Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives

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Abstract

Clinical and translational research has played a major role in advancing our understanding of pulmonary hypertension (PH), including pulmonary arterial hypertension and other forms of PH with severe vascular remodelling ( e.g. chronic thromboembolic PH and pulmonary veno-occlusive disease). However, PH remains an incurable condition with a high mortality rate, underscoring the need for a better transfer of novel scientific knowledge into healthcare interventions. Herein, we review recent findings in pathology (with the questioning of the strict morphological categorisation of various forms of PH into pre- or post-capillary involvement of pulmonary vessels) and cellular mechanisms contributing to the onset and progression of pulmonary vascular remodelling associated with various forms of PH. We also discuss ways to improve management and to support and optimise drug development in this research field.

Abstract

State of the art and research perspectives in the cellular and molecular basis and pathology of pulmonary vascular remodelling associated with various forms of pulmonary hypertension http://ow.ly/cjwp30mgzmH

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Most cited references 72

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Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension.

Thomas Bertero, William M Oldham, Katherine A. Cottrill … (2016)

Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis. Glutaminolysis, an anaplerotic pathway, replenished aspartate for anabolic biosynthesis, which was critical for sustaining proliferation and migration within stiff ECM. In vitro, GLS1 inhibition blocked aspartate production and reprogrammed cellular proliferation pathways, while application of aspartate restored proliferation. In the monocrotaline rat model of PH, pharmacologic modulation of pulmonary vascular stiffness and YAP-dependent mechanotransduction altered glutaminolysis, pulmonary vascular proliferation, and manifestations of PH. Additionally, pharmacologic targeting of GLS1 in this model ameliorated disease progression. Notably, evaluation of simian immunodeficiency virus-infected nonhuman primates and HIV-infected subjects revealed a correlation between YAP/TAZ-GLS activation and PH. These results indicate that ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis and anaplerosis, and thereby link mechanical stimuli to dysregulated vascular metabolism. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in PH.

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A novel channelopathy in pulmonary arterial hypertension.

Dominic Chung, Marc Humbert, Florent Soubrier … (2013)

Pulmonary arterial hypertension is a devastating disease with high mortality. Familial cases of pulmonary arterial hypertension are usually characterized by autosomal dominant transmission with reduced penetrance, and some familial cases have unknown genetic causes. We studied a family in which multiple members had pulmonary arterial hypertension without identifiable mutations in any of the genes known to be associated with the disease, including BMPR2, ALK1, ENG, SMAD9, and CAV1. Three family members were studied with whole-exome sequencing. Additional patients with familial or idiopathic pulmonary arterial hypertension were screened for the mutations in the gene that was identified on whole-exome sequencing. All variants were expressed in COS-7 cells, and channel function was studied by means of patch-clamp analysis. We identified a novel heterozygous missense variant c.608 G→A (G203D) in KCNK3 (the gene encoding potassium channel subfamily K, member 3) as a disease-causing candidate gene in the family. Five additional heterozygous missense variants in KCNK3 were independently identified in 92 unrelated patients with familial pulmonary arterial hypertension and 230 patients with idiopathic pulmonary arterial hypertension. We used in silico bioinformatic tools to predict that all six novel variants would be damaging. Electrophysiological studies of the channel indicated that all these missense mutations resulted in loss of function, and the reduction in the potassium-channel current was remedied by the application of the phospholipase inhibitor ONO-RS-082. Our study identified the association of a novel gene, KCNK3, with familial and idiopathic pulmonary arterial hypertension. Mutations in this gene produced reduced potassium-channel current, which was successfully remedied by pharmacologic manipulation. (Funded by the National Institutes of Health.)

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Pulmonary arterial hypertension in patients treated by dasatinib.

Emmanuel Bergot, Gerald Simonneau, Barbara Girerd … (2012)

The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (≤20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.

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Author and article information

Journal

Journal ID (nlm-ta): Eur Respir J

Journal ID (iso-abbrev): Eur. Respir. J

Journal ID (publisher-id): ERJ

Journal ID (hwp): erj

Title: The European Respiratory Journal

Publisher: European Respiratory Society

ISSN (Print): 0903-1936

ISSN (Electronic): 1399-3003

Publication date Collection: January 2019

Publication date (Electronic): 24 January 2019

Volume: 53

Issue: 1

Electronic Location Identifier: 1801887

Affiliations

[1 ]Faculté de Médecine, Université Paris-Sud and Université Paris-Saclay, Le Kremlin-Bicêtre, France

[2 ]INSERM UMR_S 999, Le Plessis-Robinson, France

[3 ]AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Hôpital de Bicêtre, Le Kremlin-Bicêtre, France

[4 ]Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Quebec, Quebec City, QC, Canada

[5 ]Dept of Medicine, Université Laval, Quebec City, QC, Canada

[6 ]Pathology Dept, Hôpital Marie Lannelongue, Le Plessis-Robinson, France

[7 ]Division of Pulmonary, Critical Care and Sleep Medicine, Dept of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA

[8 ]Cardiovascular Institute, Dept of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA

[9 ]Division of Pulmonary and Critical Care Medicine, Dept of Medicine, Stanford University School of Medicine/VA Palo Alto, Palo Alto, CA, USA

[10 ]The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford, CA, USA

[11 ]Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

[12 ]Institute of Physiology, Medical University of Graz, Graz, Austria

[13 ]Max Planck Institute for Heart and Lung Research Bad Nauheim, Bad Nauheim, Germany

[14 ]Justus-Liebig University Giessen, Excellence Cluster Cardio Pulmonary Institute (CPI), Giessen, Germany

[15 ]University of Giessen and Marburg Lung Centre (UGMLC), Justus-Liebig University Giessen and Member of the German Center for Lung Research (DZL), Excellence Cluster Cardio Pulmonary Institute (CPI), Giessen, Germany

[16 ]Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, University of Colorado, Denver, CO, USA

Author notes

Marlene Rabinovitch, Cardiovascular Institute, Dept of Pediatrics, Stanford University School of Medicine, 269 Campus Drive, CCSR Building, Room 1215A, Stanford, CA 94305-5162, USA. E-mail: marlener@ 123456stanford.edu

Marc Humbert, Université Paris-Sud, Service de Pneumologie, Hôpital Bicêtre, AP-HP, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France. E-mail: marc.humbert@ 123456aphp.fr

Author information

Marc Humbert https://orcid.org/0000-0003-0703-2892

Christophe Guignabert https://orcid.org/0000-0002-8545-4452

Peter Dorfmüller https://orcid.org/0000-0003-2499-6829

Soni S. Pullamsetti https://orcid.org/0000-0003-0440-8831

Ralph T. Schermuly https://orcid.org/0000-0002-5167-6970

Article

Publisher ID: ERJ-01887-2018

DOI: 10.1183/13993003.01887-2018

PMC ID: 6351340

PubMed ID: 30545970

SO-VID: 3413e1de-f7c7-442c-9d21-dea259d6557f

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This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives

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Inflamed lung in vitro co-culture models

Most cited references 72

Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension.

A novel channelopathy in pulmonary arterial hypertension.

Pulmonary arterial hypertension in patients treated by dasatinib.

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