Tissue factor and thrombin mediate myocardial ischemia-reperfusion injury.
Reperfusion of the ischemic heart is necessary to prevent irreversible injury of the myocardium, which leads to permanent organ dysfunction. However, reperfusion in itself leads to myocardial ischemia/reperfusion (I/R) injury, which is characterized by an acute inflammatory response mediated by activated inflammatory cells, chemokines, cytokines, and adhesion molecules. The molecular mechanisms of myocardial I/R injury are not completely known. Tissue factor (TF) and thrombin, two potent procoagulant and proinflammatory mediators, are recognized to play significant roles in myocardial I/R injury. To investigate the role of TF and thrombin in myocardial I/R injury, we used rabbit and murine in situ coronary artery ligation models. Increased TF mRNA, antigen, and activity were found in ischemic cardiomyocytes. Administration of an inhibitory antirabbit TF monoclonal antibody before or during the onset of ischemia resulted in a significant reduction in infarct size. Functional inhibition of thrombin with hirudin also reduced the infarct size. However, defibrinogenating rabbits with ancrod had no effect on infarct size, suggesting a requirement of thrombin generation but not fibrin deposition in myocardial I/R injury.
Chong
Albert J
AJ
Division of Cardiothoracic Surgery, The University of Washington, Seattle, Washington 98104, USA.
Pohlman
Timothy H
TH
Hampton
Craig R
CR
Shimamoto
Akira
A
Mackman
Nigel
N
Verrier
Edward D
ED
D000721:Ancrod / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006629:Hirudins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000648:ultrastructure; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000502:physiology; D013917:Thrombin / Q000502:physiology*; D013925:Thromboplastin / Q000502:physiology*
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D006629:Hirudins; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D013925:Thromboplastin; D000721:Ancrod; D013917:Thrombin