Abstract 12639: Ca2+/Calmodulin-Dependent Kinase Kinsae Beta Contributes to Energy Supply in Adaptive Phase of Pressure-Overload-Induced Heart Failure
BACKGROUND: AMP-activated protein kinase (AMPK) plays an important role in regulating myocardial metabolism and protein synthesis. The activation of AMPK involves allosteric regulation by the AMP/ATP ratio as well as phosphorylation by upstream AMPK kinases (AMPKKs), including LKB1 and CaMKKβ. However, it remains unknown whether CaMKKβ is involved in heart failure.
METHODS AND RESULTS: We subjected wild-type (WT) mice to transverse aortic constriction (TAC) for 3 weeks. CaMKKβ mRNA and protein levels were higher in mouse hearts after TAC compared to those after sham operation. To examine the pathophysiological role of CaMKKβ in pressure overload-induced heart failure, we generated cardiac-specific transgenic (TG) mice expressing a kinase-dead form of CaMKKβ. Although TG mice showed no changes in ventricular function and morphology under control conditions, they showed significantly decreased left ventricular fractional shortening (fractional shortening decreased by 25% in wild-type mice compared with a 60% decrease in KO mice) and increased left ventricular dilatation after TAC. Although WT mice exhibited hypertrophy, which is considered to be an adaptive phase against pressure overload, at 3 weeks after TAC, TG mice already showed a dilated cardiomyopathy-like morphology. TG mouse hearts showed the significant inhibition of downstream signaling molecules, such as AMPK, CaMKI, and CREB phosphorylation. TG mice demonstrated decreased PGC-1α mRNA and target genes of PGC-1α expression compared to WT mice after TAC. Furthermore, TG mice had a higher mortality rate than WT mice after TAC (n=15, p<0.001). To assess the energy state in the TAC heart, we measured PCr/β-ATP ratios employing MR spectroscopy. TG mice demonstrated significantly decreased energy pooling compared to WT mice after TAC (% of reduction in PCr/ β -ATP ratios : 28% in WT mice, 45% in TG mice, n=5, p<0.05).
CONCLUSION: These data indicate that CaMKKβ induces cardiac adaptive energy pooling against pressure-overload-induced heart failure, and increasing CaMKKβ activity may have a therapeutic potential in the treatment of heart failure.
- © 2010 by American Heart Association, Inc.