Contribution of transient receptor potential canonical channels in human and experimental pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is due to progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated store-operated Ca entry (SOCE) contributes to PAH pathogenesis, mediating human PA smooth muscle cell (hPASMC) abnormalities. The transient receptor potential canonical channels (TRPC family) are Ca-permeable channels contributing to SOCE in different cell types, including PASMCs.

Iron Deficiency in Pulmonary Arterial Hypertension: A Deep Dive into the Mechanisms.

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease that is caused by the progressive occlusion of the distal pulmonary arteries, eventually leading to right heart failure and death. Almost 40% of patients with PAH are iron deficient. Although widely studied, the mechanisms linking between PAH and iron deficiency remain unclear.

Trichloroethylene increases pulmonary endothelial permeability: implication for pulmonary veno-occlusive disease.

Trichloroethylene exposure is a major risk factor for pulmonary veno-occlusive disease. We demonstrated that trichloroethylene alters the endothelial barrier integrity, at least in part, through vascular endothelial (VE)-Cadherin internalisation, and suggested that this mechanism may play a role in the development of pulmonary veno-occlusive disease.

Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells.

The physiopathology of pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) and endothelial cell (PAEC) dysfunction, contributing to pulmonary arterial obstruction and PAH progression. KCNK3 loss of function mutations are responsible for the first channelopathy identified in PAH. Loss of KCNK3 function/expression is a hallmark of PAH.

Multimodal Imaging Mass Spectrometry to Identify Markers of Pulmonary Arterial Hypertension in Human Lung Tissue Using MALDI-ToF, ToF-SIMS, and Hybrid SIMS.

Pulmonary arterial hypertension (PAH) is a rare and deadly disease affecting roughly 15-60 people per million in Europe with a poorly understood pathology. There are currently no diagnostic tools for early detection nor does a curative treatment exist. The lipid composition of arteries in lung tissue samples from human PAH and control patients were investigated using matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) combined with time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging.

In vivo miR-138-5p inhibition alleviates monocrotaline-induced pulmonary hypertension and normalizes pulmonary KCNK3 and SLC45A3 expression.

Background: The pathogenesis of pulmonary arterial hypertension (PAH) involves many signalling pathways. MicroRNAs are potential candidates involved in simultaneously coordinating multiple genes under such multifactorial conditions.

Methods And Results: MiR-138-5p is overexpressed in pulmonary arterial smooth muscle cells (PASMCs) from PAH patients and in lungs from rats with monocrotaline-induced pulmonary hypertension (MCT-PH).

Implication of the deacetylase sirtuin-1 on synovial angiogenesis and persistence of experimental arthritis.

Objectives: To decipher the phenotype of endothelial cells (ECs) derived from circulating progenitors issued from patients with rheumatoid arthritis (RA).

Methods: RA and control ECs were compared according to their proliferative capacities, apoptotic profile, response to tumour necrosis factor (TNF)-α stimulation and angiogenic properties. Microarray experiments were performed to identify gene candidates relevant to pathological angiogenesis.

Functional interaction between PDGFβ and GluN2B-containing NMDA receptors in smooth muscle cell proliferation and migration in pulmonary arterial hypertension.

In this study, we explored the complex interactions between platelet-derived growth factor (PDGF) and N-methyl-d-aspartate receptor (NMDAR) and their effect on the excessive proliferation and migration of smooth muscle cells leading to obstructed arteries in pulmonary arterial hypertension (PAH). We report lower expression of glutamate receptor NMDA-type subunit 2B (GluN2B), a subunit composing NMDARs expected to affect cell survival/proliferation of pulmonary artery smooth muscle cells (PASMCs), in PAH patient lungs. PASMC exposure to PDGF-BB stimulated immediate increased levels of phosphorylated Src family kinases (SFKs) together with increased phosphorylated GluN2B (its active form) and cell surface relocalization, suggesting a cross talk between PDGFR-recruited SFKs and NMDAR.

How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?

