Abstract
Hyperglycemia 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 hyperglycemia enhances Txnip expression and consequently exacerbates myocardial ischemia/reperfusion (MI/R) injury. Adult male SD rats were subjected to MI/R (30 min/4 h) and treated with saline or high glucose (HG, 500 g/L, 4 ml/kg/h, intravenously throughout the whole MI/R). In vitro study was performed on cultured neonatal rat cardiomyocytes subjected to simulated ischemia/reperfusion (SI/R) and incubated with HG (25 mM) or normal glucose (5.6 mM) medium. In vivo HG infusion significantly reduced the ± LV d P /dt max 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 MI/R hearts. Additionally, HG significantly activated p38 MAPK and inhibited Akt in I/R hearts ( 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 enhanced HG-induced superoxide generation and aggravated cell apoptosis (n=6, P <0.05), while Txnip RNAi 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 ( P <0.05) in HG-treated rats. 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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