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Updated: Jun 10, 2026
Transverse Aortic Constriction in Mice
Published on: April 21, 2010
An mTORC1-Dependent Mouse Model for Cardiac Sarcoidosis
Carlos Bueno-Beti1, Clarice X Lim2, Alexandros Protonotarios3
1Clinical Cardiology Academic Group, Molecular and Clinical Research Science Institute St George's University of London London United Kingdom.
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.
Insights
This study reveals chronic mTORC1 signaling activation causes cardiac sarcoidosis in mice. mTOR inhibition with everolimus resolved inflammation and improved heart function, suggesting a potential therapy.
Area of Science:
- Cardiovascular Biology
- Immunology
- Pathology
Background:
- Sarcoidosis is a multisystem granulomatous disease potentially affecting the heart, leading to fibrosis, arrhythmias, and heart failure.
- Chronic inflammation in the heart can cause significant cardiac dysfunction and is of unknown etiology.
- Understanding the mechanisms driving cardiac sarcoidosis is crucial for developing effective treatments.
Purpose of the Study:
- To characterize the cardiac phenotype in a mouse model with chronic activation of mammalian target of rapamycin (mTOR) complex 1 signaling in myeloid cells.
- To investigate the role of mTOR signaling in the pathogenesis of cardiac sarcoidosis.
- To evaluate the therapeutic potential of mTOR inhibition in a preclinical model of cardiac sarcoidosis.
Main Methods:
- Generated a mouse model (TSC2(KO)) with conditional deletion of the tuberous sclerosis 2 (TSC2) gene in CD11c+ cells to activate mTORC1 signaling.
- Assessed cardiac function using transthoracic echocardiography and invasive hemodynamic measurements.
- Treated TSC2(KO) mice with everolimus (mTOR inhibitor) or Bay11-7082 (NF-kB inhibitor) and analyzed myocardial samples.
Main Results:
- Chronic mTORC1 activation in CD11c+ cells induced progressive cardiac granulomatous infiltrates, fibrosis, and impaired function.
- Cardiac dysfunction was associated with decreased plakoglobin and abnormal connexin 43 distribution, predisposing to arrhythmias.
- Everolimus treatment resolved granulomas, prevented fibrosis, and improved cardiac function in TSC2(KO) mice.
- Activated mTOR signaling was observed in macrophages from human cardiac sarcoidosis patient hearts.
Conclusions:
- This study presents the first animal model of cardiac sarcoidosis that mirrors key features of the human disease.
- Targeting mTOR signaling, particularly with mTOR inhibitors like everolimus, shows promise as a therapeutic strategy for cardiac sarcoidosis.
- Further research into mTOR-driven pathways may uncover novel therapeutic targets for this debilitating condition.
