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タイトル: | 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 |
著者: | Watanabe, Shin Horie, Takahiro Nagao, Kazuya Kuwabara, Yasuhide Baba, Osamu Nishi, Hitoo Sowa, Naoya Narazaki, Michiko Matsuda, Tetsuya https://orcid.org/0000-0002-2339-1521 (unconfirmed) Takemura, Genzou Wada, Hiromichi Hasegawa, Koji Kimura, Takeshi Ono, Koh |
著者名の別形: | 尾野, 亘 |
発行日: | 25-Sep-2014 |
出版者: | Public Library of Science |
誌名: | PLoS ONE |
巻: | 9 |
号: | 9 |
論文番号: | e108201 |
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. |
著作権等: | © 2014 Watanabe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
URI: | http://hdl.handle.net/2433/191101 |
DOI(出版社版): | 10.1371/journal.pone.0108201 |
PubMed ID: | 25255457 |
出現コレクション: | 学術雑誌掲載論文等 |
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