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Molecular Research on Pulmonary Hypertension
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Molecular Research on Pulmonary 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 (31 October 2018) | Viewed by 112968

Special Issue Editor

Prof. Dr. Sébastien Bonnet

E-Mail Website
Guest Editor
Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec City, QC G1V 4G5, Canada
Interests: pulmonary hypertension; miRNA; metabolism; vascular remodeling; DNA damage; mitochondria apoptosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pulmonary arterial hypertension (PAH) is a chronic and incurable disease characterized by a progressive increase of arterial blood pressure in the lungs. Endothelial cells (ECs) dysfunction and aberrant proliferation of pulmonary arterial smooth muscle cells (PASMCs) and fibroblasts contribute to a progressive obliteration of the precapillary vessels that leads to increased pulmonary arterial pressure and ultimately, right heart failure and death. This Special Issue focuses on molecular mechanisms contributing to endothelial dysfunction, vascular remodelling in the lungs as well as the systemic adverse effects seen in PAH including skeletal muscle and right heart dysfunctions. We warmly welcome submissions, including original papers and reviews, on this widely discussed topic.

Prof. Dr. Sébastien Bonnet
Guest Editor

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Keywords

  • endothelial dysfunction
  • vascular remodelling
  • metabolism
  • right heart failure
  • epigenetic
  • inflammation

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Published Papers (18 papers)

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Research

Jump to: Review

14 pages, 2508 KiB  
Article
Energy Metabolism in the Failing Right Ventricle: Limitations of Oxygen Delivery and the Creatine Kinase System
by Ewan D. Fowler, David Hauton, John Boyle, Stuart Egginton, Derek S. Steele and Ed White
Int. J. Mol. Sci. 2019, 20(8), 1805; https://doi.org/10.3390/ijms20081805 - 12 Apr 2019
Cited by 12 | Viewed by 5095
Abstract
Pulmonary arterial hypertension (PAH) results in hypertrophic remodeling of the right ventricle (RV) to overcome increased pulmonary pressure. This increases the O2 consumption of the myocardium, and without a concomitant increase in energy generation, a mismatch with demand may occur. Eventually, RV [...] Read more.
Pulmonary arterial hypertension (PAH) results in hypertrophic remodeling of the right ventricle (RV) to overcome increased pulmonary pressure. This increases the O2 consumption of the myocardium, and without a concomitant increase in energy generation, a mismatch with demand may occur. Eventually, RV function can no longer be sustained, and RV failure occurs. Beta-adrenergic blockers (BB) are thought to improve survival in left heart failure, in part by reducing energy expenditure and hypertrophy, however they are not currently a therapy for PAH. The monocrotaline (MCT) rat model of PAH was used to investigate the consequence of RV failure on myocardial oxygenation and mitochondrial function. A second group of MCT rats was treated daily with the beta-1 blocker metoprolol (MCT + BB). Histology confirmed reduced capillary density and increased capillary supply area without indications of capillary rarefaction in MCT rats. A computer model of O2 flux was applied to the experimentally recorded capillary locations and predicted a reduction in mean tissue PO2 in MCT rats. The fraction of hypoxic tissue (defined as PO2 < 0.5 mmHg) was reduced following beta-1 blocker (BB) treatment. The functionality of the creatine kinase (CK) energy shuttle was measured in permeabilized RV myocytes by sequential ADP titrations in the presence and absence of creatine. Creatine significantly decreased the KmADP in cells from saline-injected control (CON) rats, but not MCT rats. The difference in KmADP with or without creatine was not different in MCT + BB cells compared to CON or MCT cells. Improved myocardial energetics could contribute to improved survival of PAH with chronic BB treatment. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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18 pages, 10947 KiB  
Article
Caffeic Acid Phenethyl Ester Rescues Pulmonary Arterial Hypertension through the Inhibition of AKT/ERK-Dependent PDGF/HIF-1α In Vitro and In Vivo
by Chin-Chang Cheng, Pei-Ling Chi, Min-Ci Shen, Chih-Wen Shu, Shue-Ren Wann, Chun-Peng Liu, Ching-Jiunn Tseng and Wei-Chun Huang
Int. J. Mol. Sci. 2019, 20(6), 1468; https://doi.org/10.3390/ijms20061468 - 22 Mar 2019
Cited by 21 | Viewed by 4501
Abstract
Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial proliferation and remodeling, resulting in a specific increase in right ventricle systolic pressure (RVSP) and, ultimately right ventricular failure. Recent studies have demonstrated that caffeic acid phenethyl ester (CAPE) exerts a protective role in [...] Read more.
Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial proliferation and remodeling, resulting in a specific increase in right ventricle systolic pressure (RVSP) and, ultimately right ventricular failure. Recent studies have demonstrated that caffeic acid phenethyl ester (CAPE) exerts a protective role in NF-κB-mediated inflammatory diseases. However, the effect of CAPE on PAH remains to be elucidated. In this study, monocrotaline (MCT) was used to establish PAH in rats. Two weeks after the induction of PAH by MCT, CAPE was administrated by intraperitoneal injection once a day for two weeks. Pulmonary hemodynamic measurements and pulmonary artery morphological assessments were examined. Our results showed that administration of CAPE significantly suppressed MCT-induced vascular remodeling by decreasing the HIF-1α expression and PDGF-BB production, and improved in vivo RV systolic performance in rats. Furthermore, CAPE inhibits hypoxia- and PDGF-BB-induced HIF-1α expression by decreasing the activation of the AKT/ERK pathway, which results in the inhibition of human pulmonary artery smooth muscle cells (hPASMCs) proliferation and prevention of cells resistant to apoptosis. Overall, our data suggest that HIF-1α is regarded as an alternative target for CAPE in addition to NF-κB, and may represent a promising therapeutic agent for the treatment of PAH diseases. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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14 pages, 4918 KiB  
Article
Macrophage Migration Inhibitory Factor (MIF) Inhibition in a Murine Model of Bleomycin-Induced Pulmonary Fibrosis
by Sven Günther, Jennifer Bordenave, Thông Hua-Huy, Carole Nicco, Amélie Cumont, Raphaël Thuillet, Ly Tu, Timothée Quatremarre, Thomas Guilbert, Gaël Jalce, Frédéric Batteux, Marc Humbert, Laurent Savale, Christophe Guignabert and Anh-Tuan Dinh-Xuan
Int. J. Mol. Sci. 2018, 19(12), 4105; https://doi.org/10.3390/ijms19124105 - 18 Dec 2018
Cited by 22 | Viewed by 6355
Abstract
Background: Pulmonary hypertension (PH) is a common complication of idiopathic pulmonary fibrosis (IPF) that significantly contributes to morbidity and mortality. Macrophage migration inhibitory factor (MIF) is a critical factor in vascular remodeling of the pulmonary circulation. Objectives: We tested the effects of two [...] Read more.
Background: Pulmonary hypertension (PH) is a common complication of idiopathic pulmonary fibrosis (IPF) that significantly contributes to morbidity and mortality. Macrophage migration inhibitory factor (MIF) is a critical factor in vascular remodeling of the pulmonary circulation. Objectives: We tested the effects of two small molecules targeting MIF on bleomycin (BLM)-induced collagen deposition, PH, and vascular remodeling in mouse lungs. Methods: We examined the distribution pattern of MIF, CD74, and CXCR4 in the lungs of patients with IPF-PH and the lungs of BLM-injected mice. Then, treatments were realized with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and N-(3-hydroxy-4-fluorobenzyl)-5 trifluoromethylbenzoxazol-2-thione 31 (20 mg/kg/day per os for 3 weeks) started 24 h after an intratracheal BLM administration. Results: More intense immunoreactivity was noted for MIF, CD74, and CXCR4 in lungs from IPF-PH patients and BLM-injected mice. Furthermore, we found that treatments of BLM-injected mice with ISO-1 or compound 31 attenuated lung collagen deposition and right ventricular systolic pressure increase. Additionally, reduced pulmonary inflammatory infiltration and pulmonary arterial muscularization were observed in the lungs of BLM-injected mice treated with ISO-1 or compound 31. Conclusions: Treatments with ISO-1 or compound 31 attenuates BLM-induced inflammation and fibrosis in lung, and prevents PH development in mice, suggesting that MIF is an important factor for IPF-PH development. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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14 pages, 1392 KiB  
Article
Blood Outgrowth and Proliferation of Endothelial Colony Forming Cells are Related to Markers of Disease Severity in Patients with Pulmonary Arterial Hypertension
by Josien Smits, Dimitar Tasev, Stine Andersen, Robert Szulcek, Liza Botros, Steffen Ringgaard, Asger Andersen, Anton Vonk-Noordegraaf, Pieter Koolwijk and Harm Jan Bogaard
Int. J. Mol. Sci. 2018, 19(12), 3763; https://doi.org/10.3390/ijms19123763 - 27 Nov 2018
Cited by 13 | Viewed by 3933
Abstract
In pulmonary arterial hypertension (PAH), lung-angioproliferation leads to increased pulmonary vascular resistance, while simultaneous myocardial microvessel loss contributes to right ventricular (RV) failure. Endothelial colony forming cells (ECFC) are highly proliferative, angiogenic cells that may contribute to either pulmonary vascular obstruction or to [...] Read more.
