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Calcineurin expression, activation, and function in cardiac pressure-overload hypertrophy
H W Lim1, L J De Windt, L Steinberg
1Department of Pediatrics, Children's Hospital Medical Center, University of Cincinnati, Ohio, USA.
Insights
Calcineurin activity increases with cardiac load, contributing to heart hypertrophy. Inhibiting calcineurin with cyclosporine A (CsA) attenuated and partially reversed this hypertrophy in rats.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Physiology
Background:
- Vascular hypertension increases cardiac load, leading to left ventricular hypertrophy and heart disease.
- Molecular pathways regulating cardiac hypertrophy are not fully understood.
- Calcineurin, a calcium-sensitive phosphatase, is a potential regulator of cardiac hypertrophy.
Purpose of the Study:
- To investigate the role of calcineurin in pressure-overload-induced cardiac hypertrophy.
- To determine if calcineurin activity and expression increase with cardiac load.
- To assess the effect of calcineurin inhibition on cardiac hypertrophy.
Main Methods:
- Induced pressure-overload hypertrophy in rats via abdominal aortic banding.
- Measured calcineurin enzymatic activity and protein content in heart tissue.
- Utilized Western blot analysis to assess calcineurin and calmodulin association.
- Administered cyclosporine A (CsA), a calcineurin inhibitor, to rats.
Main Results:
- Calcineurin enzymatic activity and protein content increased significantly in response to pressure-overload hypertrophy.
- Increased calcineurin protein content was associated with increased calmodulin binding.
- CsA administration prevented and partially reversed cardiac hypertrophy in a dose-dependent manner.
- CsA treatment attenuated histological and molecular markers of hypertrophy.
Conclusions:
- Calcineurin is a key upstream regulator of load-induced cardiac hypertrophy.
- Inhibiting calcineurin with CsA offers a potential therapeutic strategy for managing cardiac hypertrophy.
Background:
Vascular hypertension resulting in increased cardiac load is associated with left ventricular hypertrophy and is a leading predicator for progressive heart disease. The molecular signaling pathways that respond to increases in cardiac load are poorly understood. One potential regulator of the hypertrophic response is the calcium-sensitive phosphatase calcineurin.
Methods And Results:
We showed that calcineurin enzymatic activity is increased 3. 2-fold in the heart in response to pressure-overload hypertrophy induced by abdominal aortic banding in the rat. Western blot analysis further demonstrates that calcineurin A (catalytic subunit) protein content and association with calmodulin are increased in response to pressure-overload hypertrophy. This increase in calcineurin protein content was prevented by administration of the calcineurin inhibitor cyclosporine A (CsA). CsA administration attenuated load-induced cardiac hypertrophy in a dose-dependent manner over a 14-day treatment protocol. CsA administration also partially reversed pressure-overload hypertrophy in aortic-banded rats after 14 days. CsA also attenuated the histological and molecular indexes of pressure-overload hypertrophy.
Conclusions:
These data suggest that calcineurin is an important upstream regulator of load-induced hypertrophy.
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