Effect of dimerized thrombin fragment TP508 on acute myocardial ischemia reperfusion injury in hypercholesterolemic swine.
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.
Oyamada
Shizu
S
Division of Cardiothoracic Surgery, Rhode Island Hospital and Alpert Medical School, Brown University, Cardiovascular Research Center, Providence, Rhode Island 02903, USA.
Osipov
Robert
R
Bianchi
Cesario
C
Robich
Michael P
MP
Feng
Jun
J
Liu
Yuhong
Y
Burgess
Thomas A
TA
Bell
Timothy M
TM
Sheller
Michael R
MR
Sellke
Frank W
FW
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
D001786:Blood Glucose; D008055:Lipids; D010446:Peptide Fragments; D012996:Solutions; C412222:rusalatide acetate; D013917:Thrombin
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