Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

The Ca2+-calmodulin-activated Ser/Thr protein phosphatase calcineurin and t he downstream transcriptional effecters of calcineurin, nuclear factor of a ctivated T cells, have been implicated in the hypertrophic response of the myocardium. Recently, the calcineurin inhibitory agents cyclosporine A and FK506 have been extensively used to evaluate the importance of this signali ng pathway in rodent models of cardiac hypertrophy. However, pharmacologic approaches have rendered equivocal results necessitating more specific or g enetic-based inhibitory strategies. In this regard, we have generated Tg mi ce expressing the calcineurin inhibitory domains of Cain/Cabin-1 and A-kina se anchoring protein 79 specifically in the heart. Delta Cain and DeltaA-ki nase-anchoring protein Tg mice demonstrated reduced cardiac calcineurin act ivity and reduced hypertrophy in response to catecholamine infusion or pres sure overload. In a second approach, adenoviral-mediated gene transfer of D elta Cain was performed in the adult rat myocardium to evaluate the effecti veness of an acute intervention and any potential species dependency. Delta Cain adenoviral gene transfer inhibited cardiac calcineurin activity and r educed hypertrophy in response to pressure overload without reducing aortic pressure. These results provide genetic evidence implicating calcineurin a s an important mediator of the cardiac hypertrophic response in vivo.