title: Thrombin fragment (TP508) decreases myocardial infarction and apoptosis after ischemia reperfusion injury.
abstract: BACKGROUND
  Myocardial ischemia-reperfusion injury may lead to cardiac dysfunction or death. This study investigates the potential efficacy of a novel thrombin fragment (TP508) on myocardial ischemia-reperfusion injury.
  
  
  METHODS
  Fourteen male Yucatan pigs underwent 60 minutes of mid-left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. Pigs received either saline vehicle (control, n = 7) or thrombin fragment TP508 (n = 7) as a bolus (0.5 mg/kg) 50 minutes into the ischemic period, followed by continuous intravenous infusion (1.25 mg x kg(-1) x h(-1)) during reperfusion. Myocardial function was monitored throughout the experiments. Monastryl blue/triphenyl tetrazolium chloride staining was utilized to measure the area at risk and infarcted tissue. Apoptosis was assessed by Western blotting and dUTP nick-end labeling (TUNEL) staining. Coronary microvascular reactivity to endothelium-dependent factors (adenosine diphosphate, substance P, A23187) and endothelium-independent factor (sodium nitroprusside) was examined.
  
  
  RESULTS
  Global and regional left ventricular function was not significantly different between groups. Endothelium-dependent coronary microvascular relaxation was greater in the TP508 group and associated with higher endothelial nitric oxide synthase phosphorylation. Both infarct size and TUNEL staining was significantly decreased in the TP508 group compared with the control group (p < 0.05). Expression of the cell survival proteins B-cell lymphoma 2 (2.2-fold, p < 0.05) and heat shock protein-73 (1.6-fold, p < 0.05) was higher in the TP508 group. Expression of the cell-death-signaling proteins poly adenosine diphosphate-ribose polymerase (1.6-fold, p < 0.05), cleaved poly adenosine diphosphate-ribose polymerase (6.4-fold, p < 0.05), and B-cell lymphoma 2/adenovirus E1B 19 kDa-interacting protein 3 (3.8-fold, p < 0.05) was significantly higher in the TP508 group in the ischemic territory.
  
  
  CONCLUSIONS
  This study demonstrates that TP508 decreases infarct size, improves endothelial microvascular function, and induces cell-survival signaling in the setting of ischemia-reperfusion injury. Thus, TP508 may be a useful agent to attenuate myocardial reperfusion injury.
authors.affiliation: Department of General Surgery, Cardiothoracic Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Osipov
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Shu-Hua
authors.initials: SH
authors.lastname: Xu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Robich
authors.forename: John
authors.initials: J
authors.lastname: Wagstaff
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology* / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine; D013917:Thrombin
chemical_list: D010446:Peptide Fragments; C412222:rusalatide acetate; D013917:Thrombin