title: FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism.
abstract: Ischemic heart disease is one of the leading causes of death. Fibroblast growth factor 21 (FGF21) is a circulating factor with an anti-diabetic property. Skeletal muscle is an important source of FGF21 production. Here, we investigated whether skeletal muscle-derived FGF21 modulates cardiac remodeling in a murine model of myocardial infarction. Myocardial infarction was produced in C57BL/6J wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery (LAD). Adenoviral vectors expressing FGF21 (Ad-FGF21) or control β-galactosidase were intramuscularly injected into mice at 3 days before permanent LAD ligation. Intramuscular injection of Ad-FGF21 increased plasma FGF21 levels in WT mice compared with control. Treatment of WT mice with Ad-FGF21 led to improvement of left ventricular systolic dysfunction and dilatation at 2 weeks after LAD ligation. Ad-FGF21 administration to WT mice also led to enhancement of capillary density in the infarct border zone, and reduction of myocyte apoptosis in the remote zone, which were accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, treatment of WT mice with Ad-FGF21 increased plasma levels of adiponectin, which is a cardioprotective adipokine. The beneficial effects of Ad-FGF21 on cardiac dysfunction and inflammatory response after myocardial infarction were diminished in adiponectin-knockout mice. These data suggest that muscle-derived FGF21 ameliorates adverse cardiac remodeling after myocardial infarction, at least in part, through an adiponectin-dependent mechanism.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Joki
authors.affiliation: Molecular Cardiovascular Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: ohashik@med.nagoya-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yuasa
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kambara
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Uemura
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Hayakawa
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Hiramatsu-Ito
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Kanemura
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Daida
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Molecular Cardiovascular Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: nouchi@med.nagoya-u.ac.jp.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
mesh_terms: D052242:Adiponectin / Q000097:blood / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002196:Capillaries / Q000502:physiology; D003331:Coronary Vessels / Q000601:surgery; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000008:administration & dosage* / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D007273:Injections, Intramuscular; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000473:pathology; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000503:physiopathology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D016207:Cytokines; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D001616:beta-Galactosidase
keywords: Adiponectin; Cardiac remodeling; FGF21; Myocardial infarction; Myokine