Partial downregulation of junctin enhances cardiac calcium cycling without eliciting ventricular arrhythmias in mice.

Human failing hearts exhibit significant decreases in junctin expression levels with almost nondetectable levels, which may be associated with premature death, induced by lethal cardiac arrhythmias, based on mouse models. However, the specific contribution of junctin to the delayed afterdepolarizations has been difficult to delineate in the phase of increased Na(+)-Ca(2+) exchanger activity accompanying junctin ablation. Thus we characterized the heterozygous junctin-deficient hearts, which expressed 54% of junctin levels and similar increases in Na(+)-Ca(2+) exchanger activity, as the null model. Cardiac contractile parameters, Ca(2+) transients, and sarcoplasmic reticulum Ca(2+) content were significantly increased in junctin heterozygous hearts, although they did not reach the levels of null hearts. However, Ca(2+) spark properties were not altered in heterozygous cardiomyocytes, compared with wild-types, and there were no aftercontractions elicited by the increased frequency of stimulation in the presence of isoproterenol, unlike the junctin-deficient cells. Furthermore, heterozygous mice did not exhibit an increased susceptibility to arrhythmia upon catecholamine challenge in vivo, and there were no premature deaths up to 1 yr of age. These findings suggest that a partial downregulation of junctin enhances sarcoplasmic reticulum Ca(2+) cycling but does not elicit cardiac arrhythmias even in the context of increased Na(+)-Ca(2+) exchanger activity.

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