An mTORC1‐Dependent Mouse Model for Cardiac Sarcoidosis
Open accessAbstract
Background: Sarcoidosis is an inflammatory, granulomatous disease of unknown cause affecting multiple organs, including the heart. Untreated, unresolved granulomatous inflammation can lead to cardiac fibrosis, arrhythmias, and eventually heart failure. Here we characterize the cardiac phenotype of mice with chronic activation of mammalian target of rapamycin (mTOR) complex 1 signaling in myeloid cells known to cause spontaneous pulmonary sarcoid‐like granulomas. Methods and Results: The cardiac phenotype of mice with conditional deletion of the tuberous sclerosis 2 ( TSC2 ) gene in CD11c + cells (TSC2 fl/fl CD11c‐Cre; termed TSC2 KO ) and controls ( TSC2 fl/fl ) was determined by histological and immunological stains. Transthoracic echocardiography and invasive hemodynamic measurements were performed to assess myocardial function. TSC2 KO animals were treated with either everolimus, an mTOR inhibitor, or Bay11‐7082, a nuclear factor‐kB inhibitor. Activation of mTOR signaling was evaluated on myocardial samples from sudden cardiac death victims with a postmortem diagnosis of cardiac sarcoidosis. Chronic activation of mTORC1 signaling in CD11c + cells was sufficient to initiate progressive accumulation of granulomatous infiltrates in the heart, which was associated with increased fibrosis, impaired cardiac function, decreased plakoglobin expression, and abnormal connexin 43 distribution, a substrate for life‐threatening arrhythmias. Mice treated with the mTOR inhibitor everolimus resolved granulomatous infiltrates, prevented fibrosis, and improved cardiac dysfunction. In line, activation of mTOR signaling in CD68 + macrophages was detected in the hearts of sudden cardiac death victims who suffered from cardiac sarcoidosis. Conclusions: To our best knowledge this is the first animal model of cardiac sarcoidosis that recapitulates major pathological hallmarks of human disease. mTOR inhibition may be a therapeutic option for patients with cardiac sarcoidosis.
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Activation of mTOR signaling specifically in CD11c-expressing cells in mice results in a granulomatous phenotype and fibrosis in the heart resembling cardiac sarcoidosis in humans.
“the activation of mTOR signaling specifically in CD11c-expressing cells in mice resulted in a granulomatous phenotype and fibrosis in the heart, resembling cardiac sarcoidosis in humans”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [63]
mTOR signaling is a potential therapeutic target for cardiac sarcoidosis.
“suggesting mTOR signaling as a potential therapeutic target”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [63]
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The human heart contains distinct macrophage subsets with divergent origins and functions
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Self-citationTranscriptional and Immune Landscape of Cardiac Sarcoidosis
Liu, J., Ma, P., Lai, L., Villanueva, A., Koenig, A., Bean, G. R., Bowles, D. E., Glass, C., Watson, M., Lavine, K. J., et al. (2022) · Circulation Research · doi:10.1161/circresaha.121.320449 · Cited by 78 · see citing works
Histopathological Features and Protein Markers of Arrhythmogenic Cardiomyopathy
Bueno-Beti, C., & Asimaki, A. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.746321 · Cited by 12 · see citing works
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Autoimmune Myocarditis, Old Dogs and New Tricks.
Won, T., Song, E. J., Kalinoski, H. M., Moslehi, J. J., & Čiháková, D. (2024) · Circulation Research · doi:10.1161/circresaha.124.323816 · Cited by 51 · see citing works
- Authors
- Bueno‐Beti, C., Lim, C. X., Protonotarios, A., Szabo, P. L., Westaby, J., Mazic, M., Sheppard, M. N., Behr, E., Hamza, O., Kiss, A., Podesser, B. K., Hengstschläger, M., Weichhart, T., & Asimaki, A.
- Affiliations
- Clinical Cardiology Academic Group, Molecular and Clinical Research Science Institute St George’s University of London London United Kingdom
- Medical University of Vienna (AT)
- University College London (GB)
- Center for Biomedical Research Medical University of Vienna Vienna Austria
- St George's, University of London (GB)
- Corresponding author
- Weichhart, Thomas
- Asimaki, Angeliki
- ORCID
- Venue
- Journal of the American Heart Association
- Published
- 2023-10-03
- Volume
- 12
- Issue
- 19
- Pages
- e030478-e030478
- ISSN
- 2047-9980 (ISSN-L)
- PMC
- PMC10727264
- OpenAlex
- W4387032936
- Cited by
- 34
- References
- 7
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 12
- FWCI
- 6.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- St George's Online Research Archive (St George's University of London) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Wellcome Trust (208460/Z/17/Z, Z/17/Z)
- National Institute for Health and Care Research (CL-2022-16-002)
- British Heart Foundation (PG/18/27/33616)
- Rosetrees Trust
- Vienna Science and Technology Fund (P34266-B, P34023-B, LS18-058)
- Austrian Science Fund (P34266-B, P34023-B)
- Topics
- Health Sciences › Medicine › Physiology › Sarcoidosis and Beryllium Toxicity Research
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Health Sciences › Medicine › Physiology › Histiocytic Disorders and Treatments
- Keywords
- cardiac sarcoidosis, mTORC1 signaling, myeloid cells, granulomatous inflammation, myocardial fibrosis, cardiac function, everolimus, mTOR inhibition, NF-κB, plakoglobin, connexin 43, sudden cardiac death, macrophages, animal models
- MeSH terms
- Everolimus, Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 2 Protein, Animals, Disease Models, Animal, Fibrosis, Humans, Mammals, Cardiomyopathies, Myocarditis, Sarcoidosis, Death, Sudden, Cardiac, Sirolimus, Tumor Suppressor Proteins, Multiprotein Complexes, Mice, TOR Serine-Threonine Kinases
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