Targeted inhibition of calcineurin with cain or AKAP79 significantly attenuated cardiomyocyte hypertrophy and atrial natriuretic factor expression in response to hypertrophic agonists.
Does targeted inhibition of calcineurin prevent agonist-induced cardiomyocyte hypertrophy in cultured neonatal rat cardiomyocytes?
Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy in vitro, suggesting a mechanism by which cyclosporin A and FK506 may attenuate cardiac hypertrophy.
p-value: p=<0.0001
Cardiac hypertrophy is a major predictor of future morbidity and mortality. Recent investigation has centered around identifying the molecular signaling pathways that regulate cardiac myocyte reactivity with the goal of modulating pathologic hypertrophic programs. One potential regulator of cardiomyocyte hypertrophy is the calcium-sensitive phosphatase calcineurin. We show here that calcineurin enzymatic activity, mRNA, and protein levels are increased in cultured neonatal rat cardiomyocytes by hypertrophic agonists such as angiotensin II, phenylephrine, and 1% fetal bovine serum. This induction of calcineurin activity was associated with an increase in calcineurin Abeta (CnAbeta) mRNA and protein, but not in CnAalpha or CnAgamma. Agonist-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., Blackshaw, S. & Snyder, S. H. (1998) J. Biol. Chem. 273, 18325-18331. Targeted inhibition of calcineurin with cain or an adenovirus expressing only the calcineurin inhibitory domain of AKAP79 attenuated cardiomyocyte hypertrophy and atrial natriuretic factor expression in response to angiotensin II, phenylephrine, and 1% fetal bovine serum. These data demonstrate that calcineurin is an important regulator of cardiomyocyte hypertrophy in response to certain agonists and suggest that cyclosporin A and FK506 function to attenuate cardiac hypertrophy by specifically inhibiting calcineurin.
Taigen et al. (Tue,) conducted a other in Cardiomyocyte hypertrophy. Adcain (adenovirus expressing cain peptide) or AdAKAP vs. Adbgal (control adenovirus) or uninfected was evaluated on Calcineurin phosphatase activity and cardiomyocyte cell surface area (p=<0.0001). Targeted inhibition of calcineurin with cain or AKAP79 significantly attenuated cardiomyocyte hypertrophy and atrial natriuretic factor expression in response to hypertrophic agonists.