Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension

Rhodes, Christopher J.; Ghataorhe, Pavandeep; Wharton, John; Rue-Albrecht, Kévin; Hadinnapola, Charaka; Watson, G. Keith; Bleda, Marta; Haimel, Matthias; Coghlan, Gerry; Corris, Paul A.; Howard, Luke; Kiely, David G.; Peacock, Andrew J.; Pepke‐Zaba, Joanna; Toshner, Mark; Wort, Stephen J.; Gibbs, J. Simon R.; Lawrie, Allan; Gräf, Stefan; Morrell, Nicholas W.; Wilkins, Martin R.

doi:10.1161/circulationaha.116.024602

Cited by 179 publications

(235 citation statements)

References 51 publications

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“…Further validation of predicted targets using a panel of 105 circulating plasma metabolites in PAH patients confirmed the association of right ventricular‐pulmonary vascular dysfunction with circulating indoleamine 2,3‐dioxygenase (IDO)‐dependent tryptophan metabolites (TMs), tricarboxylic acid intermediates and purine metabolites . Reports from recent study are also congruent with these findings where they demonstrate a strong strength of association between patient survival and metabolic profiles in PAH …”

Section: Introductionmentioning

confidence: 59%

“…7 Reports from recent study are also congruent with these findings where they demonstrate a strong strength of association between patient survival and metabolic profiles in PAH. 8 However, the metabolic profile of individuals is dependent on race, sex and dietary habits. Till now, no studies focusing on the metabolomic changes in a primarily Chinese PAH patient cohort have been documented.…”

Section: Introductionmentioning

confidence: 99%

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Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China

Chen

Luo

et al. 2020

J Cellular Molecular Medi

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The specific mechanism of pulmonary arterial hypertension (PAH) remains elusive. The present study aimed to explore the underlying mechanism of PAH through the identity of novel biomarkers for PAH using metabolomics approach. Serum samples from 40 patients with idiopathic PAH (IPAH), 20 patients with congenital heart disease‐associated PAH (CHD‐PAH) and 20 healthy controls were collected and analysed by ultra‐high‐performance liquid chromatography coupled with high‐resolution mass spectrometry (UPLC‐HRMS). Orthogonal partial least square‐discriminate analysis (OPLS‐DA) was applied to screen potential biomarkers. These results were validated in monocrotaline (MCT)‐induced PAH rat model. The OPLS‐DA model was successful in screening distinct metabolite signatures which distinguished IPAH and CHD‐PAH patients from healthy controls, respectively (26 and 15 metabolites). Unbiased analysis from OPLS‐DA identified 31 metabolites from PAH patients which were differentially regulated compared to the healthy controls. Our analysis showed dysregulation of the different metabolic pathways, including lipid metabolism, glucose metabolism, amino acid metabolism and phospholipid metabolism pathways in PAH patients compared to their healthy counterpart. Among these metabolites from dysregulated metabolic pathways, a panel of metabolites from lipid metabolism and fatty acid oxidation (lysophosphatidylcholine, phosphatidylcholine, perillic acid, palmitoleic acid, N‐acetylcholine‐d‐sphingomyelin, oleic acid, palmitic acid and 2‐Octenoylcarnitine metabolites) were found to have a close association with PAH. The results from the analysis of both real‐time quantitative PCR and Western blot showed that expression of LDHA, CD36, FASN, PDK1 GLUT1 and CPT‐1 in right heart/lung were significantly up‐regulated in MCT group than the control group.

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Section: Introductionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China

Chen

Luo

et al. 2020

J Cellular Molecular Medi

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“…22 Because of its physiological roles, circulating or urinary pseudouridine is considered a marker of RNA degradation and cell turnover. 23 Prior studies have reported higher concentrations of circulating pseudouridine in patients with pulmonary arterial hypertension, 24 heart failure, 25 impaired kidney function, 26,27 end-stage renal disease, 28,29 and cancer. 30 The relationships between circulating pseudouridine and posttranscriptional pseudouridylation of RNA and what role, if any, pseudouridine has in processes contributing to AF risk, requires further investigation.…”

Section: Bile Acids and Afmentioning

confidence: 99%

Serum metabolomics and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) Study

Alonso

Yu²,

Sun

et al. 2018

Preprint

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We have previously identified associations of two circulating secondary bile acids (glycocholenate and glycolithocolate sulfate) with atrial fibrillation (AF) risk among blacks. We aimed to replicate these findings in an independent sample including both whites and blacks, and performed a new metabolomic analysis in the combined sample. We studied 3,922 participants from the ARIC cohort followed between 1987 and 2013. Of these, 1,919 had been included in the prior analysis and 2,003 were new samples.Metabolomic profiling was done in baseline serum samples using gas and liquid chromatography mass spectrometry. AF was ascertained from electrocardiograms, hospitalizations, and death certificates. We used multivariable Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) of AF by one standard deviation difference of metabolite levels. Over a mean follow-up of 20 years, 608 participants developed AF. Glycocholenate sulfate was associated with AF in the replication and combined samples (HR 1.10, 95%CI 1.00, 1.21 and HR 1.13, 95%CI 1.04, 1.22, respectively).Glycolithocolate sulfate was not related to AF risk in the replication sample (HR 1.02, 95%CI 0.92, 1.13).An analysis of 245 metabolites in the combined cohort identified three additional metabolites associated with AF after multiple-comparison correction: pseudouridine (HR 1.18, 95%CI 1.10, 1.28), uridine (HR 0.86, 95%CI 0.79, 0.93) and acisoga (HR 1.17, 95%CI 1.09, 1.26). To conclude, we replicated a prospective association between a previously identified secondary bile acid, glycocholenate sulfate, and AF incidence, and identified new metabolites involved in nucleoside and polyamine metabolism as markers of AF risk.

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“…Histone deacetylases 1(HDAC1) was dramatically elevated in pulmonary arteries of human with pulmonary hypertension [27]. In PAH, plasma metabolomics approach showed modified transfer RNAs and altered bioenergetics [44].…”

Section: Genetics and Genomics Progress Of Pulmonary Hypertensionmentioning

confidence: 99%

Genetic and genomic approaches to pulmonary vascular diseases

Li¹,

Zhang²

2017

Biomed Genet Genomics

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Pulmonary vascular diseases include pulmonary arterial hypertension, pulmonary venous hypertension, pulmonary embolism and chronic thromboembolic disease. The mutations of BMPR2 were identified as major causes of primary pulmonary hypertension. The Factor V Leiden mutation is the most common genetic risk for pulmonary embolism. Candidate gene studies, genome-wide association studies, epigenetic studies, transcriptional profiling, miRNA profiling also identified novel causes for the diseases. Genetic and genomic approaches for pulmonary vascular disease provided new insights of the mechanisms and revealed the novel therapeutic targets. In this review, we summarise the current progress of genetic and genomic approaches for pulmonary vascular diseases and also discuss the future directions of the research for the diseases.

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Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension

Abstract: Supplemental Digital Content is available in the text.

Cited by 179 publications

References 51 publications

Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China

Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China

Serum metabolomics and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) Study

Genetic and genomic approaches to pulmonary vascular diseases

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