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Pulmonary Hypertension: Pre-clinical Research on New Molecular Targets and Therapeutic Strategies

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 (20 December 2024) | Viewed by 7956

Special Issue Editor

Dr. Pedro Mendes-Ferreira

E-Mail Website
Guest Editor
Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
Interests: pulmonary arterial hypertension; right ventricle function; animal models; receptor tyrosine kinase signalling; bone morphogenetic protein receptor type 2; heart failure

Special Issue Information

Dear Colleagues,

Pulmonary hypertension is a disorder with a complex pathophysiology that can be associated with multiple conditions, including primary vascular disease, heart failure, interstitial lung disease, thromboembolic disease, or other multifactorial or unknown causes.

While an earlier diagnosis and combinational therapies promote a better prognosis, it is still associated with a worse quality of life and survival.

In recent years, significant efforts, including the description of new signalling pathways and genetic mutations associated with the disease, the development of new animal models, and new therapeutic interventions, have resulted in generating a better understanding of the disease. Despite that, new efficacious treatments are still being developed, specifically ones that can halt disease progression and the deadly development of right ventricular failure.

In this Special Issue, we aim to highlight basic and translational research that can move the field of PH forward, by describing new pathways to be targeted, defining new therapeutic strategies, creating new animal models, or better characterizing the disease both at pulmonary and cardiac levels.

Dr. Pedro Mendes-Ferreira
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pulmonary hypertension
  • right ventricle
  • animal models
  • heart failure
  • pulmonary arterial hypertension

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Published Papers (4 papers)

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Research

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15 pages, 3011 KiB  
Article
Connexin 43 Affects Pulmonary Artery Reactivity via Changes in Nitric Oxide Production and Influences Proliferative and Migratory Responses in Mouse Pulmonary Artery Fibroblasts
by Saad Wali, Abdmajid Hwej, David J. Welsh, Kathryn Wilson, Simon Kennedy and Yvonne Dempsie
Int. J. Mol. Sci. 2025, 26(3), 1280; https://doi.org/10.3390/ijms26031280 - 1 Feb 2025
Viewed by 864
Abstract
Pulmonary hypertension (PH) is a complex condition characterized by pulmonary artery constriction and vascular remodeling. Connexin 43 (Cx43), involved in cellular communication, may play a role in PH development. Cx43 heterozygous (Cx43+/−) mice show partial protection against hypoxia-induced pulmonary remodeling, with [...] Read more.
Pulmonary hypertension (PH) is a complex condition characterized by pulmonary artery constriction and vascular remodeling. Connexin 43 (Cx43), involved in cellular communication, may play a role in PH development. Cx43 heterozygous (Cx43+/−) mice show partial protection against hypoxia-induced pulmonary remodeling, with prior research highlighting its role in rat pulmonary artery fibroblast (PAF) proliferation and migration. However, inhibiting Cx43 may compromise nitric oxide (NO)-mediated vascular relaxation. This study evaluated the effects of Cx43 on mouse PAF (MPAF) proliferation, migration, NO-dependent and independent pulmonary vascular relaxation, and NO synthesis. Proliferation and migration were assessed in Cx43+/− MPAFs under normoxic and hypoxic conditions. Vascular responses were analyzed in intra-lobar pulmonary artery rings with acetylcholine (ACh), SNAP, and U46619, while NO production was measured in lung tissue. Both genetic knockdown and pharmacological inhibition of Cx43 significantly reduced serum-induced proliferation but not migration under normoxia, while 37,43Gap27 inhibited hypoxia-induced proliferation and migration. The effects of genetic knockdown and pharmacological inhibition of Cx43 on vascular reactivity were also investigated. NO-dependent and independent relaxations and NO production were reduced in Cx43+/− mice by 37,43Gap27. In conclusion, while Cx43 inhibition may protect against PAF proliferation and migration, it could also impair pulmonary vascular relaxation, at least in part through a reduction in NO signaling. Further studies are needed to fully understand the mechanisms by which Cx43 influences NO signaling. Full article
(This article belongs to the Special Issue Pulmonary Hypertension: Pre-clinical Research on New Molecular Targets and Therapeutic Strategies)
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Review

