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

European Respiratory Journal, Journal Year: 2018, Volume and Issue: 53(1), P. 1801887 - 1801887

Published: Dec. 13, 2018

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

Language: Английский

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Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio‐Oncology Council of the European Society of Cardiology (ESC)

European Journal of Heart Failure, Journal Year: 2020, Volume and Issue: 22(9), P. 1504 - 1524

Published: July 4, 2020

Language: Английский

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The cancer theory of pulmonary arterial hypertension

Pulmonary Circulation, Journal Year: 2017, Volume and Issue: 7(2), P. 285 - 299

Published: March 1, 2017

Pulmonary arterial hypertension (PAH) remains a mysterious killer that, like cancer, is characterized by tremendous complexity. PAH development occurs under sustained and persistent environmental stress, such as inflammation, shear pseudo-hypoxia, more. After inducing an initial death of the endothelial cells, these stresses contribute with time to hyper-proliferative apoptotic resistant clone cells including pulmonary artery smooth muscle fibroblasts, even allowing vascular remodeling development. Molecularly, exhibit many features common cancer offering opportunity exploit therapeutic strategies used in treat PAH. In this review, we outline signaling pathways mechanisms described that drive cells' survival proliferation discuss potential antineoplastic drugs

Language: Английский

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Novel insights on the pulmonary vascular consequences of COVID-19

AJP Lung Cellular and Molecular Physiology, Journal Year: 2020, Volume and Issue: 319(2), P. L277 - L288

Published: June 17, 2020

In the last few months, number of cases a new coronavirus-related disease (COVID-19) rose exponentially, reaching status pandemic. Interestingly, early imaging studies documented that pulmonary vascular thickening was specifically associated with COVID-19 pneumonia, implying potential tropism virus for vasculature. Moreover, SARS-CoV-2 infection is inflammation, hypoxia, oxidative stress, mitochondrial dysfunction, DNA damage, and lung coagulopathy promoting endothelial dysfunction microthrombosis. These features are strikingly similar to what seen in diseases. Although consequences on circulation remain be explored, several viruses have been previously thought involved development Patients preexisting diseases also appear at increased risk morbidity mortality. The present article reviews molecular factors shared by coronavirus vasculature defects, clinical relevance alterations context COVID-19.

Language: Английский

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Translational Advances in the Field of Pulmonary Hypertension.From Cancer Biology to New Pulmonary Arterial Hypertension Therapeutics. Targeting Cell Growth and Proliferation Signaling Hubs

American Journal of Respiratory and Critical Care Medicine, Journal Year: 2016, Volume and Issue: 195(4), P. 425 - 437

Published: Sept. 14, 2016

Language: Английский

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Multicenter Preclinical Validation of BET Inhibition for the Treatment of Pulmonary Arterial Hypertension

American Journal of Respiratory and Critical Care Medicine, Journal Year: 2019, Volume and Issue: 200(7), P. 910 - 920

Published: May 1, 2019

Rationale: Pulmonary arterial hypertension (PAH) is a degenerative arteriopathy that leads to right ventricular (RV) failure. BRD4 (bromodomain-containing protein 4), member of the BET (bromodomain and extra-terminal motif) family, has been identified as critical epigenetic driver for cardiovascular diseases.Objectives: To explore therapeutic potential in PAH RVX208, clinically available inhibitor.Methods: Microvascular endothelial cells, smooth muscle cells isolated from distal pulmonary arteries patients with PAH, rats Sugen5416 + hypoxia- or monocrotaline shunt-induced RV pressure overload induced by artery banding were treated RVX208 three independent laboratories.Measurements Main Results: upregulated remodeled vasculature where it regulates FoxM1 PLK1, proteins implicated DNA damage response. normalized hyperproliferative, apoptosis-resistant, inflammatory phenotype microvascular PAH. Oral treatment reversed vascular remodeling improved hemodynamics two trials hypoxia-PAH shunt-PAH. could be combined safely contemporary standard care. also supported pressure-loaded rats.Conclusions: inhibitor, modulates proproliferative, prosurvival, proinflammatory pathways, potentially through interactions PLK1. This vitro, diverse rat models. vivo. Together, these data support establishment clinical trial

