Pulmonary Hypertension: A Contemporary Review

American Journal of Respiratory and Critical Care Medicine, Год журнала: 2023, Номер 208(5), С. 528 - 548

Опубликована: Июль 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.

Язык: Английский

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

JCI Insight, Год журнала: 2022, Номер 7(20)

Опубликована: Сен. 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.

Язык: Английский

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

Physiological Reviews, Год журнала: 2022, Номер 103(3), С. 1827 - 1897

Опубликована: Ноя. 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

Язык: Английский

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Interleukin-6 and pulmonary hypertension: from physiopathology to therapy

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Июнь 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.

Язык: Английский

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

Current Opinion in Cell Biology, Год журнала: 2024, Номер 86, С. 102302 - 102302

Опубликована: Янв. 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

Язык: Английский

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

Hypertension, Год журнала: 2023, Номер 80(8), С. 1683 - 1696

Опубликована: Май 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

Язык: Английский

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

Cardiovascular Drugs and Therapy, Год журнала: 2023, Номер unknown

Опубликована: Май 31, 2023

Язык: 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, Год журнала: 2023, Номер 11

Опубликована: Сен. 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.

Язык: Английский

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Pathogenesis of pulmonary hypertension caused by left heart disease

Frontiers in Cardiovascular Medicine, Год журнала: 2023, Номер 10

Опубликована: Март 3, 2023

Pulmonary hypertension has high disability and mortality rates. Among them, pulmonary caused by left heart disease (PH-LHD) is the most common type. According to 2022 ESC/ERS Guidelines for diagnosis treatment of hypertension, PH-LHD classified as group 2 hypertension. belongs postcapillary which distinguished from other types because its elevated artery wedge pressure. includes PH due systolic or diastolic ventricular dysfunction, mitral aortic valve congenital disease. The primary strategy in managing optimizing underlying cardiac Recent clinical studies have found that mechanical unloading ventricle an implantable non-pulsatile assist device with continuous flow properties can reverse patients failure. However, specific therapies LHD not yet been identified. Treatments specifically target could slow progression potentially improve severity, leading far better outcomes. Therefore, exploring current research on pathogenesis important. This paper summarizes classifies articles provide references mechanism PH-LHD, particularly molecular targeted therapy.

Язык: Английский

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Examining the contribution of Notch signaling to lung disease development

Naunyn-Schmiedeberg s Archives of Pharmacology, Год журнала: 2024, Номер 397(9), С. 6337 - 6349

Опубликована: Апрель 23, 2024

Язык: Английский

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