GW24-e1280 Thioredoxin-interacting protein contributes to aggravated myocardial ischaemia/reperfusion injury by hyperglycemia. (1st October 2013)

• Record Type: Journal Article
• Authors: Tie, Ru; Xing, Wenjuan; Ji, Lele; Su, Hui; Sun, Xin; Tao, Ling; Zhang, Haifeng
• Is Part Of: Heart. Volume 99(2013)Supplement 3
• Page Start: A50
• Page End: A50
• Publication Date: 2013-10-01
• Subjects: Heart -- Diseases -- Treatment -- Periodicals; Cardiology -- Periodicals; 616.12
• DOI: 10.1136/heartjnl-2013-304613.134
• Languages: English
• ISSNs: 1355-6037

Abstract

Abstract : Objectives: Hyperglycemia during acute myocardial infarction is common and associated with increased mortality. Thioredoxin-interacting protein (Txnip) is a modulator of cellular redox stateand contributes to cell apoptosis. The present study was aimed to investigate whether hyperglycemia enhances Txnip expression in myocardialischaemia/reperfusion (MI/R) and consequently exacerbates MI/R injury. Methods: Adult male Sprague-Dawley rats were subjected to MI/R (anaesthetised with 60 mg/kg pentobarbital sodium, intraperitoneally, MI 30 min / R 4 h) and treated with saline or high glucose (HG, 500 g/L, 4 ml/kg/h, intravenously). In vitro study was performed on cultured neonatal rat cardiomyocytes subjected to simulated ischaemia/reperfusion (SI/R) and incubated with HG (25 mM) or normal glucose (5.6 mM) medium. Results: In vivo HG infusion during MI/R significantly reduced the instantaneous first derivation of left ventricle pressure (± LVd P /dtmax ) by 13.2 and 14.1% respectively (n = 8, P < 0.05), increased infarct size and myocardial apoptosis ( P < 0.05) and increased superoxide accumulation ( P < 0.01) compared with those in the saline group. Meanwhile, Txnip expression was enhanced (Ratio of Txnip/β-actin: 1.22 ± 0.16 vs. 0.92 ± 0.05 of MI/R + saline, n = 6-8, P < 0.05) whereas thioredoxin activity was inhibited (0.50 ± 0.05 vs. 1.41 ± 0.06 μmol/min/mg protein, P < 0.01) following HG treatment in ischaemia/reperfusion (I/R) hearts. Additionally, HG significantly activated p38 mitogen-activated protein kinase (p38 MAPK) and inhibited Akt in I/R hearts (both P < 0.05). In cultured cardiomyocytes subjected to SI/R, HG incubation stimulated Txnip expression and reduced thioredoxin activity (n = 6, P < 0.05). Overexpression of Txnip enhancedHG-induced superoxide generation and aggravated cardiomyocyte apoptosis (n = 6, P < 0.05), while Txnip siRNA significantly blunted the deleterious effects of HG ( P < 0.05). 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 as evidenced by reduced infarction size (23.7 ± 1.6% vs. 43.1 ± 4.8%, n = 6, P < 0.05) and caspase 3 activity (3.05 ± 0.08 vs. 3.93 ± 0.31 nmol/h/mg protein, P < 0.05) in HG-treated rats. Conclusions: Hyperglycemia enhances myocardial Txnip expression, possibly through reciprocally modulating p38 MAPK and Akt activation, leading to aggravated oxidative stress and subsequent amplification of cardiac injury following MI/R.