BMP type II receptor as a therapeutic target in pulmonary arterial hypertension

Orriols, Mar; Gomez‐Puerto, Maria Catalina; Dijke, Peter ten

doi:10.1007/s00018-017-2510-4

Cited by 95 publications

(80 citation statements)

References 174 publications

(178 reference statements)

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“…Preserving EC survival is an effective therapy to mitigate the progress of cardiovascular diseases. Consecutive targets for promoting EC survival have been developed, including those that restore bone morphogenetic protein type II expression, modify miR‐21/PDCD4/caspase‐3 and regulate uncoupling protein 2 . Hypoxia‐induced EC apoptosis usually occurs in the early phase of cardiovascular diseases and is regarded as an initiating event.…”

Section: Discussionmentioning

confidence: 99%

“…Consecutive targets for promoting EC survival have been developed, including those that restore bone morphogenetic protein type II expression, modify miR-21/PDCD4/caspase-3 and regulate uncoupling protein 2. 30,36,37 Hypoxia-induced EC apoptosis usually occurs in the early phase of cardiovascular diseases and is regarded as an initiating event. We verified that hypoxia induced a decrease in cell survival and an increase in apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Targeting mitochondria‐associated membranes as a potential therapy against endothelial injury induced by hypoxia

Yang

et al. 2019

J of Cellular Biochemistry

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Mitochondrial dysfunction plays a principal role in hypoxia‐induced endothelial injury, which is involved in hypoxic pulmonary hypertension and ischemic cardiovascular diseases. Recent studies have identified mitochondria‐associated membranes (MAMs) that modulate mitochondrial function under a variety of pathophysiological conditions such as high‐fat diet‐mediated insulin resistance, hypoxia reoxygenation‐induced myocardial death, and hypoxia‐evoked vascular smooth muscle cell proliferation. However, the role of MAMs in hypoxia‐induced endothelial injury remains unclear. To explore this further, human umbilical vein endothelial cells and human pulmonary artery endothelial cells were exposed to hypoxia (1% O2) for 24 hours. An increase in MAM formation was uncovered by immunoblotting and immunofluorescence. Then, we performed small interfering RNA transfection targeted to MAM constitutive proteins and explored the biological effects. Knockdown of MAM constitutive proteins attenuated hypoxia‐induced elevation of mitochondrial Ca2+ and repressed mitochondrial impairment, leading to an increase in mitochondrial membrane potential and ATP production and a decline in reactive oxygen species. Then, we found that MAM disruption mitigated cell apoptosis and promoted cell survival. Next, other protective effects, such as those pertaining to the repression of inflammatory response and the promotion of NO synthesis, were investigated. With the disruption of MAMs under hypoxia, inflammatory molecule expression was repressed, and the eNOS‐NO pathway was enhanced. This study demonstrates that the disruption of MAMs might be of therapeutic value for treating endothelial injury under hypoxia, suggesting a novel strategy for preventing hypoxic pulmonary hypertension and ischemic injuries.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting mitochondria‐associated membranes as a potential therapy against endothelial injury induced by hypoxia

Yang

et al. 2019

J of Cellular Biochemistry

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“…Bone morphogenetic protein receptor 2 (BMPR2) is an important molecule to regulate pulmonary SMC remodelling, and some patients with PAH have a mutation of the BMPR2 gene (Morrell, ; Orriols et al . ). They found that ApoE is essentially protecting BMP2‐induced PPARγ signalling cascade through the inhibition of the PDGF‐MAPK pathway.…”

Section: Vascular Function In Dyslipidaemiamentioning

confidence: 97%

Pulmonary vascular dysfunction in metabolic syndrome

Willson

Watanabe

Tsuji‐Hosokawa

2018

The Journal of Physiology

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Metabolic syndrome is a critically important precursor to the onset of many diseases, such as cardiovascular disease, and cardiovascular disease is the leading cause of death worldwide. The primary risk factors of metabolic syndrome include hyperglycaemia, abdominal obesity, dyslipidaemia, and high blood pressure. It has been well documented that metabolic syndrome alters vascular endothelial and smooth muscle cell functions in the heart, brain, kidney and peripheral vessels. However, there is less information available regarding how metabolic syndrome can affect pulmonary vascular function and ultimately increase an individual's risk of developing various pulmonary vascular diseases, such as pulmonary hypertension. Here, we review in detail how metabolic syndrome affects pulmonary vascular function.

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“…; Orriols et al . ). The role of inflammatory cells, cytokines or chemokines in PH development has also been demonstrated as blocking bone‐marrow‐derived cell recruitment to the lung (Hayashida et al .…”

Section: Introductionmentioning

confidence: 97%

Mechanisms contributing to persistently activated cell phenotypes in pulmonary hypertension

Zhang

Laux

et al. 2018

The Journal of Physiology

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Chronic pulmonary hypertension (PH) is characterized by the accumulation of persistently activated cell types in the pulmonary vessel exhibiting aberrant expression of genes involved in apoptosis resistance, proliferation, inflammation and extracellular matrix (ECM) remodelling. Current therapies for PH, focusing on vasodilatation, do not normalize these activated phenotypes. Furthermore, current approaches to define additional therapeutic targets have focused on determining the initiating signals and their downstream effectors that are important in PH onset and development. Although these approaches have produced a large number of compelling PH treatment targets, many promising human drugs have failed in PH clinical trials. Herein, we propose that one contributing factor to these failures is that processes important in PH development may not be good treatment targets in the established phase of chronic PH. We hypothesize that this is due to alterations of chromatin structure in PH cells, resulting in functional differences between the same factor or pathway in normal or early PH cells versus cells in chronic PH. We propose that the high expression of genes involved in the persistently activated phenotype of PH vascular cells is perpetuated by an open chromatin structure and multiple transcription factors (TFs) via the recruitment of high levels of epigenetic regulators including the histone acetylases P300/CBP, histone acetylation readers including BRDs, the Mediator complex and the positive transcription elongation factor (Abstract figure). Thus, determining how gene expression is controlled by examining chromatin structure, TFs and epigenetic regulators associated with aberrantly expressed genes in pulmonary vascular cells in chronic PH, may uncover new PH therapeutic targets.

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BMP type II receptor as a therapeutic target in pulmonary arterial hypertension

Cited by 95 publications

References 174 publications

Targeting mitochondria‐associated membranes as a potential therapy against endothelial injury induced by hypoxia

Targeting mitochondria‐associated membranes as a potential therapy against endothelial injury induced by hypoxia

Pulmonary vascular dysfunction in metabolic syndrome

Mechanisms contributing to persistently activated cell phenotypes in pulmonary hypertension

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