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Am J Physiol Heart Circ Physiol 278: H2084-H2093, 2000;
0363-6135/00 $5.00
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Vol. 278, Issue 6, H2084-H2093, June 2000

Nonanticoagulant heparin inhibits NF-kappa B activation and attenuates myocardial reperfusion injury

Vinod H. Thourani1, Sukhdev S. Brar2, Thomas P. Kennedy2, Lisa R. Thornton3, John A. Watts3, Russell S. Ronson1, Zhi-Qing Zhao4, Anne L. Sturrock5, John R. Hoidal5, and Jakob Vinten-Johansen4

Departments of 2 Internal Medicine and 3 Emergency Medicine and the Cannon Research Center, Carolinas Medical Center, Charlotte, North Carolina 28232; 1 Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and 4 Carlyle Fraser Heart Center Cardiothoracic Research Laboratory, Crawford Long Hospital, Atlanta, Georgia 30365; and 5 Division of Respiratory, Critical Care and Occupational (Pulmonary) Medicine, University of Utah, Salt Lake City, Utah 84132

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-kappa B (NF-kappa B) from the cytoplasm to the nucleus in human endothelial cells and decreased NF-kappa B 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-kappa B.

ischemia-reperfusion; myocardial infarction; endothelium neutrophils; endothelial dysfunction


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