Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy

Cardiac hypertrophy is a major predictor of future morbidity and mortality. Recent investigation has centered around identifying the molecular signali ng pathways that regulate cardiac myocyte reactivity with the goal of modul ating pathologic hypertrophic programs. One potential regulator of cardiomy ocyte hypertrophy is the calcium-sensitive phosphatase calcineurin. We show here that calcineurin enzymatic activity, mRNA, and protein levels are inc reased in cultured neonatal rat cardiomyocytes by hypertrophic agonists suc h as angiotensin II, phenylephrine, and 1% fetal bovine serum. This inducti on of calcineurin activity was associated with an increase in calcineurin A beta (CnA beta) mRNA and protein, but not in CnA alpha or CnA gamma. Agoni st-dependent increases in calcineurin enzymatic activity were specifically inhibited with an adenovirus expressing a noncompetitive peptide inhibitor of calcineurin known as cain [Lai, M. M., Burnett, P. E., Wolosker, H., Bla ckshaw, S, & Snyder, 5. H. ('1998) J. Biol, Chem, 273, 18325-18331]. Target ed inhibition of calcineurin with cain or an adenovirus expressing only the calcineurin inhibitory domain of AKAP79 attenuated cardiomyocyte hypertrop hy and atrial natriuretic factor expression in response to angiotensin II, phenylephrine. and 1% fetal bovine serum. These data demonstrate that calci neurin is an important regulator of cardiomyocyte hypertrophy in response t o certain agonists and suggest that cyclosporin A and FK506 function to att enuate cardiac hypertrophy by specifically inhibiting calcineurin.