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CLINICAL RESEARCH

Identification of Protein Disulfide Isomerase as a Cardiomyocyte Survival Factor in Ischemic Cardiomyopathy

Anna Severino, PhD^_*, Mara Campioni, BSc, Stefania Straino, BSc, Fadi N. Salloum, PhD, Nina Schmidt, BSc^||, Ulrike Herbrand, BSc^||, Stilla Frede, BSc^||,_**, Gabriele Toietta, PhD, Giuliana Di Rocco, PhD^¶, Rossana Bussani, MD^#, Furio Silvestri, MD^#, Maddalena Piro, MD^_*, Giovanna Liuzzo, MD^_*, Luigi M. Biasucci, MD^_*, Pasquale Mellone, MD, Florinda Feroce, MD, Maurizio Capogrossi, MD, Feliciano Baldi, MD, Joachim Fandrey, PhD^||,_**, Michael Ehrmann, PhD^||, Filippo Crea, MD^_*, Antonio Abbate, MD and Alfonso Baldi, MD^,_*

^_* Institute of Cardiology, Catholic University, Rome, Italy
Istituto Dermopatico dell'Immacolata, Rome, Italy
Department of Biochemistry, Pathology Section, Second University of Naples, Naples, Italy
^¶ Laboratory of Vascular Biology and Gene Therapy, Centro Cardiologico Fondazione Monzino, Milan, Italy
^# Department of Pathology, University of Trieste, Trieste, Italy
VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia
^|| Centre for Medical Biotechnology
^_** Institute of Physiology, University of Duisburg-Essen, Essen, Germany

Manuscript received February 20, 2007; revised manuscript received May 7, 2007, accepted June 4, 2007.

^_* Reprint requests and correspondence: Dr. Alfonso Baldi, Department of Biochemistry, Pathology Section, Second University of Naples, Via L. Armanni 5, 80138 Naples, Italy (Email: alfonsobaldi{at}tiscali.it).

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.

Abbreviations and Acronyms   HF = heart failure   LVD = left ventricular dysfunction   LVEDD = left ventricular end-diastolic diameter   LVESD = left ventricular end-systolic diameter   MI = myocardial infarction   PDI = Protein Disulfide Isomerase   qPCR = quantitative reverse transcriptase polymerase chain reaction

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