TY - JOUR
T1 - Identification of Protein Disulfide Isomerase as a Cardiomyocyte Survival Factor in Ischemic Cardiomyopathy
AU - Severino, Anna
AU - Campioni, Mara
AU - Straino, Stefania
AU - Salloum, Fadi N.
AU - Schmidt, Nina
AU - Herbrand, Ulrike
AU - Frede, Stilla
AU - Toietta, Gabriele
AU - Di Rocco, Giuliana
AU - Bussani, Rossana
AU - Silvestri, Furio
AU - Piro, Maddalena
AU - Liuzzo, Giovanna
AU - Biasucci, Luigi M.
AU - Mellone, Pasquale
AU - Feroce, Florinda
AU - Capogrossi, Maurizio
AU - Baldi, Feliciano
AU - Fandrey, Joachim
AU - Ehrmann, Michael
AU - Crea, Filippo
AU - Abbate, Antonio
AU - Baldi, Alfonso
N1 - Funding Information:
This work was supported by grants from Second University of Naples, FUTURA-onlus (Rome, Italy), and the Istituto Italiano di Medicina Sociale (IIMS) to Dr. Baldi, and Deutsche Forschungsgemeinschaft grants FA 225/20-2 to Dr. Fandrey and EH 100-11-1 to Dr. Ehrmann.
PY - 2007/9/11
Y1 - 2007/9/11
N2 - Objectives: 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.
AB - Objectives: 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.
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U2 - 10.1016/j.jacc.2007.06.006
DO - 10.1016/j.jacc.2007.06.006
M3 - Article
C2 - 17825711
AN - SCOPUS:34548304089
SN - 0735-1097
VL - 50
SP - 1029
EP - 1037
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 11
ER -