Acute hyperglycaemia enhances oxidative stress and aggravates myocardial ischaemia/reperfusion injury: role of thioredoxin-interacting protein.

Abstract

Hyperglycaemia during acute myocardial infarction is common and associated with increased mortality. Thioredoxin-interacting protein (Txnip) is a modulator of cellular redox state and contributes to cell apoptosis. This study aimed to investigate whether or not hyperglycaemia enhances Txnip expression in myocardial ischaemia/reperfusion (MI/R) and consequently exacerbates MI/R injury. Rats were subjected to 30 min. of left coronary artery ligation followed by 4 hrs of reperfusion and treated with saline or high glucose (HG, 500 g/l, 4 ml/kg/h intravenously). In vitro study was performed on cultured rat cardiomyocytes subjected to simulated ischaemia/reperfusion (SI/R) and incubated with HG (25 mM) or normal glucose (5.6 mM) medium. In vivo HG infusion during MI/R significantly impaired cardiac function, aggravated myocardial injury and increased cardiac oxidative stress. Meanwhile, Txnip expression was enhanced whereas thioredoxin activity was inhibited following HG treatment in ischaemia/reperfusion (I/R) hearts. In addition, HG activated p38 MAPK and inhibited Akt in I/R hearts. In cultured cardiomyocytes subjected to SI/R, HG incubation stimulated Txnip expression and reduced thioredoxin activity. Overexpression of Txnip enhanced HG-induced superoxide generation and aggravated cardiomyocyte apoptosis, whereas Txnip RNAi significantly blunted the deleterious effects of HG. Moreover, inhibition of p38 MAPK or activation of Akt markedly blocked HG-induced Txnip expression in I/R cardiomyocytes. Most importantly, intramyocardial injection of Txnip siRNA markedly decreased Txnip expression and alleviated MI/R injury in HG-treated rats. Hyperglycaemia enhances myocardial Txnip expression, possibly through reciprocally modulating p38 MAPK and Akt activation, leading to aggravated oxidative stress and subsequently, amplification of cardiac injury following MI/R.

• Authors: Hui Su, Lele Ji, Wenjuan Xing, Wei Zhang, Heping Zhou, Xinhong Qian, Xiaoming Wang, Feng Gao, Xin Sun, Haifeng Zhang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 17 Issue 1 Pg. 181-91 (Jan 2013) ISSN: 1582-4934 [Electronic] England
• PMID: 23305039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Chemical References

• Carrier Proteins
• Cell Cycle Proteins
• RNA, Small Interfering
• TXNIP protein, rat
• Superoxides
• Malondialdehyde
• Proto-Oncogene Proteins c-akt
• p38 Mitogen-Activated Protein Kinases
• Glucose

Topics

• Animals
• Apoptosis
• Carrier Proteins (antagonists & inhibitors, genetics, metabolism)
• Cell Cycle Proteins
• Cells, Cultured
• Glucose (pharmacology)
• Hyperglycemia (complications, metabolism, pathology)
• Male
• Malondialdehyde (metabolism)
• Myocardial Reperfusion Injury (complications, metabolism, pathology)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Oxidative Stress
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (genetics)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Superoxides (metabolism)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)