Nonanticoagulant heparin inhibits NF-kappa B 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 activi ties that might diminish ischemia-reperfusion. To further probe these mecha nisms, we compared heparin or an o-desulfated nonanticoagulant heparin with greatly reduced anticomplement activity. When given at the time of coronar y artery reperfusion in a canine model of myocardial infarction, heparin or o-desulfated heparin equally reduced neutrophil adherence to ischemic-repe rfused coronary artery endothelium, influx of neutrophils into ischemic-rep erfused myocardium, myocardial necrosis, and release of creatine kinase int o plasma. Heparin or o-desulfated heparin also prevented dysfunction of end othelial-dependent coronary relaxation following ischemic injury. In additi on, heparin and o-desulfated heparin inhibited translocation of the transcr iption nuclear factor-kappa B (NF-kappa B) from the cytoplasm to the nucleu s in human endothelial cells and decreased NF-kappa B DNA binding in human endothelium and ischemic-reperfused rat myocardium. Thus heparin and nonant icoagulant heparin decrease ischemia-reperfusion injury by disrupting multi ple levels of the inflammatory cascade, including the novel observation tha t heparins inhibit activation of the proinflammatory transcription factor N F-kappa B.