NMDA-type glutamate receptors (NMDAR) are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system. NMDAR dysfunction has been found to be involved in various neurological disorders. Recent crystallographic and EM studies have shown the static structure of different states of the non-human NMDARs.

Convergent Strategy to Dizocilpine MK-801 and Derivatives.

A convergent total synthesis of MK-801 has been achieved. Key synthetic transformations include a multicomponent Barbier-type reaction to construct the α-branched amine, a selective Heck α-coupling tactic to generate the exocyclic alkene skeleton, and a late-stage intramolecular hydroamination reaction between the exocyclic alkene and the secondary protected amine. The efficacy of this method was demonstrated by the synthesis of two news analogues substituted on the aromatic rings.

NMDA-Type Glutamate Receptor Activation Promotes Vascular Remodeling and Pulmonary Arterial Hypertension.

Background: Excessive proliferation and apoptosis resistance in pulmonary vascular cells underlie vascular remodeling in pulmonary arterial hypertension (PAH). Specific treatments for PAH exist, mostly targeting endothelial dysfunction, but high pulmonary arterial pressure still causes heart failure and death. Pulmonary vascular remodeling may be driven by metabolic reprogramming of vascular cells to increase glutaminolysis and glutamate production.

Volatolomics of breath as an emerging frontier in pulmonary arterial hypertension.

There is accumulating evidence in support of the significant improvement in survival rates and clinical outcomes when pulmonary arterial hypertension (PAH) is diagnosed at early stages. Nevertheless, it remains a major clinical challenge and the outcomes are dependent on invasive right heart catheterisation.Resulting from pathophysiological processes and detectable in exhaled breath, volatile organic compounds (VOCs) have been proposed as noninvasive biomarkers for PAH.

Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules.

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined.

[The cancer paradigm in pulmonary arterial hypertension: towards anti-remodeling therapies targeting metabolic dysfunction?].

Pulmonary arterial hypertension (PAH) is a rare, complex and multifactorial disease in which pulmonary vascular remodeling plays a major role ending in right heart failure and death. Current specific therapies of PAH that mainly target the vasoconstriction/vasodilatation imbalance are not curative. Bi-pulmonary transplantation remains the only option in patients resistant to current therapies.

MicroRNA networks in pulmonary arterial hypertension: share mechanisms with cancer?

Purpose Of Review: Pulmonary arterial hypertension (PAH) is a rare disease with poor prognosis and no therapeutics. PAH is characterized by severe remodeling of precapillary pulmonary arteries, leading to increased vascular resistance, pulmonary hypertension compensatory right ventricular hypertrophy, then heart failure and death. PAH pathogenesis shares similarities with carcinogenesis such as excessive cell proliferation, apoptosis resistance, metabolic shifts, or phenotypic transition.

Chemotherapy-induced pulmonary hypertension: role of alkylating agents.

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD.

T-helper 17 cell polarization in pulmonary arterial hypertension.

Background: Inflammation may contribute to the pathobiology of pulmonary arterial hypertension (PAH). Deciphering the PAH fingerprint on the inflammation orchestrated by dendritic cells (DCs) and T cells, key driver and effector cells, respectively, of the immune system, may allow the identification of immunopathologic approaches to PAH management.

Methods: Using flow cytometry, we performed immunophenotyping of monocyte-derived DCs (MoDCs) and circulating lymphocytes from patients with idiopathic PAH and control subjects.

N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats.

Background: The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH.

Inflammation in pulmonary hypertension: what we know and what we could logically and safely target first.

Inflammation is important for the initiation and the maintenance of vascular remodeling in most of the animal models of pulmonary arterial hypertension (PAH), and therapeutic targeting of inflammation in these models blocks PAH development. In humans, pulmonary vascular lesions of PAH are the source of cytokine and chemokine production, related to inflammatory cell recruitment and lymphoid neogenesis. Circulating autoantibodies to endothelial cells and to fibroblasts have been reported in 10-40% of patients with idiopathic PAH, suggesting a possible role for autoimmunity in the pathogenesis of pulmonary vascular lesions.