An interferon gamma response signature links myocardial aging and immunosenescence.

Autor:	Ashour D; Department of Internal Medicine I, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany.; Comprehensive Heart Failure Centre, University Hospital Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany., Rebs S; Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany., Arampatzi P; Core Unit Systems Medicine, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany., Saliba AE; University of Würzburg, Faculty of Medicine, Institute of Molecular Infection Biology (IMIB), Josef-Schneider-Str. 2, 97080 Würzburg, Germany.; Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Centre for Infection Research (HZI), Josef-Schneider-Str. 2, 97080 Würzburg, Germany., Dudek J; Comprehensive Heart Failure Centre, University Hospital Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany., Schulz R; Departments of Pediatrics and Pharmacology, Mazankowski Alberta Heart Institute, University of Alberta, 4-62 HMRC, 11207 87 Ave NW, Edmonton, Alberta T6G, 2S2 Canada., Hofmann U; Department of Internal Medicine I, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany.; Comprehensive Heart Failure Centre, University Hospital Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany., Frantz S; Department of Internal Medicine I, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany.; Comprehensive Heart Failure Centre, University Hospital Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany., Cochain C; Comprehensive Heart Failure Centre, University Hospital Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany.; Institute of Experimental Biomedicine, University Hospital Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany., Streckfuß-Bömeke K; Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany.; Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Centre for Cardiovascular Research), Robert-Koch-Straße 40, 37075 Göttingen, Germany., Campos Ramos G; Department of Internal Medicine I, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany.; Comprehensive Heart Failure Centre, University Hospital Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Nov 15; Vol. 119 (14), pp. 2458-2468.
DOI:	10.1093/cvr/cvad068
Abstrakt:	Aims: Aging entails profound immunological transformations that can impact myocardial homeostasis and predispose to heart failure. However, preclinical research in the immune-cardiology field is mostly conducted in young healthy animals, which potentially weakens its translational relevance. Herein, we sought to investigate how the aging T-cell compartment associates with changes in myocardial cell biology in aged mice. Methods and Results: We phenotyped the antigen-experienced effector/memory T cells purified from heart-draining lymph nodes of 2-, 6-, 12-, and 18-month-old C57BL/6J mice using single-cell RNA/T cell receptor sequencing. Simultaneously, we profiled all non-cardiomyocyte cell subsets purified from 2- to 18-month-old hearts and integrated our data with publicly available cardiomyocyte single-cell sequencing datasets. Some of these findings were confirmed at the protein level by flow cytometry. With aging, the heart-draining lymph node and myocardial T cells underwent clonal expansion and exhibited an up-regulated pro-inflammatory transcription signature, marked by an increased interferon-γ (IFN-γ) production. In parallel, all major myocardial cell populations showed increased IFN-γ responsive signature with aging. In the aged cardiomyocytes, a stronger IFN-γ response signature was paralleled by the dampening of expression levels of transcripts related to most metabolic pathways, especially oxidative phosphorylation. Likewise, induced pluripotent stem cells-derived cardiomyocytes exposed to chronic, low grade IFN-γ treatment showed a similar inhibition of metabolic activity. Conclusions: By investigating the paired age-related alterations in the T cells found in the heart and its draining lymph nodes, we provide evidence for increased myocardial IFN-γ signaling with age, which is associated with inflammatory and metabolic shifts typically seen in heart failure. Competing Interests: Conflict of interest: None declared. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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