title: A new anti-fibrotic drug attenuates cardiac remodeling and systolic dysfunction following experimental myocardial infarction.
abstract: BACKGROUND
  Pathological deposition of extracellular matrix in the non-infarct zone (NIZ) of the ventricle post myocardial infarction (MI) is a key contributor to cardiac remodeling and heart failure. FT011, a novel antifibrotic compound, was evaluated for its efficacy in neonatal cardiac fibroblasts (NCF) and in an experimental MI model.
  
  
  RESULTS
  Collagen synthesis in NCF was determined by (3)H-proline incorporation following stimulation with TGF-β or angiotensin II (Ang II). FT011 inhibited collagen synthesis to both agents in a dose dependent manner. In vivo, Sprague Dawley rats underwent left anterior descending coronary artery ligation or sham surgery and were randomized one week later to receive either FT011 (200mg/kg/day) or vehicle for a further 4 weeks. Echocardiography and cardiac catheterization were performed, and tissues were collected for histological analysis of collagen, myocyte hypertrophy, interstitial macrophage accumulation and Smad2 phosphorylation. mRNA expression of collagens I and III and TGF-β was measured using in situ hybridization and RT-PCR, respectively. FT011 treatment was associated with improved cardiac function (increased ejection fraction, fraction shortening and preload recruitable stroke work) and myocardial remodeling (reduced left ventricular diameter and volume at both end diastolic and systolic) compared with vehicle treatment. FT011 significantly reduced collagen matrix deposition, myocyte hypertrophy and interstitial macrophage infiltration, and mRNA expression of collagens I and III in NIZ compared with vehicle treatment.
  
  
  CONCLUSIONS
  Anti-fibrotic therapy with FT011 in MI rats attenuated fibrosis and preserved systolic function.
authors.affiliation: Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Australia.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Maros
authors.initials: M
authors.lastname: Elsik
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Edgley
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Cox
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Kompa
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Christina Yan Ru
authors.initials: CY
authors.lastname: Tan
authors.forename: Fay L
authors.initials: FL
authors.lastname: Khong
authors.forename: David I
authors.initials: DI
authors.lastname: Stapleton
authors.forename: Steven
authors.initials: S
authors.lastname: Zammit
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000933:Antifibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D002109:Caffeic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D003094:Collagen / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology; D062367:ortho-Aminobenzoates / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000933:Antifibrinolytic Agents; D002109:Caffeic Acids; C576235:FT011; D062367:ortho-Aminobenzoates; D003094:Collagen