In pulmonary arterial hypertension (PAH), lung-angioproliferation leads to increased pulmonary vascular resistance, while simultaneous myocardial microvessel loss contributes to right ventricular (RV) failure. Endothelial colony forming cells (ECFC) are highly proliferative, angiogenic cells that may contribute to either pulmonary vascular obstruction or to RV microvascular adaptation. We hypothesize ECFC phenotypes (outgrowth, proliferation, tube formation) are related to markers of disease severity in a prospective cohort-study of 33 PAH and 30 healthy subjects. ECFC were transplanted in pulmonary trunk banded rats with RV failure. The presence of ECFC outgrowth in PAH patients was associated with low RV ejection fraction, low central venous saturation and a shorter time to clinical worsening (5.4 months (0.6–29.2) vs. 36.5 months (7.4–63.4), p = 0.032). Functionally, PAH ECFC had higher proliferative rates compared to control in vitro, although inter-patient variability was high. ECFC proliferation was inversely related to RV end diastolic volume (R2 = 0.39, p = 0.018), but not pulmonary vascular resistance. Tube formation-ability was similar among donors. Normal and highly proliferative PAH ECFC were transplanted in pulmonary trunk banded rats. While no effect on hemodynamic measurements was observed, RV vascular density was restored. In conclusion, we found that ECFC outgrowth associates with high clinical severity in PAH, suggesting recruitment. Transplantation of highly proliferative ECFC restored myocardial vascular density in pulmonary trunk banded rats, while RV functional improvements were not observed. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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18 pages, 3228 KiB  
Article
Inhibitory Antibodies against Activin A and TGF-β Reduce Self-Supported, but Not Soluble Factors-Induced Growth of Human Pulmonary Arterial Vascular Smooth Muscle Cells in Pulmonary Arterial Hypertension
by Tatiana V. Kudryashova, Yuanjun Shen, Andressa Pena, Emily Cronin, Evelyn Okorie, Dmitry A. Goncharov and Elena A. Goncharova
Int. J. Mol. Sci. 2018, 19(10), 2957; https://doi.org/10.3390/ijms19102957 - 28 Sep 2018
Cited by 17 | Viewed by 5641
Abstract
Increased growth and proliferation of distal pulmonary artery vascular smooth muscle cells (PAVSMC) is an important pathological component of pulmonary arterial hypertension (PAH). Transforming Growth Factor-β (TGF-β) superfamily plays a critical role in PAH, but relative impacts of self-secreted Activin A, Gremlin1, and [...] Read more.
Increased growth and proliferation of distal pulmonary artery vascular smooth muscle cells (PAVSMC) is an important pathological component of pulmonary arterial hypertension (PAH). Transforming Growth Factor-β (TGF-β) superfamily plays a critical role in PAH, but relative impacts of self-secreted Activin A, Gremlin1, and TGF-β on PAH PAVSMC growth and proliferation are not studied. Here we report that hyper-proliferative human PAH PAVSMC have elevated secretion of TGF-β1 and, to a lesser extent, Activin A, but not Gremlin 1, and significantly reduced Ser465/467-Smad2 and Ser423/425-Smad3 phosphorylation compared to controls. Media, conditioned by PAH PAVSMC, markedly increased Ser465/467-Smad2, Ser423/425-Smad3, and Ser463/465-Smad1/5 phosphorylation, up-regulated Akt, ERK1/2, and p38 MAPK, and induced significant proliferation of non-diseased PAVSMC. Inhibitory anti-Activin A antibody reduced PAH PAVSMC growth without affecting canonical (Smads) or non-canonical (Akt, ERK1/2, p38 MAPK) effectors. Inhibitory anti-TGF-β antibody significantly reduced P-Smad3, P-ERK1/2 and proliferation of PAH PAVSMC, while anti-Gremlin 1 had no anti-proliferative effect. PDGF-BB diminished inhibitory effects of anti-Activin A and anti-TGF-β antibodies. None of the antibodies affected growth and proliferation of non-diseased PAVSMC induced by PAH PAVSMC-secreted factors. Together, these data demonstrate that human PAH PAVSMC have secretory, proliferative phenotype that could be targeted by anti-Activin A and anti-TGF-β antibodies; potential cross-talk with PDGF-BB should be considered while developing therapeutic interventions. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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21 pages, 2249 KiB  
Article
Transcriptomic Signature of Right Ventricular Failure in Experimental Pulmonary Arterial Hypertension: Deep Sequencing Demonstrates Mitochondrial, Fibrotic, Inflammatory and Angiogenic Abnormalities
by Francois Potus, Charles Colin Thomas Hindmarch, Kimberly J. Dunham-Snary, Jeff Stafford and Stephen L. Archer
Int. J. Mol. Sci. 2018, 19(9), 2730; https://doi.org/10.3390/ijms19092730 - 12 Sep 2018
Cited by 35 | Viewed by 5728
Abstract
Right ventricular failure (RVF) remains the leading cause of death in pulmonary arterial hypertension (PAH). We investigated the transcriptomic signature of RVF in hemodynamically well-phenotyped monocrotaline (MCT)-treated, male, Sprague-Dawley rats with severe PAH and decompensated RVF (increased right ventricular (RV) end diastolic volume [...] Read more.
