(Circulation. 2000;101:2431.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Calcineurin Expression, Activation, and Function in Cardiac Pressure-Overload Hypertrophy
From the Department of Pediatrics, Children’s Hospital Medical Center, University of Cincinnati (Ohio).
Correspondence to Jeffery D. Molkentin, Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail molkj0{at}chmcc.org
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.
Key Words: aorta • hypertrophy • pressure
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