Document Detail


Effect of thrombin fragment (TP508) on myocardial ischemia reperfusion injury in a model of type 1 diabetes mellitus.
MedLine Citation:
PMID:  20837908     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: We investigated the efficacy of novel thrombin fragment TP508 on ischemia-reperfusion injury using a porcine model of type 1 diabetes mellitus.
METHODS AND RESULTS: Alloxan-induced diabetic male Yucatan swine underwent 60 minutes of mid-left anterior descending coronary artery occlusion, followed by 120 minutes of reperfusion. Fifty minutes into ischemia, animals received either placebo (DM; n=8) or TP508 as a bolus of 1 mg/kg followed by infusion at 2.5 mg/kg per hour (DMT; n=8). Hemodynamic parameters and myocardial function were monitored. Monastryl blue/triphenyl tetrazolium chloride staining was used to assess sizes of the areas at risk and infarction. Coronary microvascular reactivity was measured and expression of cell survival and proapoptotic proteins quantified. Preoperative serum glucose values were similar between groups (309±57 mg/dL in DM versus 318±67 mg/dL in DMT; P=0.92). Infarct size was smaller in the TP508-treated group (5.3±1.9% in DMT versus 19.4±5.6% in DM; P=0.03). There was no statistically significant difference in global or regional left ventricular function between groups. Endothelium-dependent microvessel relaxation was moderately improved in the DMT group (P=0.09), whereas endothelium-independent relaxation was similar between groups. The expression of cell survival proteins Akt, phospho-p38, and mammalian target of rapamycin was higher in the areas at risk of DMT animals compared with DM animals (P<0.05), and expressions of proapoptotic glycogen synthase kinase 3β and caspase 3 were lower in the DMT group (P<0.05).
CONCLUSIONS: This study demonstrates that, in type 1 diabetic swine, TP508 reduces infarct size after ischemia-reperfusion. Thus, TP508 may offer a novel approach in cardioprotection from ischemia-reperfusion injury in diabetic patients.
Authors:
Louis M Chu; Robert M Osipov; Michael P Robich; Jun Feng; Michael R Sheller; Frank W Sellke
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  122     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-14     Completed Date:  2010-10-01     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  S162-9     Citation Subset:  AIM; IM    
Affiliation:
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis*
Caspase 3 / metabolism
Cell Survival
Coronary Circulation / drug effects
Coronary Vessels / metabolism,  pathology,  physiopathology
Diabetes Complications / drug therapy*,  metabolism,  pathology,  physiopathology
Diabetes Mellitus, Type 1 / drug therapy*,  metabolism,  pathology,  physiopathology
Disease Models, Animal
Endothelium / metabolism*,  pathology,  physiopathology
Female
Glycogen Synthase Kinase 3 / metabolism
Intracellular Signaling Peptides and Proteins / metabolism
Male
Myocardial Reperfusion Injury / drug therapy*,  etiology,  metabolism,  pathology,  physiopathology
Peptide Fragments / pharmacology*
Protein-Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Swine
TOR Serine-Threonine Kinases
Thrombin / pharmacology*
Ventricular Function, Left / drug effects
Grant Support
ID/Acronym/Agency:
5T32-HL007734/HL/NHLBI NIH HHS; R01 HL046716-18A1/HL/NHLBI NIH HHS; R01 HL069024-08/HL/NHLBI NIH HHS; R01 HL085647-03/HL/NHLBI NIH HHS; R01HL46716/HL/NHLBI NIH HHS; R01HL69024/HL/NHLBI NIH HHS; R01HL85647/HL/NHLBI NIH HHS; T32 HL076130-05/HL/NHLBI NIH HHS; T32-HL076130/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; 0/Peptide Fragments; 0/rusalatide acetate; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 3.4.21.5/Thrombin; EC 3.4.22.-/Caspase 3
Comments/Corrections
Erratum In:
Circulation. 2011 Dec 6;124(23):e780

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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