title: Identification of protein disulfide isomerase as a cardiomyocyte survival factor in ischemic cardiomyopathy.
abstract: OBJECTIVE
  The aim of the study was to analyze the molecular mechanisms activated during postinfarction remodeling in human hearts.
  
  
  BACKGROUND
  The molecular mechanisms of initial response to ischemic insult in the heart and the pathways involved in compensation and remodeling are still largely unknown.
  
  
  METHODS
  Up-regulation or down-regulation of gene expression in the human viable peri-infarct (vs. remote) myocardial region was investigated by complementary deoxyribonucleic acid array technology and confirmed at a single-gene/protein level with reverse transcriptase polymerase chain reaction and immunohistochemistry. An in vitro model of cardiomyocyte hypoxia in HL1 cells was used to validate anti-apoptotic effects of the candidate gene/protein and to assess the associated downstream cascade. Finally, a mouse model of myocardial infarction was used to test the in vivo effects of exogenous transfection with the candidate gene/protein.
  
  
  RESULTS
  Protein disulfide isomerase (PDI), a member of the unfolded protein response, is 3-fold up-regulated in the viable peri-infarct myocardial region, and in a postmortem model, its expression is significantly inversely correlated with apoptotic rate and with presence of heart failure (HF) and biventricular dilatation. Induced PDI expression in HL1 cells conferred protection from hypoxia-induced apoptosis. Adenoviral-mediated PDI gene transfer to the mouse heart resulted in 2.5-fold smaller infarct size, significantly reduced cardiomyocyte apoptosis in the peri-infarct region, and smaller left ventricular end-diastolic diameter versus mice treated with a transgene-null adenoviral vector.
  
  
  CONCLUSIONS
  These results suggest that PDI promotes survival after ischemic damage and that zinc-superoxide dismutase is one of the PDI molecular targets. Pharmacological modulation of this pathway might prove useful for future prevention and treatment of HF.
authors.affiliation: Institute of Cardiology, Catholic University, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Severino
authors.forename: Mara
authors.initials: M
authors.lastname: Campioni
authors.forename: Stefania
authors.initials: S
authors.lastname: Straino
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.forename: Nina
authors.initials: N
authors.lastname: Schmidt
authors.forename: Ulrike
authors.initials: U
authors.lastname: Herbrand
authors.forename: Stilla
authors.initials: S
authors.lastname: Frede
authors.forename: Gabriele
authors.initials: G
authors.lastname: Toietta
authors.forename: Giuliana
authors.initials: G
authors.lastname: Di Rocco
authors.forename: Rossana
authors.initials: R
authors.lastname: Bussani
authors.forename: Furio
authors.initials: F
authors.lastname: Silvestri
authors.forename: Maddalena
authors.initials: M
authors.lastname: Piro
authors.forename: Giovanna
authors.initials: G
authors.lastname: Liuzzo
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Biasucci
authors.forename: Pasquale
authors.initials: P
authors.lastname: Mellone
authors.forename: Florinda
authors.initials: F
authors.lastname: Feroce
authors.forename: Maurizio
authors.initials: M
authors.lastname: Capogrossi
authors.forename: Feliciano
authors.initials: F
authors.lastname: Baldi
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
authors.forename: Filippo
authors.initials: F
authors.lastname: Crea
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.forename: Alfonso
authors.initials: A
authors.lastname: Baldi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018929:Cell Culture Techniques; D015687:Cell Hypoxia / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology