NMDA-Type Glutamate Receptor Activation Promotes Vascular Remodeling and Pulmonary Arterial Hypertension

Dumas, Sébastien J.; Bru–Mercier, Gilles; Courboulin, Audrey; Quatredeniers, Marceau; Rücker‐Martin, Catherine; Antigny, Fabrice; Nakhleh, Morad K.; Ranchoux, Benoît; Gouadon, Elodie; Vinhas, Maria-Candida; Vocelle, Matthieu; Raymond, Nicolas; Dorfmüller, Peter; Fadel, Élie; Perros, Frédèric; Humbert, Marc; Cohen‐Kaminsky, Sylvia

doi:10.1161/circulationaha.117.029930

Cited by 81 publications

(78 citation statements)

References 61 publications

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“…Notably, the YAP/TAZ-GLS1 axis induced glutaminolysis in SIV-induced PAH primates as well as in HIV-infected PAH patients, suggesting a mechanistic link between glutaminolysis and this enigmatic PAH subtype. Building on these findings, a separate study demonstrated that elevated glutamate, following GLS1-mediated conversion of glutamine, stimulated NMDA-type glutamate receptors, induced glutamatergic cell-cell signaling in pulmonary vessels, and promoted PH (46). Aberrant glutamine metabolism represents an increasingly promising diagnostic and therapeutic target in PH, given its fundamental roles in promoting proliferative capacity and potentially mediating pathogenic cell-cell interactions.…”

Section: R E V I E W S E R I E S : M I T O C H O N D R I a L D Y S F mentioning

confidence: 93%

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Culley

Chan

2018

Journal of Clinical Investigation

132

110

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Pulmonary hypertension (PH) is a heterogeneous and fatal disease of the lung vasculature, where metabolic and mitochondrial dysfunction may drive pathogenesis. Similar to the Warburg effect in cancer, a shift from mitochondrial oxidation to glycolysis occurs in diseased pulmonary vessels and the right ventricle. However, appreciation of metabolic events in PH beyond the Warburg effect is only just emerging. This Review discusses molecular, translational, and clinical concepts centered on the mitochondria and highlights promising, controversial, and challenging areas of investigation. If we can move beyond the "mountains" of obstacles in this field and elucidate these fundamental tenets of pulmonary vascular metabolism, such work has the potential to usher in much-needed diagnostic and therapeutic approaches for the mitochondrial and metabolic management of PH.

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Section: R E V I E W S E R I E S : M I T O C H O N D R I a L D Y S F mentioning

confidence: 93%

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Culley

Chan

2018

Journal of Clinical Investigation

132

110

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“…The NMDAR, a major glutamate receptor of excitatory neuronal synapses, is an ion channel receptor also expressed in PASMC and pulmonary arterial ECs [ 133 ]. NMDARs are a class of ionotropic glutamate receptors that also includes the AMPA receptors and kainate receptors.…”

Section: Functional and Molecular Classification Of Ion Channels Imentioning

confidence: 99%

“…Recently, NMDAR expression was demonstrated in human and rodent pulmonary vascular cells [ 133 ], which contributes to vascular cell proliferation and angiogenesis. In PAH, glutamate (a NMDAR agonist) is accumulated in pulmonary arteries from PAH patients.…”

Section: Ion Channels In Pah Pathophysiologymentioning

confidence: 99%

“…Moreover, NMDAR antagonists and nmdar −/− mice reduce the development of PH, demonstrating that a dysregulated glutamate/NMDAR axis in pulmonary arteries leads to PAH. Thus, vascular NMDAR is a potential treatment target for PAH [ 133 ].…”

Section: Ion Channels In Pah Pathophysiologymentioning

confidence: 99%

“…In vitro, Dumas and colleagues recently found that the noncompetitive NMDAR antagonists MK-801 (dizocilpine) and memantine inhibit human PASMC proliferation, and reverse PH in the MCT-PH rat model [ 133 ]. These results indicate that pharmacological inhibition of NMDAR could be considered as a therapeutic strategy in PAH.…”

Section: Targeting Ion Channels and Transporters In Pahmentioning

confidence: 99%

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Ion Channels in Pulmonary Hypertension: A Therapeutic Interest?

Lambert

Capuano

Olschewski

et al. 2018

IJMS

Self Cite

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Pulmonary arterial hypertension (PAH) is a multifactorial and severe disease without curative therapies. PAH pathobiology involves altered pulmonary arterial tone, endothelial dysfunction, distal pulmonary vessel remodeling, and inflammation, which could all depend on ion channel activities (K+, Ca2+, Na+ and Cl−). This review focuses on ion channels in the pulmonary vasculature and discusses their pathophysiological contribution to PAH as well as their therapeutic potential in PAH.

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Long noncoding RNA uc.4 inhibits cell differentiation in heart development by altering DNA methylation

Zhang

Feng

Zhang

et al. 2018

J of Cellular Biochemistry

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In previous studies, we have demonstrated that long noncoding RNA uc.4 may influence the cell differentiation through the TGF‐β signaling pathway, suppressed the heart development of zebrafish and resulting cardiac malformation. DNA methylation plays a significant role in the heart development and disordered of DNA methylation may cause disruption of control of gene promoter. In this study, methylated DNA immunoprecipitation was performed to identify the different expression levels of methylation regions. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were also performed to identify the possible biological process and pathway that uc.4 may join, associated with Rap1 signaling pathway, gonadotropin‐releasing hormone signaling pathway, and Calcium signaling pathway. We found that the distribution of differentially methylated regions peaks was mainly located in intergenic and intron regions. Altogether, our result showed that differentially methylated genes are significantly expressed in uc.4‐overexpression cells, providing valuable data for further exploration of the role of uc.4 in heart development.

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NMDA-Type Glutamate Receptor Activation Promotes Vascular Remodeling and Pulmonary Arterial Hypertension

Abstract: These results reveal a dysregulation of the glutamate-NMDAR axis in the pulmonary arteries of patients with PAH and identify vascular NMDARs as targets for antiremodeling treatments in PAH.

Cited by 81 publications

References 61 publications

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Ion Channels in Pulmonary Hypertension: A Therapeutic Interest?

Long noncoding RNA uc.4 inhibits cell differentiation in heart development by altering DNA methylation

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