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Novel Therapeutic Targets for Pulmonary Arterial Hypertension
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Novel Therapeutic Targets for 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 (29 April 2023) | Viewed by 17262

Special Issue Editor

Dr. Fakhrul Ahsan

E-Mail Website
Guest Editor
Department of Pharmaceutical and Biomedical Sciences, California Northstate University, Elk Grove, CA 95757, USA
Interests: pulmonary arterial hypertension

Special Issue Information

Dear Colleagues,

Currently three classes of drugs—prostacyclin analogs, endothelin receptor antagonists (ERAs) and phosphodiesterase-5 (PDE-5) inhibitors—are used to treat pulmonary arterial hypertension (PAH), a debilitating disorder of the cardiopulmonary circulation. Endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors and prostacyclin analogs have been the mainstays of PAH therapy for the past two decades. Bosentan and ambrisentan, two FDA-approved ERAs, increase the risk of liver injury, cause peripheral edema and necessitate liver function monitoring. Gaseous nitric oxide requires continuous inhalation, causes rebound PAH and exacerbates pulmonary hemodynamics. Sildenafil and tadalafil (PDE-5 inhibitors) reduce mean pulmonary arterial pressure but lack pulmonary selectivity and produce systemic hypotension. Epoprostenol, treprostinil and iloprost, three prostacyclin analogs, are available either in injectable, inhaled or both forms. Various combinations of anti-PAH drugs (prostacyclin analogs plus ERAs, ERAs plus PDE-5 inhibitors or prostacyclin analogs plus PDE-5 inhibitors) have been evaluated in Europe and the USA. However, the outcomes of the trials were discouraging. Combinations of two or more drugs produced only incremental improvement in clinical deterioration, and pulmonary hemodynamics patient mortality was no better in the combination arms. Patients unresponsive to therapy are left with the option of lung transplantation, which brings its own set of new health problems. Overall, patient outcomes are disappointing because current medications cannot cure the underlying pathophysiology: pulmonary vascular remodeling and right heart enlargement. However, no biologic-based therapy such as monoclonal antibodies, proteins or gene therapeutics are available for the treatment of PAH. Although epigenetics appears to play a major role in PAH pathogenesis, no drug is currently available which targets the epigenetic pathway. As such, we need both new therapeutic targets and agents for the treatment of PAH.

Dr. Fakhrul Ahsan
Guest Editor

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Published Papers (6 papers)

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Research

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10 pages, 1355 KiB  
Communication
Electrical Remodeling in Right Ventricular Failure Due to Pulmonary Hypertension: Unraveling Novel Therapeutic Targets
by John F. Park, Justine Liang and Soban Umar
Int. J. Mol. Sci. 2023, 24(5), 4633; https://doi.org/10.3390/ijms24054633 - 27 Feb 2023
Cited by 1 | Viewed by 1800
Abstract
Arrhythmias in the setting of right-ventricular (RV) remodeling contribute to majority of deaths in patients with pulmonary hypertension. However, the underlying mechanism of electrical remodeling remains elusive, especially ventricular arrhythmias. Here, we analyzed the RV transcriptome of pulmonary arterial hypertension (PAH) patients with [...] Read more.
Arrhythmias in the setting of right-ventricular (RV) remodeling contribute to majority of deaths in patients with pulmonary hypertension. However, the underlying mechanism of electrical remodeling remains elusive, especially ventricular arrhythmias. Here, we analyzed the RV transcriptome of pulmonary arterial hypertension (PAH) patients with compensated RV or decompensated RV and identified 8 and 45 differentially expressed genes known to be involved in regulating the electrophysiological properties of excitation and contraction of cardiac myocytes, respectively. Transcripts encoding voltage-gated Ca2+ and Na+ channels were notably decreased in PAH patients with decompensated RV, along with significant dysregulation of KV and Kir channels. We further showed similarity of the RV channelome signature with two well-known animal models of PAH, monocrotaline (MCT)- and Sugen-hypoxia (SuHx)-treated rats. We identified 15 common transcripts among MCT, SuHx, and PAH patients with decompensated RV failure. In addition, data-driven drug repurposing using the channelome signature of PAH patients with decompensated RV failure predicted drug candidates that may reverse the altered gene expression. Comparative analysis provided further insight into clinical relevance and potential preclinical therapeutic studies targeting mechanisms involved in arrhythmogenesis. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Pulmonary Arterial Hypertension)
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16 pages, 8456 KiB  
Article
Identification of JPX-RABEP1 Pair as an Immune-Related Biomarker and Therapeutic Target in Pulmonary Arterial Hypertension by Bioinformatics and Experimental Analyses
by Qian Gong, Zhewei Hu, Qiao Jin, Yan Yan, Yan Liu, Jin He, Lenan Zhuang and Huanan Wang
Int. J. Mol. Sci. 2022, 23(24), 15559; https://doi.org/10.3390/ijms232415559 - 8 Dec 2022
Cited by 3 | Viewed by 1669
Abstract
Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by pulmonary vascular remodeling and right heart enlargement the pathogenesis of PAH is complicated; no biologic-based therapy is available for the treatment of PAH, but recent studies suggest that inflammatory response and abnormal [...] Read more.
Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by pulmonary vascular remodeling and right heart enlargement the pathogenesis of PAH is complicated; no biologic-based therapy is available for the treatment of PAH, but recent studies suggest that inflammatory response and abnormal proliferation of pulmonary artery smooth muscle cells are the main pathogenic mechanism, while the role of immune-related long non-coding RNAs (lncRNAs) remains unclear. The aim of this study was to systematically analyze immune-related lncRNAs in PAH. Here, we downloaded a publicly available microarray data from PAH and control patients (GSE113439). A total of 243 up-regulated and 203 down-regulated differentially expressed genes (DEGs) were screened, and immune-related DEGs were further obtained from ImmPort. The immune-related lncRNAs were obtained by co-expression analysis of immune-related mRNAs. Then, immune-related lncRNAs-mRNAs network including 2 lncRNAs and 6 mRNAs was constructed which share regulatory miRNAs and have significant correlation. Among the lncRNA-mRNA pairs, one pair (JPX-RABEP1) was verified in the validating dataset GSE53408 and PAH mouse model. Furthermore, the immune cell infiltration analysis of the GSE113439 dataset revealed that the JPX-RABEP1 pair may participate in the occurrence and development of PAH through immune cell infiltration. Together, our findings reveal that the lncRNA-mRNA pair JPX-RABEP1 may be a novel biomarker and therapeutic target for PAH. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Pulmonary Arterial Hypertension)
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Review

