Group 3 pulmonary hypertension: Challenges and opportunities

McGettrick, Michael; Peacock, Andrew J.

doi:10.21542/gcsp.2020.6

Cited by 19 publications

(25 citation statements)

References 49 publications

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“…The pathogenesis of PH is driven or initiated by multiple factors including genetic mutations, epigenetic alterations, inflammation, altered metabolism, and environment insults such as hypoxia, drugs and toxins (de Jesus Perez, 2016). PH associated with hypoxia and lung disease (Group 3 PH) is the second most common form of PH and is associated with increased morbidity and mortality (Strange et al, 2012;McGettrick and Peacock, 2020). However, most of PAH-specific medications including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin have not shown consistent benefit in the Group 3 PH (Harder and Waxman, 2020).…”

Section: Discussionmentioning

confidence: 99%

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

Xie

Zhang

et al. 2021

Front. Pharmacol.

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Objective: Pulmonary hypertension (PH) associated with hypoxia and lung disease (Group 3) is the second most common form of PH and associated with increased morbidity and mortality. This study was aimed to identify hypoxia induced metabolism associated genes (MAGs) for better understanding of hypoxic PH.Methods: Rat pulmonary arterial smooth muscle cells (PASMCs) were isolated and cultured in normoxic or hypoxic condition for 24 h. Cells were harvested for liquid chromatography-mass spectrometry analysis. Functional annotation of distinguishing metabolites was performed using Metaboanalyst. Top 10 enriched metabolite sets were selected for the identification of metabolism associated genes (MAGs) with a relevance score >8 in Genecards. Transcriptomic data from lungs of hypoxic PH in mice/rats or of PH patients were accessed from Gene Expression Omnibus (GEO) database or open-access online platform. Connectivity Map analysis was performed to identify potential compounds to reverse the metabolism associated gene profile under hypoxia stress. The construction and module analysis of the protein-protein interaction (PPI) network was performed. Hub genes were then identified and used to generate LASSO model to determine its accuracy to predict occurrence of PH.Results: A total of 36 altered metabolites and 1,259 unique MAGs were identified in rat PASMCs under hypoxia. 38 differentially expressed MAGs in mouse lungs of hypoxic PH were revealed, with enrichment in multi-pathways including regulation of glucose metabolic process, which might be reversed by drugs such as blebbistatin. 5 differentially expressed MAGs were displayed in SMCs of Sugen 5416/hypoxia induced PH rats at the single cell resolution. Furthermore, 6 hub genes (Cat, Ephx1, Gpx3, Gstm4, Gstm5, and Gsto1) out of 42 unique hypoxia induced MAGs were identified. Higher Cat, Ephx1 and lower Gsto1 were displayed in mouse lungs under hypoxia (all p < 0.05), in consistent with the alteration in lungs of PH patients. The hub gene-based LASSO model can predict the occurrence of PH (AUC = 0.90).Conclusion: Our findings revealed six hypoxia-induced metabolism associated hub genes, and shed some light on the molecular mechanism and therapeutic targets in hypoxic PH.

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Section: Discussionmentioning

confidence: 99%

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

Xie

Zhang

et al. 2021

Front. Pharmacol.

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“…Esta situación puede ser reversible con un aumento de la concentración de oxígeno inspirado; sin embargo, con la hipoxia crónica, hay liberación de vasoconstrictores como la endotelina y serotonina, que también sirven como factores de crecimiento. Estos factores conducen a hiperplasia de la íntima e hipertrofia de la media; la hipoxia parece estimular la proliferación de fibroblastos a partir de los miofibroblastos locales, para dar inicio a la neomuscularización, todo lo cual lleva a un incremento del tono vascular (31,32) . La remodelación vascular, en algunos casos parcialmente, se revierte con oxígeno (32) (ver figura 1).…”

Section: Efecto De La Hipoxia Crónica Sobre El Sistema Vascular Pulmonarunclassified

“…Estos factores conducen a hiperplasia de la íntima e hipertrofia de la media; la hipoxia parece estimular la proliferación de fibroblastos a partir de los miofibroblastos locales, para dar inicio a la neomuscularización, todo lo cual lleva a un incremento del tono vascular (31,32) . La remodelación vascular, en algunos casos parcialmente, se revierte con oxígeno (32) (ver figura 1). Vasoconstricción pulmonar sostenida HIPOXIA CRÓNICA Figura 1.…”

