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Molecular Medicine

, Volume 17, Issue 9–10, pp 1012–1021 | Cite as

Altered Oxido-Reductive State in the Diabetic Heart: Loss of Cardioprotection due to Protein Disulfide Isomerase

  • Stefano Toldo
  • Mariarosaria Boccellino
  • Barbara Rinaldi
  • Ignacio M. Seropian
  • Eleonora Mezzaroma
  • Anna Severino
  • Lucio Quagliuolo
  • Benjamin W. Van Tassell
  • Raffaele Marfella
  • Giuseppe Paolisso
  • Francesco Rossi
  • Ramesh Natarajan
  • Norbert Voelkel
  • Antonio Abbate
  • Filippo Crea
  • Alfonso Baldi
Research Article

Abstract

Diabetes is associated with an increased risk of heart failure, in part explained by endoplasmic reticulum stress and apoptosis. Protein disulfide isomerase (PDI) prevents stressed cardiomyocytes apoptosis. We hypothesized that diabetes impairs PDI function by an alteration in its oxido-reductive state. Myocardial biopsies harvested from the anterolateral left ventricular wall from diabetic (n = 7) and nondiabetic (n = 8) patients were used to assess PDI expression and cardiomyocyte death. A mouse model of diabetes (streptozotocin injection, 130 mg/mL) was used to study PDI expression and its redox state after ischemia/reperfusion injury induced by 30-min occlusion of the left anterior coronary artery followed by reperfusion. Transthoracic echocardiography was performed to assess cardiac remodeling after 1 wk. Western blot analysis was used to analyze PDI expression, and methoxypolyethyleneglycol-maleimide was used to assess its redox state. Dehydroascorbate (DHA) administration was used to restore the PDI redox state. Diabetic patients had a greater number of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells than nondiabetic patients despite a greater myocardial PDI expression suggesting altered PDI function. Diabetic mice had a worse postinfarction remodeling associated with an altered PDI redox state. DHA treatment restored functional PDI redox state and ameliorated post-myocardial infarction remodeling. An increase in PDI levels with a paradoxical decrease of its active form occurs in the diabetic heart after ischemia and may explain the lack of protective effects of PDI in diabetes. Restoration of PDI redox state prevents adverse remodeling. The potential significance of these findings deserves to be validated in a clinical setting.

Notes

Acknowledgments

This work was supported by a Società Italiana di Cardiologia (SIC) training grant to S Toldo and by an American Heart Association Beginning Grant-in-Aid (Mid-Atlantic Affiliate) to A Abbate and by FUTURA-onlus to A Baldi.

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Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Stefano Toldo
    • 1
    • 2
  • Mariarosaria Boccellino
    • 3
  • Barbara Rinaldi
    • 4
  • Ignacio M. Seropian
    • 2
  • Eleonora Mezzaroma
    • 2
  • Anna Severino
    • 1
  • Lucio Quagliuolo
    • 3
  • Benjamin W. Van Tassell
    • 2
  • Raffaele Marfella
    • 4
  • Giuseppe Paolisso
    • 4
  • Francesco Rossi
    • 4
  • Ramesh Natarajan
    • 2
  • Norbert Voelkel
    • 2
  • Antonio Abbate
    • 2
  • Filippo Crea
    • 1
  • Alfonso Baldi
    • 3
  1. 1.Institute of CardiologyCatholic University of the Sacred HeartRomeItaly
  2. 2.Victoria Johnson Research Center and VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondUSA
  3. 3.Department of Biochemistry and Biophysics “F. Cedrangolo,” Pathology SectionSecond University of NaplesNaplesItaly
  4. 4.Department of Experimental Medicine, Excellence Center for Cardiovascular DiseasesSecond University of NaplesNaplesItaly

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