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33 pages, 2241 KiB  
Review
Pulmonary Hypertension in Left Heart Diseases: Pathophysiology, Hemodynamic Assessment and Therapeutic Management
by Zied Ltaief, Patrick Yerly and Lucas Liaudet
Int. J. Mol. Sci. 2023, 24(12), 9971; https://doi.org/10.3390/ijms24129971 - 9 Jun 2023
Cited by 3 | Viewed by 2024
Abstract
Pulmonary hypertension (PH) associated with left heart diseases (PH-LHD), also termed group 2 PH, represents the most common form of PH. It develops through the passive backward transmission of elevated left heart pressures in the setting of heart failure, either with preserved (HFpEF) [...] Read more.
Pulmonary hypertension (PH) associated with left heart diseases (PH-LHD), also termed group 2 PH, represents the most common form of PH. It develops through the passive backward transmission of elevated left heart pressures in the setting of heart failure, either with preserved (HFpEF) or reduced (HFrEF) ejection fraction, which increases the pulsatile afterload of the right ventricle (RV) by reducing pulmonary artery (PA) compliance. In a subset of patients, progressive remodeling of the pulmonary circulation resulted in a pre-capillary phenotype of PH, with elevated pulmonary vascular resistance (PVR) further increasing the RV afterload, eventually leading to RV-PA uncoupling and RV failure. The primary therapeutic objective in PH-LHD is to reduce left-sided pressures through the appropriate use of diuretics and guideline-directed medical therapies for heart failure. When pulmonary vascular remodeling is established, targeted therapies aiming to reduce PVR are theoretically appealing. So far, such targeted therapies have mostly failed to show significant positive effects in patients with PH-LHD, in contrast to their proven efficacy in other forms of pre-capillary PH. Whether such therapies may benefit some specific subgroups of patients (HFrEF, HFpEF) with specific hemodynamic phenotypes (post- or pre-capillary PH) and various degrees of RV dysfunction still needs to be addressed. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Pulmonary Arterial Hypertension)
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15 pages, 1757 KiB  
Review
MicroRNA and lncRNA as the Future of Pulmonary Arterial Hypertension Treatment
by Łukasz Wołowiec, Martyna Mędlewska, Joanna Osiak, Anna Wołowiec, Elżbieta Grześk, Albert Jaśniak and Grzegorz Grześk
Int. J. Mol. Sci. 2023, 24(11), 9735; https://doi.org/10.3390/ijms24119735 - 4 Jun 2023
Cited by 4 | Viewed by 2018
Abstract
Pulmonary hypertension (PH) is characterized by a progressive increase in pulmonary arterial pressure and pulmonary vascular resistance. In a short time, it leads to right ventricular failure and, consequently, to death. The most common causes of PH include left heart disease and lung [...] Read more.
Pulmonary hypertension (PH) is characterized by a progressive increase in pulmonary arterial pressure and pulmonary vascular resistance. In a short time, it leads to right ventricular failure and, consequently, to death. The most common causes of PH include left heart disease and lung disease. Despite the significant development of medicine and related sciences observed in recent years, we still suffer from a lack of effective treatment that would significantly influence the prognosis and prolong life expectancy of patients with PH. One type of PH is pulmonary arterial hypertension (PAH). The pathophysiology of PAH is based on increased cell proliferation and resistance to apoptosis in the small pulmonary arteries, leading to pulmonary vascular remodeling. However, studies conducted in recent years have shown that epigenetic changes may also lie behind the pathogenesis of PAH. Epigenetics is the study of changes in gene expression that are not related to changes in the sequence of nucleotides in DNA. In addition to DNA methylation or histone modification, epigenetic research focuses on non-coding RNAs, which include microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Preliminary research results give hope that targeting epigenetic regulators may lead to new, potential therapeutic possibilities in the treatment of PAH. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Pulmonary Arterial Hypertension)
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15 pages, 1139 KiB  
Review
Targeting Mitochondrial Metabolic Dysfunction in Pulmonary Hypertension: Toward New Therapeutic Approaches?
by Marianne Riou, Irina Enache, François Sauer, Anne-Laure Charles and Bernard Geny
Int. J. Mol. Sci. 2023, 24(11), 9572; https://doi.org/10.3390/ijms24119572 - 31 May 2023
Cited by 3 | Viewed by 2038
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling leading to right heart failure and death. To date, despite the three therapeutic approaches targeting the three major endothelial dysfunction pathways based on the prostacyclin, nitric oxide/cyclic guanosine monophosphate, and [...] Read more.
Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling leading to right heart failure and death. To date, despite the three therapeutic approaches targeting the three major endothelial dysfunction pathways based on the prostacyclin, nitric oxide/cyclic guanosine monophosphate, and endothelin pathways, PAH remains a serious disease. As such, new targets and therapeutic agents are needed. Mitochondrial metabolic dysfunction is one of the mechanisms involved in PAH pathogenesis in part through the induction of a Warburg metabolic state of enhanced glycolysis but also through the upregulation of glutaminolysis, tricarboxylic cycle and electron transport chain dysfunction, dysregulation of fatty acid oxidation or mitochondrial dynamics alterations. The aim of this review is to shed light on the main mitochondrial metabolic pathways involved in PAH and to provide an update on the resulting interesting potential therapeutic perspectives. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Pulmonary Arterial Hypertension)
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39 pages, 2012 KiB  
Review
New Drugs and Therapies in Pulmonary Arterial Hypertension
by Aangi J. Shah, Taylor Beckmann, Mounica Vorla and Dinesh K. Kalra
Int. J. Mol. Sci. 2023, 24(6), 5850; https://doi.org/10.3390/ijms24065850 - 19 Mar 2023
Cited by 5 | Viewed by 6644
Abstract
Pulmonary arterial hypertension is a chronic, progressive disorder of the pulmonary vasculature with associated pulmonary and cardiac remodeling. PAH was a uniformly fatal disease until the late 1970s, but with the advent of targeted therapies, the life expectancy of patients with PAH has [...] Read more.
Pulmonary arterial hypertension is a chronic, progressive disorder of the pulmonary vasculature with associated pulmonary and cardiac remodeling. PAH was a uniformly fatal disease until the late 1970s, but with the advent of targeted therapies, the life expectancy of patients with PAH has now considerably improved. Despite these advances, PAH inevitably remains a progressive disease with significant morbidity and mortality. Thus, there is still an unmet need for the development of new drugs and other interventional therapies for the treatment of PAH. One shortcoming of currently approved vasodilator therapies is that they do not target or reverse the underlying pathogenesis of the disease process itself. A large body of evidence has evolved in the past two decades clarifying the role of genetics, dysregulation of growth factors, inflammatory pathways, mitochondrial dysfunction, DNA damage, sex hormones, neurohormonal pathways, and iron deficiency in the pathogenesis of PAH. This review focuses on newer targets and drugs that modify these pathways as well as novel interventional therapies in PAH. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Pulmonary Arterial Hypertension)
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