title: Endoplasmic Reticulum Stress is Involved in DFMO Attenuating Isoproterenol-Induced Cardiac Hypertrophy in Rats.
abstract: OBJECTIVE
  Studies performed in experimental animals have shown that polyamines contribute to several physiological and pathological processes, including cardiac hypertrophy. This involves an increase in ornithine decarboxylase (ODC) activity and intracellular polyamines associated with regulation of gene expression. Difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, has attracted considerable interest for its antiproliferative role, which it exerts through inhibition of the polyamine pathway and cell turnover. Whether DFMO attenuates cardiac hypertrophy through endoplasmic reticulum stress (ERS) is unclear.
  
  
  METHODS
  Myocardial hypertrophy was simulated by isoproterenol (ISO). Polyamine depletion was achieved using DFMO. Hypertrophy was estimated using the heart/body index and atrial natriuretic peptide (ANP) gene expression. Cardiac fibrosis and apoptosis were measured by Masson and TUNEL staining. Expression of ODC and spermidine/spermine N1-acetyltransferase (SSAT) were analyzed via real-time PCR and Western blot analysis. Protein expression of ERS and apoptosis factors were analyzed using Western blot analysis.
  
  
  RESULTS
  DFMO treatments significantly attenuated hypertrophy and apoptosis induced by ISO in cardiomyocytes. DFMO down-regulated the expression of ODC, glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), cleaved caspase-12, and Bax and up-regulated the expression of SSAT and Bcl-2. Finally, these changes were partially reversed by the addition of exogenous putrescine.
  
  
  CONCLUSIONS
  The data presented here suggest that polyamine depletion could inhibit cardiac hypertrophy and apoptosis, which is closely related to the ERS pathway.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Jie
authors.initials: J
authors.lastname: Lian
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Jicheng
authors.initials: J
authors.lastname: Liu
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism; D053454:Caspase 12 / Q000378:metabolism; D015536:Down-Regulation; D000518:Eflornithine / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000737:chemistry / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000099228:Diamine N-Acetyltransferase; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000123:Acetyltransferases; D000970:Antineoplastic Agents; D009320:Atrial Natriuretic Factor; D053454:Caspase 12; D000518:Eflornithine; D006360:Heat-Shock Proteins; D007545:Isoproterenol; D009955:Ornithine Decarboxylase; D011073:Polyamines; D051742:Transcription Factor CHOP; D051028:bcl-2-Associated X Protein; D000099228:Diamine N-Acetyltransferase; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP