Chronic Elevation of Calmodulin in the Ventricles of Transgenic Mice Increases the Autonomous Activity of Calmodulin-Dependent Protein Kinase II, Which Regulates Atrial Natriuretic Factor Gene Expression

Abstract

Although isoforms of Ca2+/calmodulin-dependent protein kinase II (CaMKII) have been implicated in the regulation of gene expression in cultured cells, this issue has yet to be addressed in vivo. We report that the overexpression of calmodulin in ventricular myocytes of transgenic mice results in an increase in the Ca2+/calmodulin-independent activity of endogenous CaMKII. The calmodulin transgene is regulated by a 500-bp fragment of the atrial natriuretic factor (ANF) gene promoter which, based on cell transfection studies, is itself known to be regulated by CaMKII. The increased autonomous activity of CaMKII maintains the activity of the transgene and establishes a positive feed-forward loop, which also extends the temporal expression of the endogenous ANF promoter in ventricular myocytes. Both the increased activity of CaMKII and transcriptional activation of ANF are highly selective responses to the chronic overexpression of calmodulin. These results indicate that CaMKII can regulate gene expression in vivo and suggest that this enzyme may represent the Ca2+-dependent target responsible for reactivation of the ANF gene during ventricular hypertrophy.

CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy

“…Inhibition of CaMKII in mice by overexpression of a CaMKII inhibitory peptide in the heart blocks adverse myocardial remodeling in response to b-adrenergic stimulation and myocardial infarction, providing strong evidence that CaMKII is required for a pathological hypertrophic response (38). CaMKII has also been implicated in endothelin-1-induced cardiomyocyte hypertrophy and in ANP gene expression during hypertrophy (39)(40)(41). Moreover, forced overexpression of calmodulin or CaMKII in the heart is sufficient to induce cardiac hypertrophy (40,(42)(43)(44).…”

“…There is increasing evidence for the involvement of CaMKII in pathological cardiac hypertrophy (30,(36)(37)(38)(39)(40)(41)(42)(43)(44). Inhibition of CaMKII in mice by overexpression of a CaMKII inhibitory peptide in the heart blocks adverse myocardial remodeling in response to b-adrenergic stimulation and myocardial infarction, providing strong evidence that CaMKII is required for a pathological hypertrophic response (38).…”

“…CaMKII has also been implicated in endothelin-1-induced cardiomyocyte hypertrophy and in ANP gene expression during hypertrophy (39)(40)(41). Moreover, forced overexpression of calmodulin or CaMKII in the heart is sufficient to induce cardiac hypertrophy (40,(42)(43)(44). However, the downstream mechanisms and targets of CaMKII signaling that lead to changes in cardiac gene regulation have remained elusive.…”

CaMKIIδ Isoforms Differentially Affect Calcium Handling but Similarly Regulate HDAC/MEF2 Transcriptional Responses

“…Several transgenic (TG) mouse models have now confirmed a role for CaMK in activation of the hypertrophic gene program and development of hypertrophy in vivo. Transgenic mice overexpressing calmodulin were found to develop severe cardiac hypertrophy (19) which was subsequently shown to be associated with an increase in the activity of CaMKII in vivo (20). Pronounced hypertrophy also develops in transgenic mice that overexpress CaMKIV (18) although CaMKIV is not a major CaMK isoform in the heart nor is it required for pressure overload induced hypertrophy (1,21,22).…”

Cardiomyocyte Calcium and Calcium/Calmodulin-dependent Protein Kinase II: Friends or Foes?

“…Transgenic mice overexpressing calmodulin were generated nearly 10 years ago and shown to develop severe cardiac hypertrophy (Gruver et al, 1993). This subsequently was demonstrated to be associated with an increase in the autonomous activity of CaMKII in vivo (Colomer and Means, 2000). Pronounced hypertrophy also develops in transgenic mice that overexpress CaMKIV (Passier et al, 2000).…”