P534The anti-arrhythmic effect of CaMKII inhibition in calcineurin overexpressing hearts is independent of Cx43, Cx40, Nav1.5, and fibrosis remodeling

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Abstract

Introduction

Transgenic mice overexpressing a continuously active form of calcineurin in the heart (MHC-CnA) displayed conduction abnormalities and increased arrhythmia vulnerability relative to wildtype (WT). These impaired electrical properties were correlated with increased fibrosis and reduced protein levels for Nav1.5, Cx43 and Cx40, parameters frequently associated with the development of arrhythmias. Interestingly, CaMKII activity was reported to be increased in MHC-CnA hearts. Interbreeding of MHC-CnA mice with transgenic mice overexpressing a specific CaMKII inhibitor in the heart (MHC-CnA x AC3-I) normalized CaMKII activity and decreased arrhythmia susceptibility relative to the appropriate control (MHC-CnA x AC3-C). Since the molecular basis for the reduced arrhythmia susceptibility of MHC-CnA x AC3-I hearts is not known, we investigated Nav1.5, Cx43, and Cx40 expression at both the protein and RNA level by immunoblotting and quantitative-PCR, respectively, in all four mouse strains (n = 4 for each strain). Moreover, the level of fibrosis was determined by Sirius Red staining (n = 3 for each strain).

Results

All results (relative to WT) are schematically summarized in Table 1.

Results

In MHC-CnA, for Nav1.5 and Cx40 both protein and RNA levels were significantly reduced, whereas for Cx43 the protein, but not RNA, level was decreased. The amount of ventricular fibrosis proved to be increased relative to WT. Results comparable to MHC-CnA were found in MHC-CnA x AC3-C and MHC-CnA x AC3-I, i.e. CaMKII inhibition did not normalize the calcineurin-mediated Nav1.5, Cx43, Cx40 and fibrosis remodeling. These results suggest that, in this model, the anti-arrhythmic effect of CaMKII inhibition is not caused by improvement of impaired conduction.

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