Androgen receptor inhibitor ameliorates pulmonary arterial hypertension by enhancing the apoptosis level through suppressing the Notch3/Hes5 pathway

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 28, 2025

Pulmonary arterial hypertension (PAH) exhibits significant gender differences in prognosis, with male patients typically showing worse outcomes than females. These disparities may stem from androgen receptor expression and activity. Clinical studies suggest that the plays a crucial role pathophysiology of PAH, influencing disease progression treatment response. Despite lack targeted therapies for these findings have spurred investigations into potential therapeutic receptors. This study explores receptors PAH evaluates their potential. was induced rats via intraperitoneal injection monocrotaline (MCT). Following model establishment, Enzalutamide administered every 3 days at 10 mg/kg once total 7 times (21 days). A mouse developed by subcutaneously injecting SU5416 exposing mice to hypoxia. Androgen knockout (AR-/-) were also utilized investigate progression. Key indicators compared across groups. The vivo mechanisms through which influence examined both rat models. Additionally, pulmonary artery endothelial cells (PAECs) cultured under hypoxic conditions create an vitro facilitating further investigation pathogenesis. Compared normal group, group exhibited significantly increased rats, mice, mPAECs. accompanied pronounced wall thickening, right ventricular hypertrophy, fibrosis, elevated pressure, reduced level apoptosis vitro. Furthermore, activation Notch3/Hes5 signaling pathway observed. However, inhibitors or gene ameliorated pathological changes. Apoptosis levels vitro, effectively inhibited. Our animal models mPAECs, inhibition leads suppression pathway. mechanism likely contributes effects observed, providing insights strategies targeting hypertension.

Language: Английский

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Cyclopamine Attenuates Pulmonary Arterial Hypertension Development: Implications of Hedgehog Signaling Involvement for the Pathophysiology

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(10)

Published: May 12, 2025

ABSTRACT Pulmonary arterial hypertension (PAH) is one of the most severe pulmonary diseases. Although combination therapies key drugs have improved survival rates, unmet needs remain in its management. We examined effects cyclopamine, a Hedgehog (HH) signaling inhibitor, as potential novel therapeutic approach for PAH. C57BL/6J male mice were exposed to 10% oxygen 3 weeks induce hypertension. One week after hypoxia exposure, these treated with cyclopamine or vehicle. Cyclopamine significantly attenuated right ventricular (RV) systolic pressure (H + C: 31 mmHg vs. H: 38 mmHg, p < 0.01) and RV hypertrophy 0.28 0.37, 0.01). The fully muscularized small arteries decreased 30% 80%, 0.01), suggesting mediation by vascular remodeling inhibition. In vitro, human smooth muscle cells (HPASMC) revealed that inhibitory action was limited hypoxia‐promoted cell proliferation. single‐cell RNA sequencing analysis lungs pathways contraction cGMP‐PKG, is, regulators PAH development through remodeling, suppressed characteristics endothelial cells. hypoxia‐exposed hPASMCs related extracellular matrix regulation particularly recovered. Our animal model‐based data HH inhibition would improve suppressing remodeling.

Language: Английский

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Induction of T‐Cell Differentiation by KLF4 in T‐Cell Acute Lymphoblastic Leukemia Cells Harboring Activating Mutation in NOTCH3

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(10)

Published: May 12, 2025

ABSTRACT Krüppel‐like factor 4 (KLF4) exhibits both oncogenic and tumor‐suppressive effects depending on the type of cancer cellular context. In T‐cell acute lymphoblastic leukemia (T‐ALL), KLF4 expression is silenced by promoter methylation, induction suppresses proliferation T‐ALL cells. Therefore, thought to function as a tumor suppressor in cells; however, its role differentiation cells remains unclear. Here, we show that induced apoptosis TALL‐1 harboring an activating mutation NOTCH3. Mechanistically, directly downregulated NOTCH3 binding promoter, thereby promoting CD4/CD8 double‐positive into CD4 single‐positive cells, with differentiated subsequently undergoing apoptosis. Furthermore, found APTO‐253, small‐molecule inducer KLF4, effectively suppressed cell growth followed apoptotic death. These findings suggest promising strategy for developing novel therapies mutations.

Language: Английский

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Pathogenesis of pulmonary hypertension caused by left heart disease

Frontiers in Cardiovascular Medicine, Journal Year: 2023, Volume and Issue: 10

Published: March 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.

Language: Английский

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miR-135b: An emerging player in cardio-cerebrovascular diseases

Journal of Pharmaceutical Analysis, Journal Year: 2024, Volume and Issue: 14(10), P. 100997 - 100997

Published: May 8, 2024

miR-135 is a highly conserved miRNA in mammals and includes miR-135a miR-135b. Recent studies have shown that miR-135b key regulatory factor cardio-cerebrovascular diseases. It involved regulating the pathological process of myocardial infarction, ischemia/reperfusion injury, cardiac hypertrophy, atrial fibrillation, diabetic cardiomyopathy, atherosclerosis, pulmonary hypertension, cerebral Parkinson's disease, Alzheimer's disease. Obviously, an emerging player diseases expected to be important target for treatment However, crucial role its underlying mechanism action has not been reviewed. Therefore, this review, we aimed comprehensively summarize signaling pathway mediated by Drugs targeting related patents, highlighting importance utility as therapeutic diseases, discussed.

Language: Английский

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The emerging role of NOTCH3 receptor signalling in human lung diseases

Expert Reviews in Molecular Medicine, Journal Year: 2022, Volume and Issue: 24

Published: Jan. 1, 2022

Abstract The mammalian respiratory system or lung is a tree-like branching structure, and the main site of gas exchange with external environment. Structurally, broadly classified into proximal (or conducting) airways distal alveolar region, where occurs. In parallel tree, pulmonary vasculature starts large arteries that subdivide rapidly ending in capillaries adjacent to structures enable exchange. NOTCH signalling pathway plays an important role development, differentiation regeneration post-injury. Signalling via mediated through activation four receptors (NOTCH1-4), each receptor capable regulating unique biological processes. Dysregulation has been associated development pathophysiology multiple adult acute chronic diseases. This includes accumulating evidence alteration NOTCH3 pathogenesis obstructive disease, cancer, asthma, idiopathic fibrosis arterial hypertension. Herein, we provide comprehensive summary repair/regeneration lung, its association disease potential therapeutic strategies target activity.

Language: Английский

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Jaggeds/Notches promote endothelial‐mesenchymal transition‐mediated pulmonary arterial hypertension via upregulation of the expression of GATAs

Journal of Cellular and Molecular Medicine, Journal Year: 2023, Volume and Issue: 27(8), P. 1110 - 1130

Published: March 20, 2023

Abstract This study tested the hypothesis that Jagged2/Notches promoted endothelial‐mesenchymal transition (endMT)‐mediated pulmonary arterial hypertension (PAH) (i.e. induction by monocrotaline [MCT]/63 mg/kg/subcutaneous injection) through increasing expression of GATA‐binding factors which were inhibited propylthiouracil (PTU) 0.1% in water for daily drinking since Day 5 after PAH induction) rodent. As compared with control HUVECs), protein expressions GATAs (3/4/6) and endMT markers (Snail/Zeb1/N‐cadherin/vimentin/fibronectin/α‐SMA/p‐Smad2) significantly reduced, whereas endothelial‐phenotype (CD31/E‐cadherin) increased silenced JAG2 gene or GATA3 HUVECs (all p < 0.001). control, intercellular signallings (GATAs [3/4/6], Jagged1/2, notch1/2 Snail/Zeb1/N‐cadherin/vimentin/fibronectin/α‐SMA/p‐Smad2) upregulated TGF‐ß/monocrotaline‐treated reversed PTU treatment By 42, results animal demonstrated right‐ventricular systolic‐blood‐pressure (RVSBP), RV weight (RVW) lung injury/fibrotic scores MCT group than sham‐control (SC) + groups, oxygen saturation (%) vasorelaxation/nitric oxide production PA exhibited an opposite pattern RVW among groups 0.0001). The hypertrophic (ß‐MHC)/pressure‐overload (BNP)/oxidative‐stress (NOX‐1/NOX‐2) biomarkers signalling (GATAs3/4/6, notch1/2) (Snail/Zeb1/N‐cadherin/vimentin/fibronectin/TGF‐ß/α‐SMA/p‐Smad2) parenchyma displayed identical Jagged‐Notch‐GATAs signalling, RVSBP suppressed PTU.

Language: Английский

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Advances in the research of sulfur dioxide and pulmonary hypertension

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

Published: Oct. 12, 2023

Pulmonary hypertension (PH) is a fatal disease caused by progressive pulmonary vascular remodeling (PVR). Currently, the mechanisms underlying occurrence and progression of PVR remain unclear, effective therapeutic approaches to reverse PH are lacking. Since beginning 21st century, endogenous sulfur dioxide (SO 2 )/aspartate transaminase system has emerged as novel research focus in fields PVR. As gaseous signaling molecule, SO metabolism tightly regulated vasculature associated with development it involved regulation pathological physiological activities, such cellular inflammation, proliferation collagen metabolism, exert protective effect against PH. In this review, we present an overview studies conducted date that have provided theoretical basis for -related drug inhibit or effectively treat PH-related diseases.

Language: Английский

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CC chemokines Modulate Immune responses in Pulmonary Hypertension

Journal of Advanced Research, Journal Year: 2023, Volume and Issue: 63, P. 171 - 186

Published: Nov. 4, 2023

Pulmonary hypertension (PH) represents a progressive condition characterized by the remodeling of pulmonary arteries, ultimately culminating in right heart failure and increased mortality rates. Substantial evidence has elucidated pivotal role perivascular inflammatory factors immune dysregulation pathogenesis PH. Chemokines, class small secreted proteins, exert precise control over cell recruitment functionality, particularly with respect to their migration sites inflammation. Consequently, chemokines emerge as critical drivers facilitating infiltration into tissue during responses. This review comprehensively examines significant contributions CC maintenance homeostasis regulating The central focus this discussion is directed towards elucidating immunoregulatory actions concerning various types, including neutrophils, monocytes, macrophages, lymphocytes, dendritic cells, mast eosinophils, basophils, context pH processes. Furthermore, paper delves an exploration underlying pathogenic mechanisms that underpin development Specifically, it investigates processes such cellular pyroptosis, intricate crosstalk between bone morphogenetic protein receptor type 2 (BMPR2) mutations response, sheds light on key signaling pathways involved response. These aspects are deemed enhancing our understanding complex pathophysiology Moreover, provides comprehensive synthesis findings from experimental investigations targeting cells chemokines.

Language: Английский

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NOTCH3 and Pulmonary Arterial Hypertension

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(11), P. 6248 - 6248

Published: June 6, 2024

NOTCH3 receptor signaling has been linked to the regulation of smooth muscle cell proliferation and maintenance cells in an undifferentiated state. Pulmonary arterial hypertension (World Health Organization Group 1 idiopathic disease: PAH) is a fatal disease characterized clinically by elevated pulmonary vascular resistance caused extensive proliferation, perivascular inflammation, asymmetric neointimal hyperplasia precapillary arteries. In this review, detailed overview specific role PAH, including its mechanisms activation select ligand, downstream effectors, physiologic effects within tree, provided. Animal models showing importance pathway clinical PAH will be discussed. New drugs biologics that inhibit reverse deadly are highlighted.

Language: Английский

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