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Cardiovascular Research 2002 54(1):117-132; doi:10.1016/S0008-6363(02)00241-9
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Cardiac function and electrical remodeling of the calcineurin-overexpressed transgenic mouse

Natalia N Petrashevskayaa, Ilona Bodia, Marta Rubioa,b, Jeffery D Molkentinc and Arnold Schwartza,*

aInstitute of Molecular Pharmacology and Biophysics, Department of Surgery, Cardiovascular Research Center, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
bDepartment of Pharmacology and Cell Biophysics, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
cDepartment of Pediatrics, Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA

schwara{at}email.uc.edu

* Corresponding author. Tel.: +1-513-558-2400; fax: +1-513-558-1778

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 β-adrenergic mediated contractile response. Methods: The patch-clamp technique was used to characterize electrophysiological properties of action potentials and inward rectifier (IK1), and transient outward potassium currents (Ito). 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 β-adrenergic hypo-responsiveness at 2.0 mM [Ca2+]o. Transgenic cardiomyocytes showed marked action potential prolongation (209% in APD90) with increased Ito,peak and Isus and decreased protein expression level of Kv1.5 and Kv2.1. Lowering [Ca2+]o to 0.75 mM restored the β-adrenergic response, indicating that the calcineurin/calmodulin/adenylyl cyclase (AC) pathway may not be directly responsible for the blunted β-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 β-adrenergic contractile activation.

KEYWORDS Adrenergic (ant)agonists; Contractile function; Hypertrophy; K-channel; Membrane currents


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