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J Pharmacol Exp Ther. 2010 Aug;334(2):449-59. doi: 10.1124/jpet.110.166348. Epub 2010 May 11.

Effect of dimerized thrombin fragment TP508 on acute myocardial ischemia reperfusion injury in hypercholesterolemic swine.

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1
Division of Cardiothoracic Surgery, Rhode Island Hospital and Alpert Medical School, Brown University, Cardiovascular Research Center, Providence, Rhode Island 02903, USA.

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.

PMID:
20460385
PMCID:
PMC2913770
DOI:
10.1124/jpet.110.166348
[Indexed for MEDLINE]
Free PMC Article
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