Bueno-Beti, C;
Lim, CX;
Protonotarios, A;
Szabo, PL;
Westaby, J;
Mazic, M;
Sheppard, MN;
Behr, E;
Hamza, O;
Kiss, A;
et al.
Bueno-Beti, C; Lim, CX; Protonotarios, A; Szabo, PL; Westaby, J; Mazic, M; Sheppard, MN; Behr, E; Hamza, O; Kiss, A; Podesser, BK; Hengstschläger, M; Weichhart, T; Asimaki, A
(2023)
An mTORC1-Dependent Mouse Model for Cardiac Sarcoidosis.
J Am Heart Assoc, 12 (19).
e030478.
ISSN 2047-9980
https://doi.org/10.1161/JAHA.123.030478
SGUL Authors: Behr, Elijah Raphael Sheppard, Mary Noelle Westaby, Joseph David Asimaki, Angeliki
Abstract
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 (TSC2fl/flCD11c-Cre; termed TSC2KO) and controls (TSC2fl/fl) was determined by histological and immunological stains. Transthoracic echocardiography and invasive hemodynamic measurements were performed to assess myocardial function. TSC2KO 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.
Item Type: |
Article
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Additional Information: |
Copyright © 2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
Keywords: |
cardiac sarcoidosis, fibrosis, heart, mTORC1, mouse model, sarcoidosis, 1102 Cardiorespiratory Medicine and Haematology |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
J Am Heart Assoc |
ISSN: |
2047-9980 |
Language: |
eng |
Dates: |
Date | Event |
---|
3 October 2023 | Published | 26 September 2023 | Published Online | 15 August 2023 | Accepted |
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Publisher License: |
Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0 |
Projects: |
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PubMed ID: |
37750561 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/115748 |
Publisher's version: |
https://doi.org/10.1161/JAHA.123.030478 |
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