Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase

Stephan Baldus, Volker Rudolph, Mika Roiss, Wulf D. Ito, Tanja K. Rudolph, Jason P. Eiserich, Karsten Sydow, Denise Lau, Katalin Szöcs, Anna Klinke, Lukas Kubala, Lars Berglund, Sonja Schrepfer, Tobias Deuse, Munif Haddad, Tim Risius, Hanno Klemm, Hermann C. Reichenspurner, Thomas Meinertz, Thomas Heitzer

Research output: Contribution to journalArticle

143 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)1871-1878
Number of pages8
JournalCirculation
Volume113
Issue number15
DOIs
StatePublished - Apr 2006

Fingerprint

Peroxidase
Biological Availability
Heparin
Nitric Oxide
Blood Vessels
Coronary Artery Disease
Endothelial Cells
Extracellular Matrix Proteins
Saphenous Vein
Glycosaminoglycans
Coronary Angiography
Vascular Diseases
Forearm
Acetylcholine
Dilatation
Monocytes
Cultured Cells
Neutrophils
Leukocytes
Anti-Inflammatory Agents

Keywords

  • Atherosclerosis
  • Coronary disease
  • Endothelium
  • Inflammation
  • Leukocytes

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Baldus, S., Rudolph, V., Roiss, M., Ito, W. D., Rudolph, T. K., Eiserich, J. P., ... Heitzer, T. (2006). Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase. Circulation, 113(15), 1871-1878. https://doi.org/10.1161/CIRCULATIONAHA.105.590083

Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase. / Baldus, Stephan; Rudolph, Volker; Roiss, Mika; Ito, Wulf D.; Rudolph, Tanja K.; Eiserich, Jason P.; Sydow, Karsten; Lau, Denise; Szöcs, Katalin; Klinke, Anna; Kubala, Lukas; Berglund, Lars; Schrepfer, Sonja; Deuse, Tobias; Haddad, Munif; Risius, Tim; Klemm, Hanno; Reichenspurner, Hermann C.; Meinertz, Thomas; Heitzer, Thomas.

In: Circulation, Vol. 113, No. 15, 04.2006, p. 1871-1878.

Research output: Contribution to journalArticle

Baldus, S, Rudolph, V, Roiss, M, Ito, WD, Rudolph, TK, Eiserich, JP, Sydow, K, Lau, D, Szöcs, K, Klinke, A, Kubala, L, Berglund, L, Schrepfer, S, Deuse, T, Haddad, M, Risius, T, Klemm, H, Reichenspurner, HC, Meinertz, T & Heitzer, T 2006, 'Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase', Circulation, vol. 113, no. 15, pp. 1871-1878. https://doi.org/10.1161/CIRCULATIONAHA.105.590083
Baldus, Stephan ; Rudolph, Volker ; Roiss, Mika ; Ito, Wulf D. ; Rudolph, Tanja K. ; Eiserich, Jason P. ; Sydow, Karsten ; Lau, Denise ; Szöcs, Katalin ; Klinke, Anna ; Kubala, Lukas ; Berglund, Lars ; Schrepfer, Sonja ; Deuse, Tobias ; Haddad, Munif ; Risius, Tim ; Klemm, Hanno ; Reichenspurner, Hermann C. ; Meinertz, Thomas ; Heitzer, Thomas. / Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase. In: Circulation. 2006 ; Vol. 113, No. 15. pp. 1871-1878.
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T1 - Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase

AU - Baldus, Stephan

AU - Rudolph, Volker

AU - Roiss, Mika

AU - Ito, Wulf D.

AU - Rudolph, Tanja K.

AU - Eiserich, Jason P.

AU - Sydow, Karsten

AU - Lau, Denise

AU - Szöcs, Katalin

AU - Klinke, Anna

AU - Kubala, Lukas

AU - Berglund, Lars

AU - Schrepfer, Sonja

AU - Deuse, Tobias

AU - Haddad, Munif

AU - Risius, Tim

AU - Klemm, Hanno

AU - Reichenspurner, Hermann C.

AU - Meinertz, Thomas

AU - Heitzer, Thomas

PY - 2006/4

Y1 - 2006/4

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Coronary disease

KW - Endothelium

KW - Inflammation

KW - Leukocytes

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