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

Background-Vascular hypertension resulting in increased cardiac load is ass ociated with left ventricular hypertrophy and is a leading predicator for p rogressive 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 increa sed 3.2-fold in the heart in response to pressure-overload hypertrophy indu ced by abdominal aortic banding in the rat. Western blot analysis further d emonstrates that calcineurin A (catalytic subunit) protein content and asso ciation with calmodulin are increased in response to pressure-overload hype rtrophy. This increase in calcineurin protein content was prevented by admi nistration of the calcineurin inhibitor cyclosporine A (CsA), CsA administr ation attenuated load-induced cardiac hypertrophy in a dose-dependent manne r over a 14-day treatment protocol. CsA administration also partially rever sed 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 re gulator of load-induced hypertrophy.