Right ventricular failure (RVF) remains the leading cause of death in pulmonary arterial hypertension (PAH). We investigated the transcriptomic signature of RVF in hemodynamically well-phenotyped monocrotaline (MCT)-treated, male, Sprague-Dawley rats with severe PAH and decompensated RVF (increased right ventricular (RV) end diastolic volume (EDV), decreased cardiac output (CO), tricuspid annular plane systolic excursion (TAPSE) and ventricular-arterial decoupling). RNA sequencing revealed 2547 differentially regulated transcripts in MCT-RVF RVs. Multiple enriched gene ontology (GO) terms converged on mitochondria/metabolism, fibrosis, inflammation, and angiogenesis. The mitochondrial transcriptomic pathway is the most affected in RVF, with 413 dysregulated genes. Downregulated genes included TFAM (−0.45-fold), suggesting impaired mitochondrial biogenesis, CYP2E1 (−3.8-fold), a monooxygenase which when downregulated increases oxidative stress, dehydrogenase/reductase 7C (DHRS7C) (−2.8-fold), consistent with excessive autonomic activation, and polypeptide N-acetyl-galactose-aminyl-transferase 13 (GALNT13), a known pulmonary hypertension (PH) biomarker (−2.7-fold). The most up-regulated gene encodes Periostin (POSTN; 4.5-fold), a matricellular protein relevant to fibrosis. Other dysregulated genes relevant to fibrosis include latent-transforming growth factor beta-binding protein 2 (LTBP2), thrombospondin4 (THBS4). We also identified one dysregulated gene relevant to all disordered transcriptomic pathways, ANNEXIN A1. This anti-inflammatory, phospholipid-binding mediator, is a putative target for therapy in RVF-PAH. Comparison of expression profiles in the MCT-RV with published microarray data from the RV of pulmonary artery-banded mice and humans with bone morphogenetic protein receptor type 2 (BMPR2)-mutations PAH reveals substantial conservation of gene dysregulation, which may facilitate clinical translation of preclinical therapeutic and biomarkers studies. Transcriptomics reveals the molecular fingerprint of RVF to be heavily characterized by mitochondrial dysfunction, fibrosis and inflammation. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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15 pages, 3501 KiB  
Article
Pulmonary Vascular Platform Models the Effects of Flow and Pressure on Endothelial Dysfunction in BMPR2 Associated Pulmonary Arterial Hypertension
by Reid W. D’Amico, Shannon Faley, Ha-na Shim, Joanna R. Prosser, Vineet Agrawal, Leon M. Bellan and James D. West
Int. J. Mol. Sci. 2018, 19(9), 2561; https://doi.org/10.3390/ijms19092561 - 29 Aug 2018
Cited by 7 | Viewed by 4853
Abstract
Endothelial dysfunction is a known consequence of bone morphogenetic protein type II receptor (BMPR2) mutations seen in pulmonary arterial hypertension (PAH). However, standard 2D cell culture models fail to mimic the mechanical environment seen in the pulmonary vasculature. Hydrogels have emerged [...] Read more.
Endothelial dysfunction is a known consequence of bone morphogenetic protein type II receptor (BMPR2) mutations seen in pulmonary arterial hypertension (PAH). However, standard 2D cell culture models fail to mimic the mechanical environment seen in the pulmonary vasculature. Hydrogels have emerged as promising platforms for 3D disease modeling due to their tunable physical and biochemical properties. In order to recreate the mechanical stimuli seen in the pulmonary vasculature, we have created a novel 3D hydrogel-based pulmonary vasculature model (“artificial arteriole”) that reproduces the pulsatile flow rates and pressures seen in the human lung. Using this platform, we studied both Bmpr2R899X and WT endothelial cells to better understand how the addition of oscillatory flow and physiological pressure influenced gene expression, cell morphology, and cell permeability. The addition of oscillatory flow and pressure resulted in several gene expression changes in both WT and Bmpr2R899X cells. However, for many pathways with relevance to PAH etiology, Bmpr2R899X cells responded differently when compared to the WT cells. Bmpr2R899X cells were also found not to elongate in the direction of flow, and instead remained stagnant in morphology despite mechanical stimuli. The increased permeability of the Bmpr2R899X layer was successfully reproduced in our artificial arteriole, with the addition of flow and pressure not leading to significant changes in permeability. Our artificial arteriole is the first to model many mechanical properties seen in the lung. Its tunability enables several new opportunities to study the endothelium in pulmonary vascular disease with increased control over environmental parameters. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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19 pages, 3283 KiB  
Article
Prostanoid EP2 Receptors Are Up-Regulated in Human Pulmonary Arterial Hypertension: A Key Anti-Proliferative Target for Treprostinil in Smooth Muscle Cells
by Jigisha A. Patel, Lei Shen, Susan M. Hall, Chabha Benyahia, Xavier Norel, Robin J. McAnulty, Shahin Moledina, Adam M. Silverstein, Brendan J. Whittle and Lucie H. Clapp
Int. J. Mol. Sci. 2018, 19(8), 2372; https://doi.org/10.3390/ijms19082372 - 12 Aug 2018
Cited by 24 | Viewed by 9086
Abstract
Prostacyclins are extensively used to treat pulmonary arterial hypertension (PAH), a life-threatening disease involving the progressive thickening of small pulmonary arteries. Although these agents are considered to act therapeutically via the prostanoid IP receptor, treprostinil is the only prostacyclin mimetic that potently binds [...] Read more.
Prostacyclins are extensively used to treat pulmonary arterial hypertension (PAH), a life-threatening disease involving the progressive thickening of small pulmonary arteries. Although these agents are considered to act therapeutically via the prostanoid IP receptor, treprostinil is the only prostacyclin mimetic that potently binds to the prostanoid EP2 receptor, the role of which is unknown in PAH. We hypothesised that EP2 receptors contribute to the anti-proliferative effects of treprostinil in human pulmonary arterial smooth muscle cells (PASMCs), contrasting with selexipag, a non-prostanoid selective IP agonist. Human PASMCs from PAH patients were used to assess prostanoid receptor expression, cell proliferation, and cyclic adenosine monophosphate (cAMP) levels following the addition of agonists, antagonists or EP2 receptor small interfering RNAs (siRNAs). Immunohistochemical staining was performed in lung sections from control and PAH patients. We demonstrate using selective IP (RO1138452) and EP2 (PF-04418948) antagonists that the anti-proliferative actions of treprostinil depend largely on EP2 receptors rather than IP receptors, unlike MRE-269 (selexipag-active metabolite). Likewise, EP2 receptor knockdown selectively reduced the functional responses to treprostinil but not MRE-269. Furthermore, EP2 receptor levels were enhanced in human PASMCs and in lung sections from PAH patients compared to controls. Thus, EP2 receptors represent a novel therapeutic target for treprostinil, highlighting key pharmacological differences between prostacyclin mimetics used in PAH. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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17 pages, 20593 KiB  
Article
Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop
by Thomas Bertero, Adam L. Handen and Stephen Y. Chan
Int. J. Mol. Sci. 2018, 19(8), 2289; https://doi.org/10.3390/ijms19082289 - 04 Aug 2018
Cited by 25 | Viewed by 5796
Abstract
Pulmonary arterial hypertension (PAH) is characterized by occlusion of lung arterioles, leading to marked increases in pulmonary vascular resistance. Although heritable forms of PAH are known to be driven by genetic mutations that share some commonality of function, the extent to which these [...] Read more.
Pulmonary arterial hypertension (PAH) is characterized by occlusion of lung arterioles, leading to marked increases in pulmonary vascular resistance. Although heritable forms of PAH are known to be driven by genetic mutations that share some commonality of function, the extent to which these effectors converge to regulate shared processes in this disease is unknown. We have causally connected extracellular matrix (ECM) remodeling and mechanotransduction to the miR-130/301 family in a feedback loop that drives vascular activation and downstream PAH. However, the molecular interconnections between factors genetically associated with PAH and this mechano-driven feedback loop remain undefined. We performed systematic manipulation of matrix stiffness, the miR-130/301 family, and factors genetically associated with PAH in primary human pulmonary arterial cells and assessed downstream and reciprocal consequences on their expression. We found that a network of factors linked to heritable PAH converges upon the matrix stiffening-miR-130/301-PPARγ-LRP8 axis in order to remodel the ECM. Furthermore, we leveraged a computational network biology approach to predict a number of additional molecular circuits functionally linking this axis to the ECM. These results demonstrate that multiple genes associated with heritable PAH converge to control the miR-130/301 circuit, triggering a self-amplifying feedback process central to pulmonary vascular stiffening and disease. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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11 pages, 1764 KiB  
Communication
Inhibition of BET Proteins Reduces Right Ventricle Hypertrophy and Pulmonary Hypertension Resulting from Combined Hypoxia and Pulmonary Inflammation
by Clovis Chabert, Saadi Khochbin, Sophie Rousseaux, Sylvie Veyrenc, Rebecca Furze, Nicholas Smithers, Rab K Prinjha, Uwe Schlattner, Christophe Pison and Hervé Dubouchaud
Int. J. Mol. Sci. 2018, 19(8), 2224; https://doi.org/10.3390/ijms19082224 - 30 Jul 2018
Cited by 10 | Viewed by 5263
Abstract
Pulmonary hypertension is a co-morbidity, which strongly participates in morbi-mortality in patients with chronic obstructive pulmonary disease (COPD). Recent findings showed that bromodomain-containing proteins, in charge of reading histone acetylation, could be involved in pulmonary arterial hypertension. Our aim was to study the [...] Read more.
