Pulmonary Hypertension: A Contemporary Review

American Journal of Respiratory and Critical Care Medicine, Journal Year: 2023, Volume and Issue: 208(5), P. 528 - 548

Published: July 14, 2023

Major advances in pulmonary arterial hypertension, hypertension (PH) associated with lung disease, and chronic thromboembolic PH cast new light on the pathogenetic mechanisms, epidemiology, diagnostic approach, therapeutic armamentarium for vascular disease. Here, we summarize key basic, translational, clinical reports, emphasizing findings that build current state-of-the-art research. This review includes cutting-edge progress translational biology, a guide to diagnosis of patients practice, incorporating recent definition revisions continue emphasis early detection management is reviewed including an overview evolving considerations approach treatment cardiopulmonary comorbidities, as well discussion groundbreaking sotatercept data hypertension.

Language: Английский

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Single-cell transcriptomics reveals skewed cellular communication and phenotypic shift in pulmonary artery remodeling

JCI Insight, Journal Year: 2022, Volume and Issue: 7(20)

Published: Sept. 13, 2022

A central feature of progressive vascular remodeling is altered smooth muscle cell (SMC) homeostasis; however, the understanding how different populations contribute to this process limited. Here, we utilized single-cell RNA sequencing provide insight into cellular composition changes within isolated pulmonary arteries (PAs) from arterial hypertension and donor lungs. Our results revealed that skewed balanced communication network between immune structural cells, in particular SMCs. Comparative analysis with murine PAs showed human harbored heterogeneous SMC an abundant intermediary cluster displaying a gradient transition SMCs adventitial fibroblasts. Transcriptionally distinct were enriched specific biological processes could be differentiated 4 major clusters: oxygen sensing (enriched pericytes), contractile, synthetic, fibroblast-like. End-stage was associated phenotypic shift preexisting accumulation synthetic neointima. Distinctly regulated genes clusters built nonredundant regulatory hubs encompassing stress response differentiation regulators. The current study provides blueprint molecular on level are defining pathological process.

Language: Английский

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Pathophysiology and pathogenic mechanisms of pulmonary hypertension: role of membrane receptors, ion channels, and Ca²⁺ signaling

Physiological Reviews, Journal Year: 2022, Volume and Issue: 103(3), P. 1827 - 1897

Published: Nov. 24, 2022

The pulmonary circulation is a low-resistance, low-pressure, and high-compliance system that allows the lungs to receive entire cardiac output. Pulmonary arterial pressure function of output vascular resistance, resistance inversely proportional fourth power intraluminal radius artery. Therefore, very small decrease lumen diameter results in significant increase pressure. hypertension fatal progressive disease with poor prognosis. Regardless initial pathogenic triggers, sustained vasoconstriction, concentric remodeling, occlusive intimal lesions, situ thrombosis, wall stiffening are major direct causes for elevated patients other forms precapillary hypertension. In this review, we aim discuss basic principles physiological mechanisms involved regulation lung hemodynamics function, changes vasculature contribute increased pressure, development progression We focus on reviewing roles membrane receptors, ion channels, intracellular Ca

Language: Английский

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Interleukin-6 and pulmonary hypertension: from physiopathology to therapy

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: June 28, 2023

Pulmonary hypertension (PH) is a progressive, pulmonary vascular disease with high morbidity and mortality. Unfortunately, the pathogenesis of PH complex remains unclear. Existing studies have suggested that inflammatory factors are key in PH. Interleukin-6 (IL-6) multifunctional cytokine plays crucial role regulation immune system. Current reveal IL-6 elevated serum patients it negatively correlated lung function those patients. Since one most important mediators inflammation PH, signaling mechanisms targeting may become therapeutic targets for this disease. In review, we detailed potential accelerating process specific pathways. We also summarized current drugs these pathways to treat hope study will provide more theoretical basis targeted treatment future.

Language: Английский

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Jagged-mediated development and disease: Mechanistic insights and therapeutic implications for Alagille syndrome

Current Opinion in Cell Biology, Journal Year: 2024, Volume and Issue: 86, P. 102302 - 102302

Published: Jan. 9, 2024

Notch signaling controls multiple aspects of embryonic development and adult homeostasis. Alagille syndrome is usually caused by a single mutation in the jagged canonical ligand 1 (JAG1), manifests with liver disease cardiovascular symptoms that are direct consequence JAG1 haploinsufficiency. Recent insights into Jag1/Notch-controlled developmental homeostatic processes explain how pathology develops hepatic systems and, together recent elucidation mechanisms modulating regeneration, provide basis for therapeutic efforts. Importantly, presentation can be regulated genetic modifiers, may also therapeutically leverageable. Here, we summarize Jag1 relevance to syndrome, focused on Jag1/Notch functions

Language: Английский

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Notch3/Hes5 Induces Vascular Dysfunction in Hypoxia-Induced Pulmonary Hypertension Through ER Stress and Redox-Sensitive Pathways

Hypertension, Journal Year: 2023, Volume and Issue: 80(8), P. 1683 - 1696

Published: May 31, 2023

BACKGROUND: Notch3 (neurogenic locus notch homolog protein 3) is implicated in vascular diseases, including pulmonary hypertension (PH)/pulmonary arterial hypertension. However, molecular mechanisms remain elusive. We hypothesized increased activation induces oxidative and endoplasmic reticulum (ER) stress downstream redox signaling, associated with procontractile artery state, dysfunction, PH development. METHODS: Studies were performed TgNotch3 R169C mice (harboring gain-of-function [GOF] mutation) exposed to chronic hypoxia induce PH, examined by hemodynamics. Molecular cellular studies smooth muscle cells from patients mouse lung. Notch3-regulated genes/proteins, ER stress, ROCK (Rho-associated kinase) expression/activity, Ca 2+ transients generation of reactive oxygen species, nitric oxide measured. Pulmonary reactivity was assessed the presence fasudil (ROCK inhibitor) 4-phenylbutyric acid (ER inhibitor). RESULTS: Hypoxia induced a more severe phenotype versus controls. exhibited enhanced expression targets Hes Family BHLH Transcription Factor 5 (Hes5), contraction impaired vasorelaxation that improved fasudil/4-phenylbutyric acid. mutation vessel transients, activation, species generation, reduced NO blunted sGC (soluble guanylyl cyclase)/cGMP signaling. These effects ameliorated N-acetylcysteine. recapitulated Notch3/Hes5 changes observed mice. CONCLUSIONS: GOF amplifies dysfunction hypoxic PH. This involves ROCK. highlight novel role for Notch3/Hes5-redox signaling important interplay between

Language: Английский

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Inhibition of PCSK9 Improves the Development of Pulmonary Arterial Hypertension Via Down-Regulating Notch3 Expression

Cardiovascular Drugs and Therapy, Journal Year: 2023, Volume and Issue: unknown

Published: May 31, 2023

Language: Английский

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Examining the contribution of Notch signaling to lung disease development

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2024, Volume and Issue: 397(9), P. 6337 - 6349

Published: April 23, 2024

Language: Английский

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Role of histone lactylation interference RNA m6A modification and immune microenvironment homeostasis in pulmonary arterial hypertension

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Sept. 12, 2023

Pulmonary arterial hypertension (PAH) is a severe disease resulting from progressive increases in pulmonary vascular resistance and remodeling, ultimately leading to right ventricular failure even death. Hypoxia, inflammation, immune reactions, epigenetic modifications all play significant contributory roles the mechanism of PAH. Increasingly, changes their modifying factors involved reprogramming through regulation methylation or microenvironment have been identified. Among them, histone lactylation new post-translational modification (PTM), which provides novel visual angle on functional lactate promising diagnosis treatment method for This review detailed introduces function as an important molecule PAH, effects N6-methyladenosine (m6A) cells. It perspective further explore development modification.

Language: Английский

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ASH2L Deficiency in Smooth Muscle Drives Pulmonary Vascular Remodeling

Circulation Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

BACKGROUND: Histone H3 lysine 4 methylation is one of the most abundant epigenetic modifications, which has been recently linked to vascular remodeling in pulmonary hypertension (PH). SET1/MLL methyltransferase complexes comprise main enzymes responsible for methylating 4, yet their roles and PH are not fully understood. We aim assess contribution ASH2L, a core family member, pathogenesis PH. METHODS: Human artery specimens primary cells, smooth muscle cell (SMC)-specific ASH2L-deficient mice, rats with SMC-specific ASH2L overexpression, mass spectrometry, immunoprecipitation, chromatin immunoprecipitation were used define role RESULTS: Analysis bulk RNA-sequencing data sets from human lung vessels identified as only differentially expressed member compared healthy controls. Decreased expression arteries correlated clinical severity PH, contrasted elevated was primarily localized SMCs. Depletion promoted whereas its restoration ameliorated SMC proliferation Mechanistically, we revealed that functioned independently canonical trimethylation-based transcriptional activation, while it formed protein complex KLF5 FBXW7, thereby accelerating ubiquitin-proteasomal degradation KLF5. NOTCH3 discovered new downstream target KLF5, loss recruitment promoter, thus enhancing expression. Pharmacological blockage attenuated chronic hypoxia-exposed mice sugen/hypoxia-challenged rats. CONCLUSIONS: This study demonstrated deficiency causatively affects partially mediated through KLF5-dependent transcription. Activating or targeting might represent potential therapeutic strategies

Language: Английский

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