An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart
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- Wang Qi
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
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- Oka Toru
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Onco-Cardiology Unit, Department of Cardiology, Osaka Medical Center for Cancer and Cardiovascular Diseases AMED-CREST, Japan Agency for Medical Research and Development
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- Yamagami Kiyoshi
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
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- Lee Jong-Kook
- Department of Cardiovascular Regenerative Medicine, Osaka University Graduate School of Medicine AMED-CREST, Japan Agency for Medical Research and Development
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- Akazawa Hiroshi
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo AMED-CREST, Japan Agency for Medical Research and Development
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- Naito Atsuhiko T.
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo AMED-CREST, Japan Agency for Medical Research and Development
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- Yasui Taku
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
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- Ishizu Takamaru
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
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- Nakaoka Yoshikazu
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Department of Vascular Physiology, Research Institute, National Cerebral and Cardiovascular Center JST-PRESTO, Japan Science Technology Agency
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- Sakata Yasushi
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
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- Komuro Issei
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo AMED-CREST, Japan Agency for Medical Research and Development
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抄録
<p>Cardiac fibrosis is a pathological feature of myocardium of failing heart and plays causative roles in arrhythmia and cardiac dysfunction, but its regulatory mechanisms remain largely elusive. In this study, we investigated the effects of the novel EP4 receptor agonist ONO-0260164 on cardiac fibrosis in hypertrophied heart and explored the regulatory mechanisms in cardiac fibroblasts.</p><p>In a mouse model of cardiac hypertrophy generated by transverse aortic constriction (TAC), ONO-0260164 treatment significantly prevented systolic dysfunction and progression of myocardial fibrosis at 5 weeks after TAC. In cultured neonatal rat cardiac fibroblasts, transforming growth factor-β1 (TGF-β1) induced upregulation of collagen type 1, alpha 1 (Col1a1) and type 3, alpha 1 (Col3a1), which was inhibited by ONO-0260164 treatment. ONO-0260164 activated protein kinase A (PKA) in the presence of TGF-β1 in the cardiac fibroblasts. PKA activation suppressed an increase in collagen expression induced by TGF-β1, indicating the important inhibitory roles of PKA activation in TGF-β1mediated collagen induction.</p><p>We have demonstrated for the first time the antifibrotic effects of the novel EP4 agonist ONO-0260164 in vivo and in vitro, and the important role of PKA activation in the effects.</p>
収録刊行物
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- International Heart Journal
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International Heart Journal 58 (1), 107-114, 2017
一般社団法人 インターナショナル・ハート・ジャーナル刊行会