title: 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.
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Su
authors.forename: Lele
authors.initials: L
authors.lastname: Ji
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xing
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Heping
authors.initials: H
authors.lastname: Zhou
authors.forename: Xinhong
authors.initials: X
authors.lastname: Qian
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; C493796:TXNIP protein, rat; D013481:Superoxides; D008315:Malondialdehyde; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose