title: 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.
abstract: BACKGROUND
  The mechanism of cardiac energy production against sustained pressure overload remains to be elucidated.
  
  
  RESULTS
  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 binding (TAC) in α-MHC CaMKKβkd TG mice led to accelerated death and left ventricular (LV) dilatation and dysfunction, which was accompanied by significant clinical signs of heart failure. CaMKKβ downstream signaling molecules, including adenosine monophosphate-activated protein kinase (AMPK), were also suppressed in α-MHC CaMKKβkd TG mice compared with wild-type (WT) mice. The expression levels of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, which is a downstream target of both of CaMKKβ and calcium/calmodulin kinases, were also significantly reduced in α-MHC CaMKKβkd TG mice compared with WT mice after TAC. In accordance with these findings, mitochondrial morphogenesis was damaged and creatine phosphate/β-ATP ratios assessed by magnetic resonance spectroscopy were suppressed in α-MHC CaMKKβkd TG mice compared with WT mice after TAC.
  
  
  CONCLUSIONS
  These data indicate that CaMKKβ exerts protective effects on cardiac adaptive energy pooling against pressure-overload possibly through phosphorylation of AMPK and by upregulation of PGC-1α. Thus, CaMKKβ may be a therapeutic target for the treatment of heart failure.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Horie
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Nagao
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Kuwabara
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Baba
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hitoo
authors.initials: H
authors.lastname: Nishi
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sowa
authors.affiliation: Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Narazaki
authors.affiliation: Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Department of Internal Medicine, Asahi University, Gifu, Japan.
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.affiliation: Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Wada
authors.affiliation: Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Ono
mesh_terms: D000255:Adenosine Triphosphate; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: C584019:Myh6 protein, mouse; D000255:Adenosine Triphosphate; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D018995:Myosin Heavy Chains