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Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats
Christian Luck1,2, Vincent G DeMarco1,2, Abuzar Mahmood1,2
1Department of Medicine, University of Missouri, Columbia, MO, USA.
Abstract:
Diabetes is comorbid with cardiovascular disease and impaired immunity. Rapamycin improves cardiac functions and extends lifespan by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1). However, in diabetic murine models, Rapamycin elevates hyperglycemia and reduces longevity. Since Rapamycin is an immunosuppressant, we examined whether Rapamycin (750 μg/kg/day) modulates intracardiac cytokines, which affect the cardiac immune response, and cardiac function in male lean (ZL) and diabetic obese Zucker (ZO) rats. Rapamycin suppressed levels of fasting triglycerides, insulin, and uric acid in ZO but increased glucose. Although Rapamycin improved multiple diastolic parameters (E/E', E'/A', E/Vp) initially, these improvements were reversed or absent in ZO at the end of treatment, despite suppression of cardiac fibrosis and phosphoSer473Akt. Intracardiac cytokine protein profiling and Ingenuity® Pathway Analysis indicated suppression of intracardiac immune defense in ZO, in response to Rapamycin treatment in both ZO and ZL. Rapamycin increased fibrosis in ZL without increasing phosphoSer473Akt and differentially modulated anti-fibrotic IL-10, IFNγ, and GM-CSF in ZL and ZO. Therefore, fundamental difference in intracardiac host defense between diabetic ZO and healthy ZL, combined with differential regulation of intracardiac cytokines by Rapamycin in ZO and ZL hearts, underlies differential cardiac outcomes of Rapamycin treatment in health and diabetes.
Insights
Rapamycin, used to improve heart function, worsened diabetes in rats by increasing blood glucose and altering immune responses. Differences in heart immunity between diabetic and healthy rats explain these varied effects.
Area of Science:
- Cardiology
- Immunology
- Metabolism
Background:
- Diabetes is linked to cardiovascular disease and weakened immunity.
- Rapamycin (mTORC1 inhibitor) improves cardiac function and lifespan but can worsen hyperglycemia and reduce longevity in diabetic models.
- Understanding Rapamycin's effects on cardiac immune responses in diabetes is crucial.
Purpose of the Study:
- To investigate how Rapamycin affects intracardiac cytokines and cardiac function in lean (ZL) and diabetic obese (ZO) rats.
- To determine if Rapamycin modulates the cardiac immune response differently in diabetic versus healthy states.
Main Methods:
- Administration of Rapamycin (750 μg/kg/day) to male ZL and ZO rats.
- Measurement of cardiac function parameters, including diastolic function.
- Analysis of intracardiac cytokines using protein profiling and Ingenuity® Pathway Analysis.
- Assessment of cardiac fibrosis and phospho-Akt levels.
Main Results:
- Rapamycin reduced triglycerides, insulin, and uric acid but increased glucose in ZO rats.
- Initial improvements in diastolic function in ZO rats were reversed by the end of treatment.
- Rapamycin suppressed intracardiac immune defense in both ZL and ZO rats.
- Rapamycin increased cardiac fibrosis in ZL rats and differentially modulated cytokines (IL-10, IFNγ, GM-CSF) in ZL and ZO rats.
Conclusions:
- Fundamental differences in intracardiac host defense exist between diabetic ZO and healthy ZL rats.
- Rapamycin differentially regulates intracardiac cytokines in ZL and ZO rats, leading to varied cardiac outcomes.
- These findings highlight the complex interplay between diabetes, Rapamycin, and cardiac immune function.