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

• Horie, Takahiro

• Nagao, Kazuya

• Kuwabara, Yasuhide

• Baba, Osamu

• Nishi, Hitoo

• Sowa, Naoya

• Narazaki, Michiko

• Matsuda, Tetsuya

• Takemura, Genzou

• Wada, Hiromichi

• Hasegawa, Koji

• Kimura, Takeshi

• 尾野, 亘

• Vincenzo Lionetti

  editor

抄録

[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-β (CaMKKβ) transgenic (α-MHC CaMKKβ[kd] 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 CaMKKβ[kd] 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 CaMKKβ[kd] 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 CaMKKβ[kd] 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 CaMKKβ[kd] 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.

収録刊行物

• PLoS ONE

  PLoS ONE 9 (9), e108201-, 2014-09-25

  Public Library of Science

キーワード

• Multidisciplinary

詳細情報

• CRID: 1050282810773708800
• NII論文ID: 120005496630
• ISSN: 19326203
• DOI: 10.1371/journal.pone.0108201
• HANDLE: 2433/191101
• Web Site: http://dx.plos.org/10.1371/journal.pone.0108201
• 本文言語コード: en
• 資料種別: journal article
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