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.
Highlights
Hyperglycaemia commonly occurs in patients with acute myocardial infarction and is associated with increased risk of mortality and poor outcome [1, 2]
There were no significant differences in heart rate among all groups during ischaemia or reperfusion period blood pressure was significantly decreased in both groups following ischaemia
Our in vivo experimental results demonstrated that treatment with high glucose (HG) significantly increased Thioredoxin-interacting protein (Txnip) expression, inhibited Trx activity, stimulated superoxide production and aggravated myocardial injury following myocardial ischaemia/reperfusion (MI/R)
Summary
Hyperglycaemia commonly occurs in patients with acute myocardial infarction and is associated with increased risk of mortality and poor outcome [1, 2]. Evidence from our laboratory and others has demonstrated that hyperglycaemia exacerbates myocardial vulnerability to ischaemia/reperfusion (I/R) [3, 4], the underlying mechanisms remain to be identified. Strong evidence exists that increased oxidative stress, which oxidizes biological macromolecules and impairs cell functions, is a major pathogenic factor in I/R injury and diabetes [5, 6].
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