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Cardiac-specific inhibition of kinase activity in calcium/calmodulin-dependent protein kinase kinase-? leads to accelerated left ventricular remodeling and heart failure after transverse aortic constriction in mice.

ABSTRACT:

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-? (CaMKK?) transgenic (?-MHC CaMKK?kd TG) mice using ?-myosin heavy chain (?-MHC) promoter. Although CaMKK? activity was significantly reduced, these mice had normal cardiac function and morphology at baseline. Here, we show that transverse aortic binding (TAC) in ?-MHC CaMKK?kd TG mice led to accelerated death and left ventricular (LV) dilatation and dysfunction, which was accompanied by significant clinical signs of heart failure. CaMKK? downstream signaling molecules, including adenosine monophosphate-activated protein kinase (AMPK), were also suppressed in ?-MHC CaMKK?kd TG mice compared with wild-type (WT) mice. The expression levels of peroxisome proliferator-activated receptor-? coactivator (PGC)-1?, which is a downstream target of both of CaMKK? and calcium/calmodulin kinases, were also significantly reduced in ?-MHC CaMKK?kd TG mice compared with WT mice after TAC. In accordance with these findings, mitochondrial morphogenesis was damaged and creatine phosphate/?-ATP ratios assessed by magnetic resonance spectroscopy were suppressed in ?-MHC CaMKK?kd TG mice compared with WT mice after TAC.

Conclusions

These data indicate that CaMKK? exerts protective effects on cardiac adaptive energy pooling against pressure-overload possibly through phosphorylation of AMPK and by upregulation of PGC-1?. Thus, CaMKK? may be a therapeutic target for the treatment of heart failure.

SUBMITTER: Watanabe S

PROVIDER: S-EPMC4177887 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Cardiac-specific inhibition of kinase activity in calcium/calmodulin-dependent protein kinase kinase-β leads to accelerated left ventricular remodeling and heart failure after transverse aortic constriction in mice.

Watanabe Shin S Horie Takahiro T Nagao Kazuya K Kuwabara Yasuhide Y Baba Osamu O Nishi Hitoo H Sowa Naoya N Narazaki Michiko M Matsuda Tetsuya T Takemura Genzou G Wada Hiromichi H Hasegawa Koji K Kimura Takeshi T Ono Koh K

PloS one 20140925 9

<h4>Background</h4>The mechanism of cardiac energy production against sustained pressure overload remains to be elucidated.<h4>Methods and results</h4>We generated cardiac-specific kinase-dead (kd) calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ) transgenic (α-MHC CaMKKβkd TG) mice using α-myosin heavy chain (α-MHC) promoter. Although CaMKKβ activity was significantly reduced, these mice had normal cardiac function and morphology at baseline. Here, we show that transverse aortic bin ...[more]

PMID: 25255457

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