Altered oxido-reductive state in the diabetic heart: loss of cardioprotection due to protein disulfide isomerase

Mol Med. Sep-Oct 2011;17(9-10):1012-21. doi: 10.2119/molmed.2011.00100. Epub 2011 May 31.

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 methoxy-polyethyleneglycol-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Apoptosis
  • Blood Pressure
  • Blotting, Western
  • Cells, Cultured
  • Dehydroascorbic Acid / pharmacology
  • Diabetes Mellitus / enzymology*
  • Diabetes Mellitus / physiopathology
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / physiopathology
  • Echocardiography
  • Female
  • Heart Failure / diagnostic imaging
  • Heart Failure / enzymology*
  • Heart Failure / physiopathology
  • Humans
  • In Situ Nick-End Labeling
  • Male
  • Mice
  • Middle Aged
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / etiology
  • Myocardial Infarction / physiopathology
  • Myocardium / enzymology*
  • Myocardium / pathology
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology
  • Oxidation-Reduction / drug effects
  • Protein Disulfide-Isomerases / metabolism*
  • Reperfusion Injury / complications
  • Reperfusion Injury / physiopathology
  • Ventricular Remodeling

Substances

  • Protein Disulfide-Isomerases
  • Dehydroascorbic Acid