Abstract 3737: Redundant Roles of CaM Kinase IIδ and γ in Cardiac Hypertrophic Signaling
CaMKIIδ and γ are the major CaMKII isoforms expressed in the heart, and both are upregulated in response to pressure overload. However, their specific roles in cardiac diseases are poorly understood, in particular due to the lack of genetic loss of function models. Very recently, we have demonstrated that CaMKIIδ single knockout mice (δSKO) are protected against cardiac hypertrophy and remodeling, possibly due to a loss of phosphorylation of the transcriptional repressor HDAC4. However, the role of CaMKIIγ and potential redundant functions of CaMKIIγ and δ are still elusive. The aim of the present study was to evaluate the function of CaMKIIδ and γ by generating double knockout mice. Mice with a global deletion of CaMKIIδ and γ died shortly after birth. Therefore, we generated a cardiomyocyte-specific mouse model that lacks CaMKIIδ and γ (DCKO). Strikingly, whereas δ- and γSKO mice displayed only slightly reduced levels of cardiac phospholamban (PLN) phosphorylation at the CaMKII phosphorylation site Thr-17, in DCKO there was almost no residual PLN-Thr-17 phosphorylation detectable. However, under unstressed conditions, DCKO did not show any cardiac abnormalities or dysfunction. Surprisingly, after β-adrenergic stimulation with isoproterenol (Iso, 10 mg/Kg s.c.) or pressure overload induced by transverse aortic constriction (TAC), DCKO mice developed cardiac hypertrophy, which was comparable with wildtype littermates. Likewise, whereas äSKO showed a blunted hypertrophic response after TAC, the additional global deletion of one copy of CaMKIIã resulted in an intermediate hypertrophic response. Microarray analysis revealed the expression of different subsets of cardiac genes after TAC in wildtype and DCKO mice. Moreover, like in äSKO mice, cardiac fibrosis in response to Iso or TAC, was markedly abolished in DCKO. In summary, CaMKIIä and ã play redundant roles with regard to phosphorylation of the cytosolic target PLN, whereas the deletion of only CaMKIIä leads to a loss of phosphorylation of the nuclear target HDAC4. Moreover, DCKO mice develop a distinct type of cardiac hypertrophy. The underlying anti-hypertrophic pathway induced by CaMKII is under current investigation.