Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner.

Autor: ElBeck Z; Department of Medicine Huddinge, Karolinska Institutet, Campus Flemingsberg, 141 57, Huddinge, Sweden. zaher.elbeck@ki.se.; Departmenty of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. zaher.elbeck@ki.se., Hossain MB; Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Siga H; Department of Medicine Huddinge, Karolinska Institutet, Campus Flemingsberg, 141 57, Huddinge, Sweden., Oskolkov N; Department of Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Lund University, Lund, Sweden., Karlsson F; Data Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Lindgren J; Translational Genomics, Centre for Genomics Research, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Walentinsson A; Translational Science & Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Koppenhöfer D; Department of Medicine Huddinge, Karolinska Institutet, Campus Flemingsberg, 141 57, Huddinge, Sweden., Jarvis R; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Bürli R; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Jamier T; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Franssen E; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Firth M; Data Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Degasperi A; Data Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.; Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom., Bendtsen C; Data Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Menzies RI; Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Streckfuss-Bömeke K; Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.; Clinic for Cardiology and Pneumology, Georg-August University Göttingen and DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany.; Department of Translational Research, Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany., Kohlhaas M; Department of Translational Research, Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany., Nickel AG; Department of Translational Research, Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany., Lund LH; Department of Medicine Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden., Maack C; Department of Translational Research, Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany., Végvári Á; Division of Chemistry I, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden., Betsholtz C; Department of Medicine Huddinge, Karolinska Institutet, Campus Flemingsberg, 141 57, Huddinge, Sweden.; Departmenty of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Mar 20; Vol. 15 (1), pp. 2358. Date of Electronic Publication: 2024 Mar 20.
DOI: 10.1038/s41467-024-46384-8
Abstrakt: While excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidative defense mechanism. Paradoxically reduced expression of IDH2 associated with ventricular eccentric hypertrophy is counterbalanced by an increase in the enzyme activity. We unveil redox-dependent sex dimorphism, and extensive mutual regulation of the antioxidative activities of IDH2 and NRF2 by a feedforward network that involves 2-oxoglutarate and L-2-hydroxyglutarate and mediated in part through unconventional hydroxy-methylation of cytosine residues present in introns. Consequently, conditional targeting of ROS in a murine model of heart failure improves cardiac function in sex- and phenotype-dependent manners. Together, these insights may explain why previous attempts to treat heart failure with antioxidants have been unsuccessful and open new approaches to personalizing and, thereby, improving such treatment.
(© 2024. The Author(s).)
Databáze: MEDLINE
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