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.
The mechanism of cardiac energy production against sustained pressure overload remains to be elucidated.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. Althou...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4177887?pdf=render |
| _version_ | 1811194128454647808 |
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| author | Shin Watanabe Takahiro Horie Kazuya Nagao Yasuhide Kuwabara Osamu Baba Hitoo Nishi Naoya Sowa Michiko Narazaki Tetsuya Matsuda Genzou Takemura Hiromichi Wada Koji Hasegawa Takeshi Kimura Koh Ono |
| author_facet | Shin Watanabe Takahiro Horie Kazuya Nagao Yasuhide Kuwabara Osamu Baba Hitoo Nishi Naoya Sowa Michiko Narazaki Tetsuya Matsuda Genzou Takemura Hiromichi Wada Koji Hasegawa Takeshi Kimura Koh Ono |
| author_sort | Shin Watanabe |
| collection | DOAJ |
| description | The mechanism of cardiac energy production against sustained pressure overload remains to be elucidated.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.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. |
| first_indexed | 2024-04-12T00:20:44Z |
| format | Article |
| id | doaj.art-ecc13d2be7d642a299af22c245b5f04f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T00:20:44Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-ecc13d2be7d642a299af22c245b5f04f2022-12-22T03:55:44ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0199e10820110.1371/journal.pone.0108201Cardiac-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.Shin WatanabeTakahiro HorieKazuya NagaoYasuhide KuwabaraOsamu BabaHitoo NishiNaoya SowaMichiko NarazakiTetsuya MatsudaGenzou TakemuraHiromichi WadaKoji HasegawaTakeshi KimuraKoh OnoThe mechanism of cardiac energy production against sustained pressure overload remains to be elucidated.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.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.http://europepmc.org/articles/PMC4177887?pdf=render |
| spellingShingle | Shin Watanabe Takahiro Horie Kazuya Nagao Yasuhide Kuwabara Osamu Baba Hitoo Nishi Naoya Sowa Michiko Narazaki Tetsuya Matsuda Genzou Takemura Hiromichi Wada Koji Hasegawa Takeshi Kimura Koh Ono 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. PLoS ONE |
| 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | 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 |
| url | http://europepmc.org/articles/PMC4177887?pdf=render |
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