Targeting the Wnt signaling pathways in pulmonary arterial hypertension

Perez, Vinicio de Jesus; Yuan, Ke; Alastalo, Tero-Pekka; Spiekerkoetter, Edda; Rabinovitch, Marlene

doi:10.1016/j.drudis.2014.06.014

Cited by 43 publications

(38 citation statements)

References 47 publications

(46 reference statements)

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“…PAH is a chronic progressive and fatal disease ( 24 ), which is characterized by a continuous increase in pulmonary vascular resistance and pulmonary arterial pressure, leading to right heart failure and death ( 25 ). The pathogenesis of PAH is associated with inflammation, increased vascular tension and hPASMC proliferation, as well as resistance to apoptosis ( 4 ).…”

Section: Discussionmentioning

confidence: 99%

miR‑760 mediates hypoxia-induced proliferation and apoptosis of human pulmonary artery smooth muscle cells via targeting TLR4

et al. 2018

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MicroRNAs (miRNAs) have a key role in the pathogenesis of pulmonary arterial hypertension (PAH), a disease characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells. In the present study, miR-760 was demonstrated to be downregulated in PAH lung tissues compared with normal lung tissues, an effect that may be associated with the development of PAH. Hypoxia is an important stimulus for human pulmonary artery smooth muscle cell (hPASMC) proliferation and the occurrence of PAH. Therefore, the effect of miR-760 in hypoxia-treated and normal hPASMCs was investigated. Expression of exogenous miR-760 decreased cell proliferation in hypoxia-induced hPASMCs, and promoted cell apoptosis with an increase in the BCL2 associated X/BCL2 ratio and the expression levels of Caspase-3 and Caspase-9. In addition, overexpression of miR-760 suppressed the migration of hPASMCs under hypoxic conditions. Furthermore, miR-760 was demonstrated to mediate its anti-proliferation effect via the regulation of toll-like receptor 4 (TLR4), a direct target of miR-760. The results revealed that knockdown of TLR4 restrained the hypoxia-induced hPASMC proliferation and induced cell apoptosis. The present study uncovered a novel regulatory pathway involving miR-760 and suggested that miR-760 may be explored as a potential therapy for PAH in the future.

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Section: Discussionmentioning

confidence: 99%

miR‑760 mediates hypoxia-induced proliferation and apoptosis of human pulmonary artery smooth muscle cells via targeting TLR4

et al. 2018

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“…In the first one, activation of Wnt leads to GSK-3β inhibition and Snail-and β-catenin-induced EndoMT [3,15,16]. In the noncanonical one, Wnt activates GTPases Rac/Rho/cdc42, all involved in migration and cytoskeleton rearrangement [24]. Several growth factor signaling that act through RTKs are found up-regulated in PAH, including epidermal growth factor, fibroblast growth factor, vascular endothelial growth factor and platelet-derived growth factor [1].…”

Section: Molecular Pathways Of Endomt In Pahmentioning

confidence: 99%

Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

Ranchoux

Tanguay

Perros

2020

Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension

122

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Pulmonary arterial hypertension (PAH) is an incurable disease characterized by an intense thickening of the pulmonary arteries leading to their progressive obliteration. This vascular remodeling is a direct consequence of an aberrant accumulation of α-smooth muscle actin (α-SMA)-positive cells in the intravascular area. This process is multifactorial and complex. Recent studies have demonstrated that part of α-SMA-positive cells from intimal and plexiform lesions have an endothelial origin through a process called endothelial-to-mesenchymal transition (EndoMT). Interestingly most of molecular pathways implicated in PAH are known inducers of EndoMT. This review describes how EndoMT appears to play a crucial role in PAH progression.

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“… 18 , 19 In addition to pulmonary fibrosis, the Wnt/β-catenin signaling pathway has important roles in pulmonary arterial hypertension, in which vascular smooth muscle cell proliferation is a key characteristic. 20 …”

Section: Introductionmentioning

confidence: 99%

The Wnt/β-catenin signaling pathway regulates the development of airway remodeling in patients with asthma

et al. 2015

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Airway remodeling is a key characteristic of chronic asthma, particularly in patients with a fixed airflow limitation. The mechanisms underlying airway remodeling are poorly understood, and no therapeutic option is available. The Wnt/β-catenin signaling pathway is involved in various physiological and pathological processes, including fibrosis and smooth muscle hypertrophy. In this study, we investigated the roles of Wnt/β-catenin signaling in airway remodeling in patients with asthma. Wnt7a mRNA expression was prominent in induced sputum from patients with asthma compared with that from healthy controls. Next, we induced a chronic asthma mouse model with airway remodeling features, including subepithelial fibrosis and airway smooth muscle hyperplasia. Higher expression of Wnt family proteins and β-catenin was detected in the lung tissue of mice with chronic asthma compared to control mice. Blocking β-catenin expression with a specific siRNA attenuated airway inflammation and airway remodeling. Decreased subepithelial fibrosis and collagen accumulation in the β-catenin siRNA-treated mice was accompanied by reduced expression of transforming growth factor-β. We further showed that suppressing β-catenin in the chronic asthma model inhibited smooth muscle hyperplasia by downregulating the tenascin C/platelet-derived growth factor receptor pathway. Taken together, these findings demonstrate that the Wnt/β-catenin signaling pathway is highly expressed and regulates the development of airway remodeling in chronic asthma.

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Targeting the Wnt signaling pathways in pulmonary arterial hypertension

Cited by 43 publications

References 47 publications

miR‑760 mediates hypoxia-induced proliferation and apoptosis of human pulmonary artery smooth muscle cells via targeting TLR4

miR‑760 mediates hypoxia-induced proliferation and apoptosis of human pulmonary artery smooth muscle cells via targeting TLR4

Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

The Wnt/β-catenin signaling pathway regulates the development of airway remodeling in patients with asthma

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