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RelA-mediated signaling connects adaptation to chronic cardiomyocyte stress with myocardial and systemic inflammation in the ADCY8 model of accelerated aging

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Abstract

Mice with cardiac-specific overexpression of adenylyl cyclase (AC) type 8 (TGAC8) are under a constant state of severe myocardial stress. They have a remarkable ability to adapt to this stress, but they eventually develop accelerated cardiac aging and experience reduced longevity. We have previously demonstrated through bioinformatics that constitutive adenylyl cyclase activation in TGAC8 mice is associated with the activation of inflammation-related signaling pathways. However, the immune response associated with chronic myocardial stress in the TGAC8 mouse remains unexplored. Here we demonstrate that chronic activation of adenylyl cyclase in cardiomyocytes of TGAC8 mice results in activation of cell-autonomous RelA-mediated NF-κB signaling. This is associated with non-cell-autonomous activation of proinflammatory and age-associated signaling in myocardial endothelial cells and myocardial smooth muscle cells, expansion of myocardial immune cells, increase in serum levels of inflammatory cytokines, and changes in the size or composition of lymphoid organs. All these changes precede the appearance of cardiac fibrosis. We provide evidence indicating that RelA activation in cardiomyocytes with chronic activation of adenylyl cyclase is mediated by calcium-protein Kinase A (PKA) signaling. Using a model of chronic cardiomyocyte stress and accelerated aging, we highlight a novel, calcium/PKA/RelA-dependent connection between cardiomyocyte stress, myocardial inflammation, and systemic inflammation. These findings suggest that RelA-mediated signaling in cardiomyocytes might be an adaptive response to stress that, when chronically activated, ultimately contributes to both cardiac and systemic aging.

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Any data not already reported in the manuscript or the supplementary material is available from the corresponding authors upon reasonable request.

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Acknowledgements

The authors would like to acknowledge Sylvie Rousseau for her assistance in completing specific experiments. This study was supported by the Intramural Research Program of the NIH, National Institute of Aging (USA), and by NHLBI grants 5K08HLO145108-03 and 1R01HL160716-01 to L.A.

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Authors and Affiliations

  1. Laboratory of Cardiovascular Science, Intramural Research Program, National Institute On Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD, 21224, USA

    Vikas Kumar & Edward G. Lakatta

  2. Laboratory of Molecular Biology & Immunology, Intramural Research Program, National Institute On Aging, National Institutes of Health, Baltimore, MD, 21224, USA

    Amit Singh, Mary Kaileh & Ranjan Sen

  3. Laboratory of Clinical Investigation, Intramural Research Program, National Institute On Aging, National Institutes of Health, Baltimore, MD, 21224, USA

    Anjali Verma

  4. Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Ross Research Building – Room 809, 720 Rutland Avenue, Baltimore, MD, 21205, USA

    Kevin Christian Bermea & Luigi Adamo

  5. Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA

    Dhaneshwar Kumar

  6. Department of Medicine, NYU Grossman School of Medicine, New York, NY, 10016, USA

    Vikas Kumar

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  1. Vikas Kumar
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Highlights

1.Mice expressing transgenic, constitutively active adenylyl cyclase type 8 in cardiomyocytes (TGAC8) are a model to investigate chronic myocardial stress and myocardial aging.

2.Sustained adenylyl cyclase signaling in TGAC8 cardiomyocytes induces RelA-mediated activation of proinflammatory and age-related pathways in myocardial endothelial and smooth muscle cells together with expansion of myocardial immune cells.

3.The activation of RelA signaling in cardiomyocytes is associated with a systemic inflammatory response.

4.Activation of RelA in cardiomyocytes is calcium-PKA dependent.

5.Our findings provide mechanistic insights into the relationship between chronic myocardial stress, cardiac inflammation, and systemic inflammation, and might be relevant to cardiac and systemic aging.

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Kumar, V., Bermea, K.C., Kumar, D. et al. RelA-mediated signaling connects adaptation to chronic cardiomyocyte stress with myocardial and systemic inflammation in the ADCY8 model of accelerated aging. GeroScience (2024). https://doi.org/10.1007/s11357-024-01121-3

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