on April 10, 2006
Published online before print April 10, 2006, doi: 10.1161/CIRCULATIONAHA.105.590083
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Submitted on September 20, 2005
From the Departments of Cardiology (S.B., V.R., M.R., W.D.I., T.K.R., K. Sydow, D.L., K. Szöcs, A.K., T.R., H.K., T.M., T.H.) and Cardiovascular Surgery (S.S., T.D., H.C.R.), Heart Center, and the Department of Clinical Chemistry (M.H.), University Hospital Hamburg-Eppendorf, Hamburg, Germany; and the Departments of Internal Medicine and Human Physiology (J.P.E., L.K., L.B.), University of California, Davis. * To whom correspondence should be addressed. E-mail: baldus{at}uke.uni-hamburg.de.
Background--Neutrophils and monocytes are centrally linked to vascular inflammatory disease, and leukocyte-derived myeloperoxidase (MPO) has emerged as an important mechanistic participant in impaired vasomotor function. MPO binds to and transcytoses endothelial cells in a glycosaminoglycan-dependent manner, and MPO binding to the vessel wall is a prerequisite for MPO-dependent oxidation of endothelium-derived nitric oxide (NO) and impairment of endothelial function in animal models. In the present study, we investigated whether heparin mobilizes MPO from vascular compartments in humans and defined whether this translates into increased vascular NO bioavailability and function. Methods and Results--Plasma MPO levels before and after heparin administration were assessed by ELISA in 109 patients undergoing coronary angiography. Whereas baseline plasma MPO levels did not differ between patients with or without angiographically detectable coronary artery disease (CAD), the increase in MPO plasma content on bolus heparin administration was higher in patients with CAD (P=0.01). Heparin treatment also improved endothelial NO bioavailability, as evidenced by flow-mediated dilation (P<0.01) and by acetylcholine-induced changes in forearm blood flow (P<0.01). The extent of heparin-induced MPO release was correlated with improvement in endothelial function (r=0.69, P<0.01). Moreover, and consistent with this tenet, ex vivo heparin treatment of extracellular matrix proteins, cultured endothelial cells, and saphenous vein graft specimens from CAD patients decreased MPO burden. Conclusions--Mobilization of vessel-associated MPO may represent an important mechanism by which heparins exert antiinflammatory effects and increase vascular NO bioavailability. These data add to the growing body of evidence for a causal role of MPO in compromised vascular NO signaling in humans.
Revised on January 16, 2006
Accepted on February 10, 2006
Heparins Increase Endothelial Nitric Oxide Bioavailability by Liberating Vessel-Immobilized Myeloperoxidase
Stephan Baldus MD*,
Key words: atherosclerosis • coronary disease • endothelium • inflammation • leukocytes
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