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.

Thioredoxin‐Interacting Protein Mediates NLRP3 Inflammasome Activation Involved in the Susceptibility to Ischemic Acute Kidney Injury in Diabetes

“…Liu et al demonstrated that TXNIP-mediated NLRP3 inflammasome activation was involved in myocardial I/R injury [47]. Hyperglycaemia has been identified as an inducer of TXNIP expression in various cells including HK-2 [21, 22]; meanwhile, enhanced myocardial TXNIP expression that contributes to hyperglycaemia-aggravated oxidative stress and exacerbates cardiac injury following I/R has been reported [48]. TXNIP expression is markedly upregulated in human diabetes and diabetic complications [49, 50], indicating that TXNIP is a potential therapeutic target of diabetes.…”

Variations of thioredoxin system contributes to increased susceptibility to apoptosis in cardiomyocytes of type 2 diabetic rats

“…Another candidate is p38 kinase. Recently, Su et al [42] have proved that hyperglycemia enhances myocardial TXNIP expression, possibly through reciprocally modulating p38 MAPK and Akt activation. According to their report, p38 kinase is located at the upstream of TXNIP, which is proposed by other groups [12].…”

Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress

“…Superoxide production in the tissues and cells was measured using lucigenin-enhanced chemiluminescence, as described previously [30] . Superoxide production was expressed as relative light units (RLU) per second per milligram heart weight (RLU·mg -1 ·s -1 ).…”

“…Superoxide production was expressed as relative light units (RLU) per second per milligram heart weight (RLU·mg -1 ·s -1 ). The MDA levels and the activities of the antioxidant SOD in the heart homogenates were determined spectrophotometrically, as previously described [30] .…”

“…Superoxide production was expressed as relative light units (RLU) per second per milligram heart weight (RLU·mg -1 ·s -1 ). The MDA levels and the activities of the antioxidant SOD in the heart homogenates were determined spectrophotometrically, as previously described [30] .Cell culture and siRNA transfection H9C2 embryonic rat myocardium-derived cells (Shanghai Tiancheng Technology Co, Ltd), a well-characterized cell line used to study myocardial cell ischemia, were grown in Dulbecco's modified Eagle's medium (DMEM, GIBCO) supplemented with 10% inactivated fetal bovine serum (FBS, GIBCO), 50 U/mL penicillin and 50 μg/mL streptomycin (GIBCO) at 37 °C in a humidified atmosphere with 5% CO 2 . The siRNA transfection was carried out according to the manufacturer's instructions.…”