Suppressive Effects of Glucose-Dependent Insulinotropic Polypeptide on Cardiac Hypertrophy and Fibrosis in Angiotensin II-Infused Mouse Models
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- Hiromura Munenori
- Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine
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- Mori Yusaku
- Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine
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- Kohashi Kyoko
- Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine
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- Terasaki Michishige
- Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine
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- Shinmura Kyoko
- Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine
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- Negoro Takaharu
- Department of Pharmacogenomics, Showa University School of Pharmacy
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- Kawashima Hikaru
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences
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- Kogure Mao
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences
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- Wachi Toshimi
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences
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- Watanabe Rena
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences
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- Sato Kengo
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences
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- Kushima Hideki
- Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine
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- Tomoyasu Masako
- Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine
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- Nakano Yasuko
- Department of Pharmacogenomics, Showa University School of Pharmacy
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- Yamada Yuichiro
- Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine
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- Watanabe Takuya
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences
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- Hirano Tsutomu
- Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine
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Abstract
<p>Background:Activation of glucose-dependent insulinotropic polypeptide receptor (GIPR) has been shown to be protective against atherosclerosis. However, effects of GIP on the heart have remained unclear. To address this question, in vitro and in vivo experiments were conducted.</p><p>Methods and Results:In isolated mouse cardiomyocytes, GIPR mRNA was detected by reverse transcription-polymerase chain reaction, and GIP stimulation increased adenosine 3′,5′-cyclic monophosphate production. In apolipoprotein E-knockout mice, infusion of angiotensin II (AngII; 2,000 ng·kg–1·min–1) significantly increased the heart weights, and co-administration of GIP (25 nmol·kg–1·day–1) reversed this increase (both P<0.01). In the left ventricular walls, GIP suppressed AngII-induced cardiomyocyte hypertrophy by 34%, apoptosis by 77%, and interstitial fibrosis by 79% (all P<0.01). Furthermore, GIP reduced AngII-induced expression of transforming growth factor-β1 (TGF-β1) and hypoxia inducible factor-1α. In wild-type mice, cardiac hypertrophy was induced by AngII to a lesser extent, and prevented by GIP. In contrast, GIP did not show any cardioprotective effect against AngII-induced cardiac hypertrophy in GIPR-knockout mice. In an in vitro experiment using mouse cardiomyocytes, GIP suppressed AngII-induced mRNA expression of B-type natriuretic peptide and TGF-β1.</p><p>Conclusions:It was demonstrated that cardiomyocytes represent a direct target of GIP action in vitro, and that GIP ameliorated AngII-induced cardiac hypertrophy via suppression of cardiomyocyte enlargement, apoptosis, and fibrosis in vivo. (Circ J 2016; 80: 1988–1997)</p>
Journal
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- Circulation Journal
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Circulation Journal 80 (9), 1988-1997, 2016
The Japanese Circulation Society