Effect of thrombin fragment (TP508) on myocardial ischemia-reperfusion injury in hypercholesterolemic pigs.
Myocardial ischemia-reperfusion (IR) injury occurs frequently in the setting of hypercholesterolemia. We investigated the potential efficacy of a novel thrombin fragment (TP508) on IR injury in a hypercholesterolemic porcine model. Twenty-one hypercholesterolemic male Yucatan pigs underwent 60 min of mid-left anterior descending coronary artery occlusion followed by 120 min of reperfusion. Pigs received either placebo (control, n = 7) or TP508 in two doses (TP508 low dose, n = 7, as bolus of 0.5 mg/kg 50 min into ischemia and an infusion of 1.25 mg.kg(-1).h(-1) during reperfusion period or TP508 high dose, n = 7, a double dose of TP508 low-dose group). Myocardial function was monitored throughout the experiment. The area at risk and myocardial necrosis were determined by Monastryl blue/triphenyl tetrazolium chloride staining. Apoptosis in the ischemic territory was assessed. Coronary microvascular reactivity to endothelium-dependent and -independent factors was measured. Myocardial necrosis was lower in both TP508-treated groups vs. control (P < 0.05). Regional left ventricular function was improved only in the TP508 high-dose group (P < 0.05). Endothelium-dependent coronary microvascular reactivity was greater in both TP508-treated groups (P < 0.05) vs. control. The expression of proteins favoring cell survival, 90-kDa heat shock protein and phospho-Bad (Ser112) was higher in the TP508 high-dose group (P < 0.05). The expression of the cell death signaling proteins, cleaved caspase-3 (P < 0.05), apoptosis-inducing factor (P < 0.05), and poly-ADP ribose polymerase (P = 0.07) was lower in the TP508 low-dose group vs. TP508 high-dose and control. The terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling positive cell count was lower in both TP508 groups compared with the control (P < 0.05). This study demonstrates that, in hypercholesterolemic pigs, TP508 decreases myocardial necrosis and apoptosis after IR. Thus TP508 may offer a novel approach in protecting the myocardium from IR injury.
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Robert M
RM
Osipov
Michael P
MP
Robich
Jun
J
Feng
Richard T
RT
Clements
Yuhong
Y
Liu
Hilary P
HP
Glazer
John
J
Wagstaff
Cesario
C
Bianchi
Frank W
FW
Sellke
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D054059:Coronary Occlusion / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009336:Necrosis / Q000139:chemically induced; D010446:Peptide Fragments / Q000627:therapeutic use*; D013552:Swine; D013556:Swine, Miniature; D013917:Thrombin; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology
D018841:HSP90 Heat-Shock Proteins; D010446:Peptide Fragments; C412222:rusalatide acetate; D013917:Thrombin