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Cardiac function and electrical remodeling of the calcineurin-overexpressed transgenic mouse
Natalia N Petrashevskaya1, Ilona Bodi, Marta Rubio
1Institute of Molecular Pharmacology and Biophysics, Department of Surgery, Cardiovascular Research Center, University of Cincinnati, 231 Albert Sabin Way, OH 45267, USA.
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.
Insights
Calcineurin overexpression in mice causes a hyperdynamic heart but reduces response to beta-adrenergic stimulation. This suggests a negative feedback loop between calcium handling and heart contractility.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Cardiac Remodeling
Background:
- Calcineurin is a phosphatase involved in cellular signaling.
- Chronic activation of calcineurin in the heart can lead to pathological changes.
- Understanding calcineurin's role in cardiac function is crucial for treating heart disease.
Purpose of the Study:
- To investigate the effects of cardiac-specific calcineurin overexpression on heart contractility and electrical activity.
- To determine if sustained calcineurin activation impairs beta-adrenergic responses.
Main Methods:
- Patch-clamp electrophysiology to assess action potentials and ion currents (I(K1), I(to)).
- Isolated heart perfusion to analyze contractile performance.
- Measurement of ion concentrations ([Ca2+](o)).
Main Results:
- Transgenic mice exhibited a hypercontractile phenotype with significantly reduced beta-adrenergic responsiveness.
- Cardiomyocytes showed prolonged action potentials and altered potassium currents (increased I(to,peak) and I(sus)).
- Restoration of beta-adrenergic response at lower calcium levels suggested the calcineurin/calmodulin/adenylyl cyclase pathway is not solely responsible for blunted inotropism.
Conclusions:
- Calcineurin overexpression induces a hyperdynamic cardiac phenotype with enhanced calcium influx.
- This functional hypertrophic remodeling involves a negative feedback mechanism between calcium handling and beta-adrenergic signaling.