title: Suppressive Effects of Glucose-Dependent Insulinotropic Polypeptide on Cardiac Hypertrophy and Fibrosis in Angiotensin II-Infused Mouse Models.
abstract: 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.
  
  
  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.
  
  
  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).
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine.
authors.forename: Munenori
authors.initials: M
authors.lastname: Hiromura
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Mori
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kohashi
authors.forename: Michishige
authors.initials: M
authors.lastname: Terasaki
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinmura
authors.forename: Takaharu
authors.initials: T
authors.lastname: Negoro
authors.forename: Hikaru
authors.initials: H
authors.lastname: Kawashima
authors.forename: Mao
authors.initials: M
authors.lastname: Kogure
authors.forename: Toshimi
authors.initials: T
authors.lastname: Wachi
authors.forename: Rena
authors.initials: R
authors.lastname: Watanabe
authors.forename: Kengo
authors.initials: K
authors.lastname: Sato
authors.forename: Hideki
authors.initials: H
authors.lastname: Kushima
authors.forename: Masako
authors.initials: M
authors.lastname: Tomoyasu
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Nakano
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirano
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D002460:Cell Line; D005355:Fibrosis; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D005749:Gastric Inhibitory Polypeptide