Pulmonary hypertension is a co-morbidity, which strongly participates in morbi-mortality in patients with chronic obstructive pulmonary disease (COPD). Recent findings showed that bromodomain-containing proteins, in charge of reading histone acetylation, could be involved in pulmonary arterial hypertension. Our aim was to study the effect of I-BET151, an inhibitor of bromodomain and extra-terminal domain (BET), on the right ventricle hypertrophy and pulmonary hypertension, induced by a combination of chronic hypoxia and pulmonary inflammation, as the two main stimuli encountered in COPD. Adult Wistar male rats, exposed to chronic hypoxia plus pulmonary inflammation (CHPI), showed a significant right ventricle hypertrophy (+57%, p < 0.001), an increase in systolic pressure (+46%, p < 0.001) and in contraction speed (+36%, p < 0.001), when compared to control animals. I-BET151 treated animals (CHPI-iB) showed restored hemodynamic parameters to levels similar to control animals, despite chronic hypoxia plus exposure to pulmonary inflammation. They displayed lower right ventricle hypertrophy and hematocrit compared to the CHPI group (respectively −16%, p < 0.001; and −9%, p < 0.05). Our descriptive study shows a valuable effect of the inhibition of bromodomain and extra-terminal domain proteins on hemodynamic parameters, despite the presence of chronic hypoxia and pulmonary inflammation. This suggests that such inhibition could be of potential interest for COPD patients with pulmonary hypertension. Further studies are needed to unravel the underlying mechanisms involved and the net benefits of inhibiting adaptations to chronic hypoxia. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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12 pages, 4134 KiB  
Article
EP4 Agonist L-902,688 Suppresses EndMT and Attenuates Right Ventricular Cardiac Fibrosis in Experimental Pulmonary Arterial Hypertension
by Ying-Ju Lai, I-Chen Chen, Hsin-Hsien Li and Chung-Chi Huang
Int. J. Mol. Sci. 2018, 19(3), 727; https://doi.org/10.3390/ijms19030727 - 03 Mar 2018
Cited by 23 | Viewed by 4428
Abstract
Right ventricular (RV) hypertrophy is characterized by cardiac fibrosis due to endothelial–mesenchymal transition (EndMT) and increased collagen production in pulmonary arterial hypertension (PAH) patients, but the mechanisms for restoring RV function are unclear. Prostanoid agonists are effective vasodilators for PAH treatment that bind [...] Read more.
Right ventricular (RV) hypertrophy is characterized by cardiac fibrosis due to endothelial–mesenchymal transition (EndMT) and increased collagen production in pulmonary arterial hypertension (PAH) patients, but the mechanisms for restoring RV function are unclear. Prostanoid agonists are effective vasodilators for PAH treatment that bind selective prostanoid receptors to modulate vascular dilation. The importance of prostanoid signaling in the RV is not clear. We investigated the effects of the EP4-specific agonist L-902,688 on cardiac fibrosis and TGF-β-induced EndMT. EP4-specific agonist treatment reduced right ventricle fibrosis in the monocrotaline (MCT)-induced PAH rat model. L-902,688 (1 µM) attenuated TGF-β-induced Twist and α-smooth muscle actin (α-SMA) expression, but these effects were reversed by AH23848 (an EP4 antagonist), highlighting the crucial role of EP4 in suppressing TGF-β-induced EndMT. These data indicate that the selective EP4 agonist L-902,688 attenuates RV fibrosis and suggest a potential approach to reducing RV fibrosis in patients with PAH. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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15 pages, 720 KiB  
Review
Molecular Research in Chronic Thromboembolic Pulmonary Hypertension
by Isabelle Opitz and Michaela B. Kirschner
Int. J. Mol. Sci. 2019, 20(3), 784; https://doi.org/10.3390/ijms20030784 - 12 Feb 2019
Cited by 18 | Viewed by 4498
Abstract
Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a debilitating disease, for which the underlying pathophysiological mechanisms have yet to be fully elucidated. Occurrence of a pulmonary embolism (PE) is a major risk factor for the development of CTEPH, with non-resolution of the thrombus being [...] Read more.
Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a debilitating disease, for which the underlying pathophysiological mechanisms have yet to be fully elucidated. Occurrence of a pulmonary embolism (PE) is a major risk factor for the development of CTEPH, with non-resolution of the thrombus being considered the main cause of CTEPH. Polymorphisms in the α-chain of fibrinogen have been linked to resistance to fibrinolysis in CTEPH patients, and could be responsible for development and disease progression. However, it is likely that additional genetic predisposition, as well as genetic and molecular alterations occurring as a consequence of tissue remodeling in the pulmonary arteries following a persistent PE, also play an important role in CTEPH. This review summarises the current knowledge regarding genetic differences between CTEPH patients and controls (with or without pulmonary hypertension). Mutations in BMPR2, differential gene and microRNA expression, and the transcription factor FoxO1 have been suggested to be involved in the processes underlying the development of CTEPH. While these studies provide the first indications regarding important dysregulated pathways in CTEPH (e.g., TGF-β and PI3K signaling), additional in-depth investigations are required to fully understand the complex processes leading to CTEPH. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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15 pages, 651 KiB  
Review
Identification of Novel Therapeutic Targets for Pulmonary Arterial Hypertension
by Kimio Satoh, Nobuhiro Kikuchi, Taijyu Satoh, Ryo Kurosawa, Shinichiro Sunamura, Mohammad Abdul Hai Siddique, Junichi Omura, Nobuhiro Yaoita and Hiroaki Shimokawa
Int. J. Mol. Sci. 2018, 19(12), 4081; https://doi.org/10.3390/ijms19124081 - 17 Dec 2018
Cited by 15 | Viewed by 4052
Abstract
Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are fatal diseases; however, their pathogenesis still remains to be elucidated. We have recently screened novel pathogenic molecules and have performed drug discovery targeting those molecules. Pulmonary artery smooth muscle cells (PASMCs) in [...] Read more.
Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are fatal diseases; however, their pathogenesis still remains to be elucidated. We have recently screened novel pathogenic molecules and have performed drug discovery targeting those molecules. Pulmonary artery smooth muscle cells (PASMCs) in patients with PAH (PAH-PASMCs) have high proliferative properties like cancer cells, which leads to thickening and narrowing of distal pulmonary arteries. Thus, we conducted a comprehensive analysis of PAH-PASMCs and lung tissues to search for novel pathogenic proteins. We validated the pathogenic role of the selected proteins by using tissue-specific knockout mice. To confirm its clinical significance, we used patient-derived blood samples to evaluate the potential as a biomarker for diagnosis and prognosis. Finally, we conducted a high throughput screening and found inhibitors for the pathogenic proteins. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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15 pages, 2797 KiB  
Review
Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia
by Veronique M. M. Vorselaars, Anna E. Hosman, Cornelis J. J. Westermann, Repke J. Snijder, Johannes J. Mager, Marie-Jose Goumans and Marco C. Post
Int. J. Mol. Sci. 2018, 19(10), 3203; https://doi.org/10.3390/ijms19103203 - 17 Oct 2018
Cited by 31 | Viewed by 7743
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by multisystemic vascular dysplasia. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT. Both diseases can be the result of genetic mutations in ACVLR1 and ENG encoding for [...] Read more.
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by multisystemic vascular dysplasia. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT. Both diseases can be the result of genetic mutations in ACVLR1 and ENG encoding for proteins involved in the transforming growth factor-beta (TGF-β) superfamily, a signalling pathway that is essential for angiogenesis. Changes within this pathway can lead to both the proliferative vasculopathy of HPAH and arteriovenous malformations seen in HHT. Clinical signs of the disease combination may not be specific but early diagnosis is important for appropriate treatment. This review describes the molecular mechanism and management of HPAH and HHT. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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49 pages, 4503 KiB  
Review
Ion Channels in Pulmonary Hypertension: A Therapeutic Interest?
by Mélanie Lambert, Véronique Capuano, Andrea Olschewski, Jessica Sabourin, Chandran Nagaraj, Barbara Girerd, Jason Weatherald, Marc Humbert and Fabrice Antigny
Int. J. Mol. Sci. 2018, 19(10), 3162; https://doi.org/10.3390/ijms19103162 - 14 Oct 2018
Cited by 60 | Viewed by 8470
Abstract
Pulmonary arterial hypertension (PAH) is a multifactorial and severe disease without curative therapies. PAH pathobiology involves altered pulmonary arterial tone, endothelial dysfunction, distal pulmonary vessel remodeling, and inflammation, which could all depend on ion channel activities (K+, Ca2+, Na [...] Read more.
Pulmonary arterial hypertension (PAH) is a multifactorial and severe disease without curative therapies. PAH pathobiology involves altered pulmonary arterial tone, endothelial dysfunction, distal pulmonary vessel remodeling, and inflammation, which could all depend on ion channel activities (K+, Ca2+, Na+ and Cl−). This review focuses on ion channels in the pulmonary vasculature and discusses their pathophysiological contribution to PAH as well as their therapeutic potential in PAH. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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19 pages, 1519 KiB  
Review
Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension?
by Gareth R. Willis, Angeles Fernandez-Gonzalez, Monica Reis, S. Alex Mitsialis and Stella Kourembanas
Int. J. Mol. Sci. 2018, 19(9), 2534; https://doi.org/10.3390/ijms19092534 - 27 Aug 2018
Cited by 51 | Viewed by 10178
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of the pulmonary arteries, increased pulmonary infiltrates, loss of vascular cross-sectional area, and elevated pulmonary vascular resistance. Despite recent advances in the management of PAH, there is a pressing need for the [...] Read more.
