Cardiac function and electrical remodeling of the calcineurin-overexpressed transgenic mouse.
OBJECTIVE
To study the specificity of contractile phenotype and electrophysiological remodeling in transgenic (Tg) mice with cardiac directed calcineurin (phosphatase 2B) overexpression and evaluate a possible negative role of chronically activated calcineurin in beta-adrenergic mediated contractile response.


METHODS
The patch-clamp technique was used to characterize electrophysiological properties of action potentials and inward rectifier (I(K1)), and transient outward potassium currents (I(to)). The analysis of the contractile performance was carried out on isolated retrograde perfused hearts at constant aortic pressure.


RESULTS
Tg mice demonstrated a hypercontractile phenotype characterized by a profound beta-adrenergic hypo-responsiveness at 2.0 mM [Ca2+](o). Transgenic cardiomyocytes showed marked action potential prolongation (209% in APD(90)) with increased I(to,peak) and I(sus) and decreased protein expression level of Kv1.5 and Kv2.1. Lowering [Ca2+](o) to 0.75 mM restored the beta-adrenergic response, indicating that the calcineurin/calmodulin/adenylyl cyclase (AC) pathway may not be directly responsible for the blunted beta-adrenoreceptor mediated inotropism.


CONCLUSIONS
Calcineurin overexpression leads to development of a hyperdynamic phenotype with a cellular profile of increased calcium influx. This type of functional hypertrophic remodeling is accompanied by a negative feedback regulation between increased calcium handling and beta-adrenergic contractile activation.
Petrashevskaya
Natalia N
NN
Institute of Molecular Pharmacology and Biophysics, Department of Surgery, Cardiovascular Research Center, University of Cincinnati, 231 Albert Sabin Way, OH 45267, USA.
Bodi
Ilona
I
Rubio
Marta
M
Molkentin
Jeffery D
JD
Schwartz
Arnold
A
D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000235:genetics*; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D018408:Patch-Clamp Techniques; D010477:Perfusion; D015221:Potassium Channels / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D015221:Potassium Channels; D019703:Calcineurin; D007545:Isoproterenol