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33 pages, 2624 KiB  
Review
Searching for Old and New Small-Molecule Protein Kinase Inhibitors as Effective Treatments in Pulmonary Hypertension—A Systematic Review
by Magdalena Jasińska-Stroschein and Paulina Glajzner
Int. J. Mol. Sci. 2024, 25(23), 12858; https://doi.org/10.3390/ijms252312858 - 29 Nov 2024
Viewed by 1495
Abstract
Treatment options for pulmonary arterial hypertension (PAH) have improved substantially in the last 30 years, but there is still a need for novel molecules that can regulate the excessive accumulation of pulmonary artery smooth muscle cells (PASMCs) and consequent vascular remodeling. One set [...] Read more.
Treatment options for pulmonary arterial hypertension (PAH) have improved substantially in the last 30 years, but there is still a need for novel molecules that can regulate the excessive accumulation of pulmonary artery smooth muscle cells (PASMCs) and consequent vascular remodeling. One set of possible candidates are protein kinases. The study provides an overview of existing preclinical and clinical data regarding small-molecule protein kinase inhibitors in PAH. Online databases were searched from 2001 to 2023 according to PRISMA. The corpus included preclinical studies demonstrating alterations in at least one PH-related parameter following chronic exposure to an individual protein kinase inhibitor, as well as prospective clinical reports including healthy adults or those with PAH, with primary outcomes defined as safety or efficacy of an individual small-molecule protein kinase inhibitor. Several models in preclinical protocols (93 papers) have been proposed for studying small-molecule protein kinase inhibitors in PAH. In total, 51 kinase inhibitors were tested. Meta-analysis of preclinical results demonstrated seralutinib, sorafenib, fasudil hydrochloride, and imatinib had the most comprehensive effects on PH with anti-inflammatory, anti-oxidant, and anti-proliferative potential. Fasudil demonstrated more than 70% animal survival with the longest experimental period, while dasatinib, nintedanib, and (R)-crizotinib could deteriorate PAH. The substances targeting the same kinases often varied considerably in their activity, and such heterogeneity may be due to the variety of causes. Recent studies have addressed the molecules that affect multiple networks such as PDG-FRα/β/CSF1R/c-KIT/BMPR2 or FKBP12/mTOR. They also focus on achieving a satisfactory safety profile using innovative inhalation formulations Many small-molecule protein kinase inhibitors are able to control migration, proliferation and survival in PASMCs in preclinical observations. Standardized animal models can successfully reduce inter-study heterogeneity and thereby facilitate successful identification of candidate drugs for further evaluations. Full article
(This article belongs to the Special Issue Pulmonary Hypertension: Pre-clinical Research on New Molecular Targets and Therapeutic Strategies)
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26 pages, 2335 KiB  
Review
Immunotherapy for Pulmonary Arterial Hypertension: From the Pathogenesis to Clinical Management
by Yihan Zhang, Xing Li, Shang Li, Yu Zhou, Tiantai Zhang and Lan Sun
Int. J. Mol. Sci. 2024, 25(15), 8427; https://doi.org/10.3390/ijms25158427 - 1 Aug 2024
Viewed by 2730
Abstract
Pulmonary hypertension (PH) is a progressive cardiovascular disease, which may lead to severe cardiopulmonary dysfunction. As one of the main PH disease groups, pulmonary artery hypertension (PAH) is characterized by pulmonary vascular remodeling and right ventricular dysfunction. Increased pulmonary artery resistance consequently causes [...] Read more.
Pulmonary hypertension (PH) is a progressive cardiovascular disease, which may lead to severe cardiopulmonary dysfunction. As one of the main PH disease groups, pulmonary artery hypertension (PAH) is characterized by pulmonary vascular remodeling and right ventricular dysfunction. Increased pulmonary artery resistance consequently causes right heart failure, which is the major reason for morbidity and mortality in this disease. Although various treatment strategies have been available, the poor clinical prognosis of patients with PAH reminds us that further studies of the pathological mechanism of PAH are still needed. Inflammation has been elucidated as relevant to the initiation and progression of PAH, and plays a crucial and functional role in vascular remodeling. Many immune cells and cytokines have been demonstrated to be involved in the pulmonary vascular lesions in PAH patients, with the activation of downstream signaling pathways related to inflammation. Consistently, this influence has been found to correlate with the progression and clinical outcome of PAH, indicating that immunity and inflammation may have significant potential in PAH therapy. Therefore, we reviewed the pathogenesis of inflammation and immunity in PAH development, focusing on the potential targets and clinical application of anti-inflammatory and immunosuppressive therapy. Full article
(This article belongs to the Special Issue Pulmonary Hypertension: Pre-clinical Research on New Molecular Targets and Therapeutic Strategies)
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17 pages, 509 KiB  
Review
Therapeutic Approaches in Pulmonary Arterial Hypertension with Beneficial Effects on Right Ventricular Function—Preclinical Studies
by André Balsa, Rui Adão and Carmen Brás-Silva
Int. J. Mol. Sci. 2023, 24(21), 15539; https://doi.org/10.3390/ijms242115539 - 24 Oct 2023
Cited by 6 | Viewed by 2180
Abstract
Pulmonary hypertension (PH) is a progressive condition that affects the pulmonary vessels, but its main prognostic factor is the right ventricle (RV) function. Many mice/rat models are used for research in PAH, but results fail to translate to clinical trials. This study reviews [...] Read more.
Pulmonary hypertension (PH) is a progressive condition that affects the pulmonary vessels, but its main prognostic factor is the right ventricle (RV) function. Many mice/rat models are used for research in PAH, but results fail to translate to clinical trials. This study reviews studies that test interventions on pulmonary artery banding (PAB), a model of isolated RV disfunction, and PH models. Multiple tested drugs both improved pulmonary vascular hemodynamics in PH models and improved RV structure and function in PAB animals. PH models and PAB animals frequently exhibited similar results (73.1% concordance). Macitentan, sildenafil, and tadalafil improved most tested pathophysiological parameters in PH models, but almost none in PAB animals. Results are frequently not consistent with other studies, possibly due to the methodology, which greatly varied. Some research groups start treating the animals immediately, and others wait up to 4 weeks from model induction. Treatment duration and choice of anaesthetic are other important differences. This review shows that many drugs currently under research for PAH have a cardioprotective effect on animals that may translate to humans. However, a uniformization of methods may increase comparability between studies and, thus, improve translation to clinical trials. Full article
(This article belongs to the Special Issue Pulmonary Hypertension: Pre-clinical Research on New Molecular Targets and Therapeutic Strategies)
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