pulmonary arterial function. Cardiac output was also markedly improved in Egln1Tie2Cre mice by any of the drug treatments. They only partially improved RV function and reduced RV hypertrophy and pulmonary vascular remodeling as well as improving short-term survival in a drug-dependent manner. These data demonstrate that Egln1Tie2Cre mice exhibit similar responses to these drugs as PAH patients seen in clinical trials. Thus, our study provides further evidence that the Egln1Tie2Cre mouse model of severe PAH is an ideal model of PAH and is potentially useful for enabling identification of drug targets and preclinical testing of novel PAH drug candidates. Full article
(This article belongs to the Special Issue Pathophysiology and Treatment of Pulmonary Arterial Hypertension)
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15 pages, 2144 KiB  
Article
CTLA-4 Expression Is a Promising Biomarker of Idiopathic Pulmonary Arterial Hypertension and Allows Differentiation of the Type of Pulmonary Hypertension
by Michał Tomaszewski, Paulina Małkowska, Olga Sierawska, Rafał Hrynkiewicz, Ewa Mroczek, Szymon Darocha, Anna Hymos, Piotr Błaszczak, Ewelina Grywalska and Paulina Niedźwiedzka-Rystwej
Int. J. Mol. Sci. 2022, 23(24), 15910; https://doi.org/10.3390/ijms232415910 - 14 Dec 2022
Cited by 3 | Viewed by 1870
Abstract
Pulmonary arterial hypertension (PAH) is an increasingly frequently diagnosed disease, the molecular mechanisms of which have not been thoroughly investigated. The aim of our study was to investigate subpopulations of lymphocytes to better understand their role in the molecular pathomechanisms of various types [...] Read more.
Pulmonary arterial hypertension (PAH) is an increasingly frequently diagnosed disease, the molecular mechanisms of which have not been thoroughly investigated. The aim of our study was to investigate subpopulations of lymphocytes to better understand their role in the molecular pathomechanisms of various types of PAH and to find a suitable biomarker that could be useful in the differential diagnosis of PAH. Using flow cytometry, we measured the frequencies of lymphocyte subpopulations CD4+CTLA-4+, CD8+ CTLA-4+ and CD19+ CTLA-4+ in patients with different types of PAH, namely pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH), pulmonary arterial hypertension associated with connective tissue disorders (CTD-PAH), chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH), and in an age- and sex-matched control group in relation to selected clinical parameters. Patients in the iPAH group had the significantly highest percentage of CD4+CTLA-4+ T lymphocytes among all PAH groups, as compared to those in the control group (p < 0.001), patients with CTEPH (p < 0.001), CTD-PAH (p < 0.001) and CHD-PAH (p < 0.01). In iPAH patients, the percentages of CD4+CTLA-4+ T cells correlated strongly positively with the severity of heart failure New York Heart Association (NYHA) Functional Classification (r = 0.7077, p < 0.001). Moreover, the percentage of B CD19+CTLA-4+ cells strongly positively correlated with the concentration of NT-proBNP (r = 0.8498, p < 0.001). We have shown that statistically significantly higher percentages of CD4+CTLA-4+ (p ≤ 0.01) and CD8+ CTLA-4+ (p ≤ 0.001) T cells, measured at the time of iPAH diagnosis, were found in patients who died within 5 years of the diagnosis, which allows us to consider both of the above lymphocyte subpopulations as a negative prognostic/predictive factor in iPAH. CTLA-4 may be a promising biomarker of noninvasive detection of iPAH, but its role in planning the treatment strategy of PAH remains unclear. Further studies on T and B lymphocyte subsets are needed in different types of PAH to ascertain the relationships that exist between them and the disease. Full article
(This article belongs to the Special Issue Pathophysiology and Treatment of Pulmonary Arterial Hypertension)
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Review

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19 pages, 3987 KiB  
Review
Pharmacology and Rationale for Seralutinib in the Treatment of Pulmonary Arterial Hypertension
by Soni Savai Pullamsetti, Ravikumar Sitapara, Robin Osterhout, Astrid Weiss, Laura L. Carter, Lawrence S. Zisman and Ralph Theo Schermuly
Int. J. Mol. Sci. 2023, 24(16), 12653; https://doi.org/10.3390/ijms241612653 - 10 Aug 2023
Cited by 6 | Viewed by 3747
Abstract
Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and [...] Read more.
Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and myofibroblasts. Platelet-derived growth factor receptors (PDGFR) α and β, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) are closely related kinases that have been implicated in PAH progression. In addition, emerging data indicate significant crosstalk between PDGF signaling and the bone morphogenetic protein receptor type 2 (BMPR2)/transforming growth factor β (TGFβ) receptor axis. This review will discuss the importance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis, present evidence that the inhibition of all three nodes in this kinase network is a potential therapeutic approach for PAH, and highlight the therapeutic potential of seralutinib, currently in development for PAH, which targets these pathways. Full article
(This article belongs to the Special Issue Pathophysiology and Treatment of Pulmonary Arterial Hypertension)
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20 pages, 368 KiB  
Review
Pathophysiology and Treatment of Chronic Thromboembolic Pulmonary Hypertension
by Naoyuki Otani, Ryo Watanabe, Takashi Tomoe, Shigeru Toyoda, Takanori Yasu and Takaaki Nakamoto
Int. J. Mol. Sci. 2023, 24(4), 3979; https://doi.org/10.3390/ijms24043979 - 16 Feb 2023
Cited by 11 | Viewed by 4293
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is a condition in which an organic thrombus remains in the pulmonary artery (PA) even after receiving anticoagulation therapy for more than 3 months and is complicated by pulmonary hypertension (PH), leading to right-sided heart failure and death. [...] Read more.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a condition in which an organic thrombus remains in the pulmonary artery (PA) even after receiving anticoagulation therapy for more than 3 months and is complicated by pulmonary hypertension (PH), leading to right-sided heart failure and death. CTEPH is a progressive pulmonary vascular disease with a poor prognosis if left untreated. The standard treatment for CTEPH is pulmonary endarterectomy (PEA), which is usually performed only in specialized centers. In recent years, balloon pulmonary angioplasty (BPA) and drug therapy for CTEPH have also shown good results. This review discusses the complex pathogenesis of CTEPH and presents the standard of care, PEA, as well as a new device called BPA, which is showing remarkable progress in efficacy and safety. Additionally, several drugs are now demonstrating established evidence of efficacy in treating CTEPH. Full article
(This article belongs to the Special Issue Pathophysiology and Treatment of Pulmonary Arterial Hypertension)
16 pages, 657 KiB  
Review
Inactivating the Uninhibited: The Tale of Activins and Inhibins in Pulmonary Arterial Hypertension
by Gusty Rizky Teguh Ryanto, Ahmad Musthafa, Tetsuya Hara and Noriaki Emoto
Int. J. Mol. Sci. 2023, 24(4), 3332; https://doi.org/10.3390/ijms24043332 - 7 Feb 2023
Cited by 6 | Viewed by 2630
Abstract
Advances in technology and biomedical knowledge have led to the effective diagnosis and treatment of an increasing number of rare diseases. Pulmonary arterial hypertension (PAH) is a rare disorder of the pulmonary vasculature that is associated with high mortality and morbidity rates. Although [...] Read more.
Advances in technology and biomedical knowledge have led to the effective diagnosis and treatment of an increasing number of rare diseases. Pulmonary arterial hypertension (PAH) is a rare disorder of the pulmonary vasculature that is associated with high mortality and morbidity rates. Although significant progress has been made in understanding PAH and its diagnosis and treatment, numerous unanswered questions remain regarding pulmonary vascular remodeling, a major factor contributing to the increase in pulmonary arterial pressure. Here, we discuss the role of activins and inhibins, both of which belong to the TGF-β superfamily, in PAH development. We examine how these relate to signaling pathways implicated in PAH pathogenesis. Furthermore, we discuss how activin/inhibin-targeting drugs, particularly sotatercep, affect pathophysiology, as these target the afore-mentioned specific pathway. We highlight activin/inhibin signaling as a critical mediator of PAH development that is to be targeted for therapeutic gain, potentially improving patient outcomes in the future. Full article
(This article belongs to the Special Issue Pathophysiology and Treatment of Pulmonary Arterial Hypertension)
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