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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
Authors: Watanabe, Shin  kyouindb  KAKEN_id
Horie, Takahiro  kyouindb  KAKEN_id
Nagao, Kazuya
Kuwabara, Yasuhide  kyouindb  KAKEN_id
Baba, Osamu  kyouindb  KAKEN_id
Nishi, Hitoo
Sowa, Naoya
Narazaki, Michiko
Matsuda, Tetsuya  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-2339-1521 (unconfirmed)
Takemura, Genzou
Wada, Hiromichi
Hasegawa, Koji
Kimura, Takeshi  kyouindb  KAKEN_id
Ono, Koh
Author's alias: 尾野, 亘
Issue Date: 25-Sep-2014
Publisher: Public Library of Science
Journal title: PLoS ONE
Volume: 9
Issue: 9
Thesis number: e108201
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-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.
Rights: © 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(Published Version): 10.1371/journal.pone.0108201
PubMed ID: 25255457
Appears in Collections:Journal Articles

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