title: Retinoic acid signalling is activated in the postischemic heart and may influence remodelling.
abstract: BACKGROUND
  All-trans retinoic acid (atRA), an active derivative of vitamin A, regulates cell differentiation, proliferation and cardiac morphogenesis via transcriptional activation of retinoic acid receptors (RARs) acting on retinoic acid response elements (RARE). We hypothesized that the retinoic acid (RA) signalling pathway is activated in myocardial ischemia and postischemic remodelling.
  
  
  RESULTS
  Myocardial infarction was induced through ligating the left coronary artery in mice. In vivo cardiac activation of the RARs was measured by imaging RARE-luciferase reporter mice, and analysing expression of RAR target genes and proteins by real time RT-PCR and western blot. Endogenous retinoids in postinfarcted hearts were analysed by triple-stage liquid chromatography/tandem mass spectrometry. Cardiomyocytes (CM) and cardiofibroblasts (CF) were isolated from infarcted and sham operated RARE luciferase reporter hearts and monitored for RAR activity and expression of target genes. The effect of atRA on CF proliferation was evaluated by EdU incorporation. Myocardial infarction increased thoracic RAR activity in vivo (p<0.001), which was ascribed to the heart through ex vivo imaging (p = 0.002) with the largest signal 1 week postinfarct. This was accompanied by increased cardiac gene and protein expression of the RAR target genes retinol binding protein 1 (p = 0.01 for RNA, p = 0,006 for protein) and aldehyde dehydrogenase 1A2 (p = 0.04 for RNA, p = 0,014 for protein), while gene expression of cytochrome P450 26B1 was downregulated (p = 0.007). Concomitantly, retinol accumulated in the infarcted zone (p = 0.02). CM and CF isolated from infarcted hearts had higher luminescence than those from sham operated hearts (p = 0.02 and p = 0.008). AtRA inhibited CF proliferation in vitro (p = 0.02).
  
  
  CONCLUSIONS
  The RA signalling pathway is activated in postischemic hearts and may play a role in regulation of damage and repair during remodelling.
authors.affiliation: Department of Physiology, University of Oslo, Oslo, Norway. dusan.bilbija@medisin.uio.no
authors.forename: Dusan
authors.initials: D
authors.lastname: Bilbija
authors.forename: Fred
authors.initials: F
authors.lastname: Haugen
authors.forename: Julia
authors.initials: J
authors.lastname: Sagave
authors.forename: Anton
authors.initials: A
authors.lastname: Baysa
authors.forename: Nasser
authors.initials: N
authors.lastname: Bastani
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
authors.forename: Allan
authors.initials: A
authors.lastname: Sirsjö
authors.forename: Rune
authors.initials: R
authors.lastname: Blomhoff
authors.forename: Guro
authors.initials: G
authors.lastname: Valen
mesh_terms: D000818:Animals; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009150:Mustard Compounds / Q000494:pharmacology; D009203:Myocardial Infarction / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D010666:Phenylpropionates / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: C492908:2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide; D051793:Hypoxia-Inducible Factor 1; D009150:Mustard Compounds; D010666:Phenylpropionates; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014212:Tretinoin