Calcineurin expression, activation, and function in cardiac pressure-overload 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.


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.
Lim
H W
HW
Department of Pediatrics, Children's Hospital Medical Center, University of Cincinnati, Ohio, USA.
De Windt
L J
LJ
Steinberg
L
L
Taigen
T
T
Witt
S A
SA
Kimball
T R
TR
Molkentin
J D
JD
D000818:Animals; D019703:Calcineurin / Q000378:metabolism / Q000502:physiology*; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D016572:Cyclosporine / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D006973:Hypertension / Q000150:complications*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin