Effect of Dimerized Thrombin Fragment TP508 on Acute Myocardial Ischemia Reperfusion Injury in Hypercholesterolemic Swine

Abstract

The thrombin-related peptide TP508 is a 23-amino acid monomer that represents a portion of the receptor binding domain in the thrombin molecule. TP508 is also known to readily convert to a dimer in an aqueous environment. In this study the dimeric form of TP508 was investigated in a porcine model of acute myocardial ischemia reperfusion injury (and compared with its monomer). Twenty-four hypercholesterolemic pigs underwent 60 min of mid-left anterior descending coronary artery occlusion followed by 120 min of reperfusion and received either vehicle (n = 6), TP508 monomer (n = 6), or two different doses of dimer (n = 6). Infarct size was significantly reduced in the monomer and two dimer groups compared with vehicle. Improvement in both endothelium-dependent and -independent coronary microvascular relaxations was also observed in treated groups. In addition, the expression of 27-kDa heat shock protein, alphaB-crystalline, and phosphorylated B-cell lymphoma 2 (Ser70) in the ischemic area at risk were higher in treated groups than in vehicle, whereas the expression of cleaved poly-ADP ribose polymerase was lower in treated groups. Finally, there were fewer apoptotic cells in treated groups than in vehicle. This study suggests that TP508 dimer provides a myocardial-protective effect on acute ischemia reperfusion injury in hypercholesterolemic swine, similar to TP508 monomer, by up-regulating cell survival pathways or down-regulating apoptotic pathways.