Effect of thrombin fragment (TP508) on myocardial ischemia-reperfusion injury in hypercholesterolemic pigs.

Abstract

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.

• Authors: Robert M Osipov, Michael P Robich, Jun Feng, Richard T Clements, Yuhong Liu, Hilary P Glazer, John Wagstaff, Cesario Bianchi, Frank W Sellke
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 106 Issue 6 Pg. 1993-2001 (Jun 2009) ISSN: 8750-7587 [Print] United States
• PMID: 19372304 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• HSP90 Heat-Shock Proteins
• Peptide Fragments
• rusalatide acetate
• Thrombin

Topics

• Animals
• Apoptosis (drug effects)
• Coronary Circulation (drug effects)
• Coronary Occlusion (pathology, physiopathology)
• Disease Models, Animal
• HSP90 Heat-Shock Proteins (metabolism)
• Heart (drug effects)
• Hypercholesterolemia (complications, drug therapy, pathology)
• Male
• Microvessels (drug effects, pathology)
• Myocardial Infarction (complications, pathology, prevention & control)
• Myocardial Reperfusion Injury (complications, drug therapy, pathology)
• Myocardium (pathology)
• Necrosis (chemically induced)
• Peptide Fragments (therapeutic use)
• Swine
• Swine, Miniature
• Thrombin
• Ventricular Dysfunction, Left (drug therapy, physiopathology)