title: Therapeutic impact of follistatin-like 1 on myocardial ischemic injury in preclinical models.
abstract: BACKGROUND
  Acute coronary syndrome is a leading cause of death in developed countries. Follistatin-like 1 (FSTL1) is a myocyte-derived secreted protein that is upregulated in the heart in response to ischemic insult. Here, we investigated the therapeutic impact of FSTL1 on acute cardiac injury in small and large preclinical animal models of ischemia/reperfusion and dissected its molecular mechanism.
  
  
  RESULTS
  Administration of human FSTL1 protein significantly attenuated myocardial infarct size in a mouse or pig model of ischemia/reperfusion, which was associated with a reduction of apoptosis and inflammatory responses in the ischemic heart. Administration of FSTL1 enhanced the phosphorylation of AMP-activated protein kinase in the ischemia/reperfusion-injured heart. In cultured cardiac myocytes, FSTL1 suppressed apoptosis in response to hypoxia/reoxygenation and lipopolysaccharide-stimulated expression of proinflammatory genes through its ability to activate AMP-activated protein kinase. Ischemia/reperfusion led to enhancement of bone morphogenetic protein-4 expression and Smad1/5/8 phosphorylation in the heart, and FSTL1 suppressed the increased phosphorylation of Smad1/5/8 in ischemic myocardium. Treating cardiac myocytes with FSTL1 abolished the bone morphogenetic protein-4-stimulated increase in apoptosis, Smad1/5/8 phosphorylation, and proinflammatory gene expression. In cultured macrophages, FSTL1 diminished lipopolysaccharide-stimulated expression of proinflammatory genes via activation of AMP-activated protein kinase and abolished bone morphogenetic protein-4-dependent induction of proinflammatory mediators.
  
  
  CONCLUSIONS
  Our data indicate that FSTL1 can prevent myocardial ischemia/reperfusion injury by inhibiting apoptosis and inflammatory response through modulation of AMP-activated protein kinase- and bone morphogenetic protein-4-dependent mechanisms, suggesting that FSTL1 could represent a novel therapeutic target for post-myocardial infarction, acute coronary syndrome.
authors.affiliation: Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumaicho, Showa-ku, Nagoya, 466-8550, Japan. nouchi@med.nagoya-u.ac.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ogura
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.forename: Koji
authors.initials: K
authors.lastname: Ohashi
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kataoka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kambara
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Kito
authors.forename: Sonomi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yuasa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Matsuo
authors.forename: Takashi
authors.initials: T
authors.lastname: Enomoto
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Uemura
authors.forename: Megumi
authors.initials: M
authors.lastname: Miyabe
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ishii
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D038702:Follistatin-Related Proteins / Q000008:administration & dosage* / Q000096:biosynthesis / Q000502:physiology; D006801:Humans; D007262:Infusions, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013552:Swine; D016896:Treatment Outcome
chemical_list: D038702:Follistatin-Related Proteins; C448799:FSTL1 protein, human