Nonanticoagulant heparin inhibits NF-kappaB activation and attenuates myocardial reperfusion injury.
Heparin reduces ischemia-reperfusion injury to myocardium. This effect has been attributed to complement inhibition, but heparin also has other activities that might diminish ischemia-reperfusion. To further probe these mechanisms, we compared heparin or an o-desulfated nonanticoagulant heparin with greatly reduced anticomplement activity. When given at the time of coronary artery reperfusion in a canine model of myocardial infarction, heparin or o-desulfated heparin equally reduced neutrophil adherence to ischemic-reperfused coronary artery endothelium, influx of neutrophils into ischemic-reperfused myocardium, myocardial necrosis, and release of creatine kinase into plasma. Heparin or o-desulfated heparin also prevented dysfunction of endothelial-dependent coronary relaxation following ischemic injury. In addition, heparin and o-desulfated heparin inhibited translocation of the transcription nuclear factor-kappaB (NF-kappaB) from the cytoplasm to the nucleus in human endothelial cells and decreased NF-kappaB DNA binding in human endothelium and ischemic-reperfused rat myocardium. Thus heparin and nonanticoagulant heparin decrease ischemia-reperfusion injury by disrupting multiple levels of the inflammatory cascade, including the novel observation that heparins inhibit activation of the proinflammatory transcription factor NF-kappaB.
Thourani
V H
VH
epartment of Surgery, Emory University School of Medicine, Crawford Long Hospital, Atlanta, Georgia 30365, USA.
Brar
S S
SS
Kennedy
T P
TP
Thornton
L R
LR
Watts
J A
JA
Ronson
R S
RS
Zhao
Z Q
ZQ
Sturrock
A L
AL
Hoidal
J R
JR
Vinten-Johansen
J
J
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000503:physiopathology; D001777:Blood Coagulation / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006493:Heparin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D009504:Neutrophils / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D016328:NF-kappa B; C410523:heparin, O-desulfated; D006493:Heparin