Language: Английский

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Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both

AJP Lung Cellular and Molecular Physiology, Journal Year: 2018, Volume and Issue: 314(5), P. L782 - L796

Published: Jan. 18, 2018

Pulmonary hypertension describes a heterogeneous disease defined by increased pulmonary artery pressures, and progressive increase in vascular resistance due to pathologic remodeling of the vasculature involving endothelial cells, pericytes, smooth muscle cells. This process occurs under various conditions, although these populations vary, clinical manifestations are same: dyspnea, increases right ventricular (RV) afterload dysfunction, RV-pulmonary uncoupling, right-sided heart failure with systemic circulatory collapse. The overall estimated 5-yr survival rate is 72% highly functioning patients, as low 28% for those presenting advanced symptoms. Metabolic theories have been suggested underlying pathogenesis growing evidence role mitochondrial dysfunction major proteins electron transport chain, redox-related enzymes, regulators proton gradient calcium homeostasis, apoptosis, mitophagy. There remain more studies needed characterize leading impaired relaxation, proliferation, regulatory mechanisms. effects on cells resulting interactions their microenvironment uncharted territory future discovery. Additionally, basis observations that "plexigenic lesions" resemble unregulated proliferation tumor similarities between cancer pathobiology drawn, suggesting mitochondria angiogenesis. Recently, targeting has become feasible, which may yield new therapeutic strategies. We present state-of-the-art review both potential targets processes.

Language: Английский

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Selenoprotein P Promotes the Development of Pulmonary Arterial Hypertension

Circulation, Journal Year: 2018, Volume and Issue: 138(6), P. 600 - 623

Published: April 10, 2018

Background: Excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) are key mechanisms arterial hypertension (PAH). Despite the multiple combination therapy, a considerable number patients develop severe (PH) because lack diagnostic biomarker antiproliferative therapies for PASMCs. Methods: Microarray analyses were used to identify novel therapeutic target PAH. In vitro experiments, including lung serum samples from with PAH, cultured PAH-PASMCs, high-throughput screening 3336 low-molecular-weight compounds, mechanistic study exploring agent. Five genetically modified mouse strains, PASMC-specific selenoprotein P (SeP) knockout mice PH model rats, role SeP capacity compounds development in vivo. Results: analysis revealed 32-fold increase PAH-PASMCs compared control is widely expressed extracellular protein maintaining cellular metabolism. Immunoreactivity was enhanced thickened media arteries Serum levels also elevated controls, high predicted poor outcome. SeP-knockout ( –/– ) exposed chronic hypoxia showed significantly reduced right ventricular systolic pressure, hypertrophy, remodeling controls. contrast, systemic SeP-overexpressing exacerbation hypoxia-induced PH. Furthermore, whereas neither liver-specific nor significant differences Altogether, lungs associated Mechanistic experiments demonstrated that promotes PASMC through increased oxidative stress mitochondrial dysfunction, which activated hypoxia-inducible factor-1α dysregulated glutathione It important note identified sanguinarine, plant alkaloid effects, expression PASMCs ameliorated rats. Conclusions: These results indicate PH, suggesting it disorder.

Language: Английский

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Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

Clinical Science, Journal Year: 2019, Volume and Issue: 133(24), P. 2481 - 2498

Published: Dec. 1, 2019

Abstract Notch signalling is critically involved in vascular morphogenesis and function. Four isoforms (Notch1–4) regulating diverse cellular processes have been identified. Of these, Notch3 expressed almost exclusively smooth muscle cells (VSMCs), where it development differentiation. Under pathological conditions, regulates VSMC switching between the contractile synthetic phenotypes. Abnormal plays an important role remodelling, a hallmark of several cardiovascular diseases, including pulmonary arterial hypertension (PAH). Because importance (de)differentiation, has implicated pathophysiology remodelling PAH. Here we review current literature on function with focus artery VSMCs, discuss potential implications

Language: Английский

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Resveratrol: Mechanistic and therapeutic perspectives in pulmonary arterial hypertension

Pharmacological Research, Journal Year: 2020, Volume and Issue: 163, P. 105287 - 105287

Published: Nov. 3, 2020

Language: Английский

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