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GW24-e1280 Thioredoxin-interacting protein contributes to aggravated myocardial ischaemia/reperfusion injury by hyperglycemia
  1. Ru Tie1,
  2. Wenjuan Xing2,
  3. Lele Ji2,
  4. Hui Su3,
  5. Xin Sun4,
  6. Ling Tao5,
  7. Haifeng Zhang1
  1. 1Experiment Teaching Center, Fourth Military Medical University, Xi’an, China
  2. 2Department of Physiology, Fourth Military Medical University, Xi’an, China
  3. 3Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi’an, China
  4. 4Department of Pediatrics, Xijing Hospital, Fourth Military Medical University, Xi’an, China
  5. 5Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an, China

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 (± LVdP/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.

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