Effect of thrombin fragment (TP508) on myocardial ischemia reperfusion injury in a model of type 1 diabetes mellitus.
BACKGROUND
We investigated the efficacy of novel thrombin fragment TP508 on ischemia-reperfusion injury using a porcine model of type 1 diabetes mellitus.


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.
Chu
Louis M
LM
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Osipov
Robert M
RM
Robich
Michael P
MP
Feng
Jun
J
Sheller
Michael R
MR
Sellke
Frank W
FW
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D048909:Diabetes Complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010446:Peptide Fragments / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013552:Swine; D058570:TOR Serine-Threonine Kinases; D013917:Thrombin / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; C412222:rusalatide acetate; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D013917:Thrombin; D053148:Caspase 3