title: Intermedin1-53Protects Against Myocardial Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Inflammation Induced by Homocysteine in Apolipoprotein E-Deficient Mice.
abstract: OBJECTIVE
  Endoplasmic reticulum stress (ERS) and inflammation participate in cardiac fibrosis. Importantly, a novel paracrine/autocrine peptide intermedin1-53(IMD1-53) in the heart inhibits myocardial fibrosis in rats. However, the mechanisms are yet to be fully elucidated.
  
  
  METHODS
  Myocardial fibrosis in apolipoprotein E-deficient (ApoE -/-) mice and neonatal rat cardiac fibroblasts (CFs) were induced using homocysteine (Hcy).
  
  
  RESULTS
  IMD1-53inhibited myocardial fibrosis in vivo and in vitro. Picrosirius red staining showed that IMD1-53reduced myocardial interstitial collagen deposition in ApoE-/- mice treated with Hcy and decreased the expression of myocardial collagen I and III, which was further verified in rat CFs. IMD1-53attenuated myocardial hypertrophy, as shown by cardiomyocyte cross-sectional area, ratio of heart weight to body weight, and mRNA levels of atrial natriuretic peptide and brain natriuretic peptide. IMD1-53inhibited the upregulation of ERS hallmarkers such as glucose-regulated protein 78 (GRP78), GRP94, activating transcription factor 6 (ATF6), ATF4, inositol-requiring enzyme 1α, spliced-X-box-binding protein-1, protein kinase receptor-like ER kinase, and eukaryotic translation initiation factor 2α in mouse myocardium and rat CFs treated with Hcy. In addition, IMD1-53decreased the production of inflammatory factors such as tumor necrosis factor-α, monocyte chemotactic protein-1, interleukin-6 (IL-6), and IL-1β in the mouse myocardium and rat CFs treated with Hcy. Concurrently, IMD1-53ameliorated the expression of nuclear factor-κB, transforming growth factor-β1, and c-Jun N-terminal kinase in the mouse myocardium and rat CFs treated with Hcy.
  
  
  CONCLUSIONS
  IMD potentially protects against myocardial fibrosis induced by Hcy in ApoE-/- mice, possibly via attenuating myocardial ERS and inflammation.
authors.affiliation: Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center.
authors.forename: Jin-Sheng
authors.initials: JS
authors.lastname: Zhang
authors.forename: Yue-Long
authors.initials: YL
authors.lastname: Hou
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Lu
authors.forename: Xian-Qiang
authors.initials: XQ
authors.lastname: Ni
authors.forename: Fan
authors.initials: F
authors.lastname: Lin
authors.forename: Yan-Rong
authors.initials: YR
authors.lastname: Yu
authors.forename: Chao-Shu
authors.initials: CS
authors.lastname: Tang
authors.forename: Yong-Fen
authors.initials: YF
authors.lastname: Qi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004719:Endomyocardial Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006710:Homocysteine / Q000009:adverse effects*; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001057:Apolipoproteins E; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D009479:Neuropeptides; D012333:RNA, Messenger; C514552:intermedin protein, mouse; D006710:Homocysteine