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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.
Journal of the American Heart Association
|September 26, 2023
Summary
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.