Section: Efecto De La Hipoxia Crónica Sobre El Sistema Vascular Pulmonarunclassified

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Hipertension pulmonar de altura

Díaz-Lazo¹,

Sanchez

2022

revista de salud udh

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La hipertensión pulmonar de altura (HPA) es una enfermedad producto de la exposición crónica a la altitud. La prevalencia de la HPA es variable según la localización geográfica, ambiental y genética. La población que vive en altura está expuesta crónicamente a una hipoxia alveolar debido a que la presión parcial de oxigeno se encuentra disminuido, este hecho ocasiona vasoconstricción y posteriormente una remodelación vascular pulmonar, ocurrida por la neomuscularización proliferativa de las arterias pulmonares distales y capilares previamente no muscularizados y el engrosamiento de la capa adventicial por la acumulación de fibroblastos y matriz. La HPA generalmente es asintomático, recién en estadios avanzados produce sintomatología caracterizado por disnea de esfuerzo, y fatiga. El diagnóstico preciso es con cateterismo cardiaco derecho con valores de presión arterial media (PAPm) mayor a 30 mmHg y/o presión arterial pulmonar sistólica (PAPS) mayor a 50 mmHg. El tratamiento ideal es el descenso del poblador a lugares bajos. Su pronóstico es bueno en la mayoría de casos.

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“…2 PH associated with hypoxia and lung disease (Group 3 PH) is the second most common form of PH and is associated with increased morbidity and mortality. 3,4 However, most of PAH-speci c medications including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin have not shown consistent bene t in the Group 3 PH. 5 Hence, the discovery of some targets for hypoxic PH would be of great value for those Group 3 population.…”

Section: Introductionmentioning

confidence: 99%

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

Xie

Zhang

et al. 2021

Preprint

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Objective: Pulmonary hypertension (PH) associated with hypoxia and lung disease (Group 3) is the second most common form of PH and associated with increased morbidity and mortality. This study was aimed to identify hypoxia induced metabolism associated genes (MAGs) for better understanding of hypoxic PH. Methods: Rat pulmonary arterial smooth muscle cells (PASMCs) were isolated and cultured in normoxic or hypoxic condition for 24 h. Cells were harvested for liquid chromatography-mass spectrometry analysis. Functional annotation of distinguishing metabolites was performed using Metaboanalyst. Top 10 enriched metabolite sets were selected for the identification of metabolism associated genes (MAGs) with a relevance score > 8 in Genecards. Transcriptomic data from lungs of hypoxic PH in mice/rats or of PH patients were accessed from Gene Expression Omnibus (GEO) database or open-access online platform. Connectivity Map analysis was performed to identify potential compounds to reverse the metabolism associated gene profile under hypoxia stress. The construction and module analysis of the protein-protein interaction (PPI) network was performed. Hub genes were then identified and used to generate LASSO model to determine its accuracy to predict occurrence of PH.Results: A total of 36 altered metabolites and 1259 unique MAGs were identified in rat PASMCs under hypoxia. 38 differentially expressed MAGs in mouse lungs of hypoxic PH were revealed, with enrichment in multi-pathways including regulation of glucose metabolic process, which might be reversed by drugs such as blebbistatin. 5 differentially expressed MAGs were displayed in SMCs of Sugen 5416/hypoxia induced PH rats at the single cell resolution. Furthermore, 6 hub genes (Cat, Ephx1, Gpx3, Gstm4, Gstm5 and Gsto1) out of 42 unique hypoxia induced MAGs were identified. Higher Cat, Ephx1 and lower Gsto1 were displayed in mouse lungs under hypoxia (all P < 0.05), in consistent with the alteration in lungs of PH patients. The hub gene-based LASSO model can predict the occurrence of PH (AUC=0.90). Conclusions: Our findings revealed six hypoxia-induced metabolism associated hub genes, and shed some light on the molecular mechanism and therapeutic targets in hypoxic PH.

show abstract

Group 3 pulmonary hypertension: Challenges and opportunities

Cited by 19 publications

References 49 publications

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

Hipertension pulmonar de altura

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

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