title: Myeloid cell-derived LRG attenuates adverse cardiac remodelling after myocardial infarction.
abstract: OBJECTIVE
  Leucine-rich α2-glycoprotein (LRG) is considered as a biomarker of the clinical activities of chronic inflammatory diseases, including heart failure. However, its pathophysiological roles in cardiac remodelling after myocardial infarction (MI) remain to be clarified. In this study, we have addressed functional roles of LRG in cardiac remodelling after MI.
  
  
  RESULTS
  MI was generated by ligating the left coronary artery in mice. Real-time reverse transcription (RT)-PCR and immunoblot analyses revealed that the expressions of LRG transcript and protein were up-regulated in post-infarct myocardium. LRG protein was produced by heart-infiltrating myeloid cells, such as macrophages and neutrophils. To elucidate functional roles of LRG in cardiac remodelling, we generated MI in wild-type (WT) and LRG-deficient (LRG(-/-)) mice and found that LRG gene ablation aggravated myocardial fibrosis with cardiac dysfunction after MI. Immunohistochemical analyses with anti-CD31 antibody revealed that capillary density decreased at border zone in LRG(-/-) mice compared with WT mice. Consistently, the expression of apelin receptor was reduced in LRG(-/-) mice, implying that the impaired angiogenic activity is associated with adverse cardiac remodelling in LRG(-/-) mice. Moreover, LRG gene ablation suppressed the activation of smad1/5/8, a pro-angiogenic signalling pathway. Finally, the transplantation of WT bone marrow cells into LRG(-/-) mice attenuated cardiac fibrosis with functional improvement after MI, accompanied by restoration of capillary density compared with the bone marrow transplantation from LRG(-/-) mice.
  
  
  CONCLUSIONS
  LRG, produced by heart-infiltrating myeloid cells, suppresses adverse cardiac remodelling after MI as a novel cardioprotective factor. LRG signalling could be a therapeutic target against cardiovascular diseases.
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmacological Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Kumagai
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmacological Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Laboratory of Immune Signals, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Laboratory of Immune Signals, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Honda
authors.affiliation: Laboratory of Immune Signals, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.affiliation: Department of Pathology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ishibashi-Ueda
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasai
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmacological Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Obana
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmacological Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, Japan tnaka@nibio.go.jp fujio@phs.osaka-u.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.affiliation: Laboratory of Immune Signals, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, Japan tnaka@nibio.go.jp fujio@phs.osaka-u.ac.jp.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics*; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000473:pathology; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D006023:Glycoproteins; C530631:LRG1 protein, mouse
keywords: Angiogenesis; Cardiac remodelling; LRG; Myeloid cells; Myocardial infarction