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Unraveling the Metabolic Derangements Occurring in Non-infarcted Areas of Pig Hearts With Chronic Heart Failure
University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. (Translationell bioinformatik, Translational Bioinformatics)
Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
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2021 (English)In: Frontiers in Cardiovascular Medicine, E-ISSN 2297-055X, Vol. 8, article id 753470Article in journal (Refereed) Published
Abstract [en]

Objective: After myocardial infarction (MI), the non-infarcted left ventricle (LV) ensures appropriate contractile function of the heart. Metabolic disturbance in this region greatly exacerbates post-MI heart failure (HF) pathology. This study aimed to provide a comprehensive understanding of the metabolic derangements occurring in the non-infarcted LV that could trigger cardiovascular deterioration. Methods and Results: We used a pig model that progressed into chronic HF over 3 months following MI induction. Integrated gene and metabolite signatures revealed region-specific perturbations in amino acid- and lipid metabolism, insulin signaling and, oxidative stress response. Remote LV, in particular, showed impaired glutamine and arginine metabolism, altered synthesis of lipids, glucose metabolism disorder, and increased insulin resistance. LPIN1, PPP1R3C, PTPN1, CREM, and NR0B2 were identified as the main effectors in metabolism dysregulation in the remote zone and were found differentially expressed also in the myocardium of patients with ischemic and/or dilated cardiomyopathy. In addition, a simultaneous significant decrease in arginine levels and altered PRCP, PTPN1, and ARF6 expression suggest alterations in vascular function in remote area. Conclusions: This study unravels an array of dysregulated genes and metabolites putatively involved in maladaptive metabolic and vascular remodeling in the non-infarcted myocardium and may contribute to the development of more precise therapies to mitigate progression of chronic HF post-MI.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021. Vol. 8, article id 753470
Keywords [en]
chronic heart failure, decompensated heart failure, metabolome, myocardial infarction (MI), transcriptome (RNA-seq)
National Category
Cardiology and Cardiovascular Disease
Research subject
Bioinformatics
Identifiers
URN: urn:nbn:se:his:diva-20688DOI: 10.3389/fcvm.2021.753470ISI: 000713488600001PubMedID: 34722683Scopus ID: 2-s2.0-85168795369OAI: oai:DiVA.org:his-20688DiVA, id: diva2:1608923
Funder
AstraZenecaKnowledge Foundation, 2014/301Knowledge Foundation, 2016/294Knowledge Foundation, 2016/330
Note

CC BY 4.0

Received: 04 August 2021. Accepted: 16 September 2021. Published: 13 October 2021 

Correspondence:

Cláudia Correia claudia.correia@astrazeneca.com

Jane Synnergren jane.synnergren@his.se

Funding: This work was supported by AstraZeneca and the University of Skövde, Sweden under grants from the Knowledge Foundation [2014/301, 2016/294, and 2016/330]. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

Available from: 2021-11-04 Created: 2021-11-04 Last updated: 2025-02-10Bibliographically approved

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Ulfenborg, BenjaminSartipy, PeterSynnergren, Jane

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