title: 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.
authors.affiliation: Division of Cardiothoracic Surgery, Rhode Island Hospital and Alpert Medical School, Brown University, Cardiovascular Research Center, Providence, Rhode Island 02903, USA.
authors.forename: Shizu
authors.initials: S
authors.lastname: Oyamada
authors.forename: Robert
authors.initials: R
authors.lastname: Osipov
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Michael P
authors.initials: MP
authors.lastname: Robich
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Burgess
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Bell
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sheller
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D019281:Dimerization; D004355:Drug Stability; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000150:complications* / Q000503:physiopathology; D066298:In Vitro Techniques; D008055:Lipids / Q000097:blood; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D010446:Peptide Fragments / Q000097:blood / Q000627:therapeutic use*; D012996:Solutions; D013552:Swine; D013917:Thrombin / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D008055:Lipids; D010446:Peptide Fragments; D012996:Solutions; C412222:rusalatide acetate; D013917:Thrombin
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