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

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

doi:10.2119/molmed.2011.00100

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.

Highlights

Ischemic heart disease is the most frequent cause of cardiovascular mortality in the United States and worldwide [1]
We explored the possibility that administration of DHA, for which myocardial uptake is apparently not altered by diabetes [17], could modify protein disulfide isomerase (PDI) expression and/or its redox state in our experimental model, reverting the detrimental effects of diabetes on post–myocardial infarction on the left ventricular wall remodeling
The risks of developing coronary artery disease and mortality after acute myocardial infarction (AMI) are increased two- to four-fold compared with nondiabetic patients [3,4,5]

Summary

Introduction

Ischemic heart disease is the most frequent cause of cardiovascular mortality in the United States and worldwide [1]. Individuals with DM are at a significantly greater risk of developing coronary artery disease [3] and are at an increased risk of developing heart failure [4]. DM impairs the ability of the unfolded protein response to restore the physiological state by altering the function of its key components, one of which is the protein disulfide isomerase (PDI) [8]. This enzyme is necessary for appropriate protein folding and prevention of protein misfolding during stress, as occurs during ischemic myocardial injury [9,10]. We analyzed (a) PDI expression and cell death in the heart of diabetic patients undergoing coronary artery bypass

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