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of the pulmonary arteries, increased pulmonary infiltrates, loss of vascular cross-sectional area, and elevated pulmonary vascular resistance. Despite recent advances in the management of PAH, there is a pressing need for the development of new tools to effectively treat and reduce the risk of further complications. Dysregulated immunity underlies the development of PAH, and macrophages orchestrate both the initiation and resolution of pulmonary inflammation, thus, manipulation of lung macrophage function represents an attractive target for emerging immunomodulatory therapies, including cell-based approaches. Indeed, mesenchymal stem cell (MSC)-based therapies have shown promise, effectively modulating the macrophage fulcrum to favor an anti-inflammatory, pro-resolving phenotype, which is associated with both histological and functional benefits in preclinical models of pulmonary hypertension (PH). The complex interplay between immune system homeostasis and MSCs remains incompletely understood. Here, we highlight the importance of macrophage function in models of PH and summarize the development of MSC-based therapies, focusing on the significance of MSC exosomes (MEx) and the immunomodulatory and homeostatic mechanisms by which such therapies may afford their beneficial effects. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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24 pages, 941 KiB  
Review
Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension
by Adam Andruska and Edda Spiekerkoetter
Int. J. Mol. Sci. 2018, 19(9), 2499; https://doi.org/10.3390/ijms19092499 - 24 Aug 2018
Cited by 54 | Viewed by 10041
Abstract
Since its association with familial pulmonary arterial hypertension (PAH) in 2000, Bone Morphogenetic Protein Receptor II (BMPR2) and its related signaling pathway have become recognized as a key regulator of pulmonary vascular homeostasis. Herein, we define BMPR2 deficiency as either an inactivation of [...] Read more.
Since its association with familial pulmonary arterial hypertension (PAH) in 2000, Bone Morphogenetic Protein Receptor II (BMPR2) and its related signaling pathway have become recognized as a key regulator of pulmonary vascular homeostasis. Herein, we define BMPR2 deficiency as either an inactivation of the receptor, decreased receptor expression, or an impairment of the receptor’s downstream signaling pathway. Although traditionally the phenotypic consequences of BMPR2 deficiency in PAH have been thought to be limited to the pulmonary vasculature, there is evidence that abnormalities in BMPR2 signaling may have consequences in many other organ systems and cellular compartments. Revisiting how BMPR2 functions throughout health and disease in cells and organs beyond the lung vasculature may provide insight into the contribution of these organ systems to PAH pathogenesis as well as the potential systemic manifestation of PAH. Here we review our knowledge of the consequences of BMPR2 deficiency across multiple organ systems. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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26 pages, 1314 KiB  
Review
Myeloid-Derived Suppressor Cells and Pulmonary Hypertension
by Andrew J. Bryant, Borna Mehrad, Todd M. Brusko, James D. West and Lyle L. Moldawer
Int. J. Mol. Sci. 2018, 19(8), 2277; https://doi.org/10.3390/ijms19082277 - 03 Aug 2018
Cited by 8 | Viewed by 5959
Abstract
Myeloid–derived suppressor cells (MDSCs) comprised a heterogeneous subset of bone marrow–derived myeloid cells, best studied in cancer research, that are increasingly implicated in the pathogenesis of pulmonary vascular remodeling and the development of pulmonary hypertension. Stem cell transplantation represents one extreme interventional strategy [...] Read more.
Myeloid–derived suppressor cells (MDSCs) comprised a heterogeneous subset of bone marrow–derived myeloid cells, best studied in cancer research, that are increasingly implicated in the pathogenesis of pulmonary vascular remodeling and the development of pulmonary hypertension. Stem cell transplantation represents one extreme interventional strategy for ablating the myeloid compartment but poses a number of translational challenges. There remains an outstanding need for additional therapeutic targets to impact MDSC function, including the potential to alter interactions with innate and adaptive immune subsets, or alternatively, alter trafficking receptors, metabolic pathways, and transcription factor signaling with readily available and safe drugs. In this review, we summarize the current literature on the role of myeloid cells in the development of pulmonary hypertension, first in pulmonary circulation changes associated with myelodysplastic syndromes, and then by examining intrinsic myeloid cell changes that contribute to disease progression in pulmonary hypertension. We then outline several tractable targets and pathways relevant to pulmonary hypertension via MDSC regulation. Identifying these MDSC-regulated effectors is part of an ongoing effort to impact the field of pulmonary hypertension research through identification of myeloid compartment-specific therapeutic applications in the treatment of pulmonary vasculopathies. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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