Identification of protein disulfide isomerase as a cardiomyocyte survival factor in ischemic cardiomyopathy.
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.
Severino
Anna
A
Institute of Cardiology, Catholic University, Rome, Italy.
Campioni
Mara
M
Straino
Stefania
S
Salloum
Fadi N
FN
Schmidt
Nina
N
Herbrand
Ulrike
U
Frede
Stilla
S
Toietta
Gabriele
G
Di Rocco
Giuliana
G
Bussani
Rossana
R
Silvestri
Furio
F
Piro
Maddalena
M
Liuzzo
Giovanna
G
Biasucci
Luigi M
LM
Mellone
Pasquale
P
Feroce
Florinda
F
Capogrossi
Maurizio
M
Baldi
Feliciano
F
Fandrey
Joachim
J
Ehrmann
Michael
M
Crea
Filippo
F
Abbate
Antonio
A
Baldi
Alfonso
A
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