Novel and emerging therapies in pulmonary arterial hypertension

Frontiers in Drug Discovery, Journal Year: 2022, Volume and Issue: 2

Published: Dec. 15, 2022

Pulmonary arterial hypertension (PAH), defined as a mean pulmonary artery pressure exceeding 20 mmHg with vascular resistance of 3 or more Wood units, is an incurable and progressive condition. The cornerstone PAH treatment vasodilators, which act on the vasculature to reduce pressures prevent progression right heart failure. number available vasodilator therapies has grown markedly in last 10 years, alongside rapidly expanding body literature establishing strategies for their use. Up-front combination therapy, typically two medications, become standard care based landmark trials showing superior outcomes over single alone. Complex risk stratification matrices have begun see widespread use tools guide changes individual patients. Strategies using vasodilators common continue be evaluated exploring concepts such up-front triple therapy substitution patients not meeting therapeutic goals. Alongside established PAH, there broad spectrum experimental that are being studied disease. These include both conventional medications pathways targeted by existing well non-vasodilator treatments novel methods action, may vasodilate address detrimental ventricular remodeling. Many these emerging focus active phase 2 trials. Finally, been significant interest left failure, hope adapting efficacious failure well. explorations treated goal-directed medical device pacing, resynchronization cardiac monitoring devices. options show promise represent complementary approach allowing multimodal improve patient outcomes.

Language: Английский

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Ferroptosis Promotes Pulmonary Hypertension

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 20, 2023

Abstract Background Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species (ROS) generation, results in peroxidation ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation macrophage recruitment. In pulmonary arterial hypertension (PAH), endothelial cells (PAEC) exhibit cellular phenotypes promote Moreover, there ectopic deposition accumulation the vasculature. However, effects ferroptosis inhibition on these pathogenic mechanisms landscape vasculature are incompletely defined. Methods Multi-omics physiological analyses evaluated how modulated preclinical PAH. The impact AAV1-mediated expression pro-ferroptotic protein ACSL4 PAH was determined, a genetic association study humans further probed relationship between (PH). Results Ferrostatin-1, small-molecule inhibitor, mitigated severity monocrotaline rats. RNA-seq proteomics demonstrated associated with severity. RNA-seq, proteomics, confocal microscopy revealed pro-inflammatory cytokines/chemokines were suppressed ferrostatin-1. Additionally, ferrostatin-1 combatted changes endothelial, smooth muscle, interstitial abundance gene patterns as deconvolution RNA-seq. Ferroptotic PAEC damage molecular restructured transcriptomic signature, mitochondrial morphology, promoted proliferation artery muscle cells, created phenotype monocytes vitro . AAV1- Acsl4 induced Finally, single-nucleotide polymorphisms six genes identified potential link PH Vanderbilt BioVU repository. Conclusions through metabolic

Language: Английский

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The Potential Application and Promising Role of Targeted Therapy in Pulmonary Arterial Hypertension

Biomedicines, Journal Year: 2022, Volume and Issue: 10(6), P. 1415 - 1415

Published: June 15, 2022

Pulmonary arterial hypertension (PAH) is a rare yet serious progressive disorder that currently incurable. This female-predominant disease unfolds as pan-vasculopathy affects all layers of the vessel wall. Five classes pharmacological agents exist to target three major cellular signaling pathways identified in PAH but are incapable effectively reversing progression. While several targets have been for therapy, none current specific therapies curative and cost-effective they fail reverse vascular remodeling do not address cancer-like features PAH. Our purpose review literature on therapeutic management PAH, well molecular under consideration therapy so shed light potential role future promise novel strategies treating this high-mortality disease. study summarizes discusses be employed against In addition conventional already used targeting PDGF/PDGFR signaling, regulators glycolytic metabolism, PI3K/AKT pathways, mitochondrial heat shock protein 90 (HSP90), high-mobility group box-1 (HMGB1), bromodomain extra-terminal (BET) proteins by using their inhibitors, or induction p53 expression, could attractive

Language: Английский

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Pirfenidone and nintedanib attenuates pulmonary artery endothelial and smooth muscle cells transformations induced by IL-11

European Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 972, P. 176547 - 176547

Published: March 30, 2024

Idiopathic pulmonary fibrosis (IPF) associated to hypertension (PH) portends a poor prognosis, characterized by lung parenchyma and artery remodeling. Serum levels of Interleukin 11 (IL-11) are elevated in IPF-PH patients contributes remodeling PH. However, the effect current approved therapies against IPF induced IL-11 is unknown. The aim this study analyze effects nintedanib pirfenidone on endothelial smooth muscle cell vitro. Our results show that (NTD) (PFD) ameliorates mesenchymal transition (EnMT), myofibroblast-like transformation precision cut slices. This provided also evidence inhibitory PFD NTD IL-11-induced cells proliferation senescence. these drugs monocyte arrest angiogenesis was studied. Finally, we observed canonical signal transducer activator transcription 3 (STAT3) non-canonical mitogen-activated protein kinase 1/2 (ERK1/2) phosphorylation, but, only inhibited ERK1/2 phosphorylation. Therefore, markers IL-11.

Language: Английский

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Dehydrodiisoeugenol inhibits PDGF-BB-induced proliferation and migration of human pulmonary artery smooth muscle cells via the mTOR/HIF1-α/HK2 signaling pathway

Toxicology and Applied Pharmacology, Journal Year: 2024, Volume and Issue: 495, P. 117212 - 117212

Published: Dec. 22, 2024

Language: Английский

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