title: Susceptibility to myocardial ischemia reperfusion injury at early stage of type 1 diabetes in rats.
abstract: BACKGROUND
  Large body of evidences accumulated in clinical and epidemiological studies indicate that hearts of diabetic subjects are more sensitive to ischemia reperfusion injury (IRI), which results in a higher rate of mortality at post-operation than that of non-diabetes. However, experimental results are equivocal and point to either increased or decreased susceptibility of the diabetic hearts to IRI, especially at the early stage of the disease. The present study was designed to test the hypothesis that the duration/severity of the indexed ischemia is a major determinant of the vulnerability to myocardial IRI at early stage of diabetes.
  
  
  METHODS
  Four weeks streptozotocin (STZ)-induced diabetic (D) and non-diabetic (C) Sprague-Dawley rats were randomly assigned to receive 30 or 45 min of left anterior descending artery ligation followed by 2 or 3 hours of reperfusion, respectively. Cardiac function was recorded by using Pressure-Volume (PV) conduction system. Myocardial infarct size was determined with triphenyltetrazolium chloride staining. Plasma Creatine kinase-MB (CK-MB), Lactate dehydrogenase (LDH) release, myocardial nitric oxide(NO) content and nitrotyrosine formation, 15-F(2t)-Isoprostane and plasma superoxide dismutase (SOD) were measured with colorimetric assays. Cardiomyocyte apoptosis was assessed by TUNEL staining. Myocardial TNFα, Caspase-3, STAT3, Akt, and GSK-3β were determined by Western blotting.
  
  
  RESULTS
  Prolongation of ischemia but not reperfusion from 30 min to 45 min significantly increased infarct size in D compared to C rats (P < 0.05), accompanied with significantly increased plasma CK-MB (P < 0.05). Prolongation of the duration of either ischemia or reperfusion significantly increased plasma LDH release and myocardial 15-F(2t)-Isoprostane and reduced plasma SOD activity, with concomitant reduction of myocardial NO and increase of nitrotyrosine formation in D relative to C (P < 0.05). Prolongation of ischemia and reperfusion significantly reduced left ventricular ejection fraction and increased the peak rate of pressure, accompanied with increased end systolic pressure in D relative to C rats (P < 0.05) but reduced phosphorylations of myocardial STAT3 at site Ser727 and Akt at site Ser473 as well as GSK-3β at Ser 9 (P < 0.05).
  
  
  CONCLUSIONS
  Diabetic hearts, even at early stage of the disease are more sensitive to IRI, and this increased severity of post-ischemic myocardial injury depends more on the duration of ischemia than that of reperfusion.
authors.affiliation: Department of Anesthesiology, The University of Hong Kong, Hong Kong SAR, China. zyxia@hku.hk.
authors.forename: Haobo
authors.initials: H
authors.lastname: Li
authors.forename: Zipeng
authors.initials: Z
authors.lastname: Liu
authors.forename: Junwen
authors.initials: J
authors.lastname: Wang
authors.forename: Gordon T
authors.initials: GT
authors.lastname: Wong
authors.forename: Chi-Wai
authors.initials: CW
authors.lastname: Cheung
authors.forename: Liangqing
authors.initials: L
authors.lastname: Zhang
authors.forename: Can
authors.initials: C
authors.lastname: Chen
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
authors.forename: Michael G
authors.initials: MG
authors.lastname: Irwin
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D053148:Caspase 3 / Q000378:metabolism; D052276:Creatine Kinase, BB Form / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D015425:Myocardial Reperfusion / Q000009:adverse effects*; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012720:Severity of Illness Index; D013318:Stroke Volume; D013482:Superoxide Dismutase / Q000097:blood; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: D015415:Biomarkers; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014409:Tumor Necrosis Factor-alpha; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D015237:Dinoprost; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D052276:Creatine Kinase, BB Form; C505410:Casp3 protein, rat; D053148:Caspase 3
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