title: Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Cardiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. baldus@uke.uni-hamburg.de
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.forename: Volker
authors.initials: V
authors.lastname: Rudolph
authors.forename: Mika
authors.initials: M
authors.lastname: Roiss
authors.forename: Wulf D
authors.initials: WD
authors.lastname: Ito
authors.forename: Tanja K
authors.initials: TK
authors.lastname: Rudolph
authors.forename: Jason P
authors.initials: JP
authors.lastname: Eiserich
authors.forename: Karsten
authors.initials: K
authors.lastname: Sydow
authors.forename: Denise
authors.initials: D
authors.lastname: Lau
authors.forename: Katalin
authors.initials: K
authors.lastname: Szöcs
authors.forename: Anna
authors.initials: A
authors.lastname: Klinke
authors.forename: Lukas
authors.initials: L
authors.lastname: Kubala
authors.forename: Lars
authors.initials: L
authors.lastname: Berglund
authors.forename: Sonja
authors.initials: S
authors.lastname: Schrepfer
authors.forename: Tobias
authors.initials: T
authors.lastname: Deuse
authors.forename: Munif
authors.initials: M
authors.lastname: Haddad
authors.forename: Tim
authors.initials: T
authors.lastname: Risius
authors.forename: Hanno
authors.initials: H
authors.lastname: Klemm
authors.forename: Hermann C
authors.initials: HC
authors.lastname: Reichenspurner
authors.forename: Thomas
authors.initials: T
authors.lastname: Meinertz
authors.forename: Thomas
authors.initials: T
authors.lastname: Heitzer
mesh_terms: D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001682:Biological Availability; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology; D016022:Case-Control Studies; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000097:blood; D009195:Peroxidase / Q000097:blood / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D009569:Nitric Oxide; D006493:Heparin; D009195:Peroxidase; D010196:Pancreatic Elastase