Cardiac-Specific Inhibition of Kinase Activity in Calcium/ Calmodulin-Dependent Protein Kinase Kinase-b Leads to Accelerated Left Ventricular Remodeling and Heart Failure after Transverse Aortic Constriction in Mice

Background: The mechanism of cardiac energy production against sustained pressure overload remains to be elucidated. Methods and Results: We generated cardiac-specific kinase-dead (kd) calcium/calmodulin-dependent protein kinase kinase-b (CaMKKb) transgenic (a-MHC CaMKKbkd TG) mice using a-myosin heavy chain (a-MHC) promoter. Although CaMKKb activity was significantly reduced, these mice had normal cardiac function and morphology at baseline. Here, we show that transverse aortic binding (TAC) in a-MHC CaMKKbkd TG mice led to accelerated death and left ventricular (LV) dilatation and dysfunction, which was accompanied by significant clinical signs of heart failure. CaMKKb downstream signaling molecules, including adenosine monophosphate-activated protein kinase (AMPK), were also suppressed in a-MHC CaMKKbkd TG mice compared with wild-type (WT) mice. The expression levels of peroxisome proliferator-activated receptor-c coactivator (PGC)-1a, which is a downstream target of both of CaMKKb and calcium/calmodulin kinases, were also significantly reduced in a-MHC CaMKKbkd TG mice compared with WT mice after TAC. In accordance with these findings, mitochondrial morphogenesis was damaged and creatine phosphate/b-ATP ratios assessed by magnetic resonance spectroscopy were suppressed in a-MHC CaMKKbkd TG mice compared with WT mice after TAC. Conclusions: These data indicate that CaMKKb exerts protective effects on cardiac adaptive energy pooling against pressure-overload possibly through phosphorylation of AMPK and by upregulation of PGC-1a. Thus, CaMKKb may be