Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase
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Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase. / Rudolph, Volker; Rudolph, Tanja K; Schopfer, Francisco J; Bonacci, Gustavo; Lau, Denise; Szöcs, Katalin; Klinke, Anna; Meinertz, Thomas; Freeman, Bruce A; Baldus, Stephan.
in: The Journal of pharmacology and experimental therapeutics, Jahrgang 327, Nr. 2, 11.2008, S. 324-331.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase
AU - Rudolph, Volker
AU - Rudolph, Tanja K
AU - Schopfer, Francisco J
AU - Bonacci, Gustavo
AU - Lau, Denise
AU - Szöcs, Katalin
AU - Klinke, Anna
AU - Meinertz, Thomas
AU - Freeman, Bruce A
AU - Baldus, Stephan
PY - 2008/11
Y1 - 2008/11
N2 - Bivalirudin, a direct thrombin inhibitor, has emerged as an important alternative to heparin in patients undergoing percutaneous coronary intervention. However, it remains elusive if potentially adverse extracoagulant properties are responsible for the fact that its favorable effects in clinical studies are mainly driven by a reduction in bleeding events. The aim of the current study was to determine the effects and mechanisms of acute treatment with bivalirudin in comparison to heparin on NO bioavailability, an important factor for the pathogenesis of ischemic events. In particular, we studied the interaction between bivalirudin and myeloperoxidase (MPO), a leukocyte-derived enzyme that consumes endothelial-derived nitric oxide (NO), modifies a variety of biological targets, and thus affects the integrity of the vessel wall. In patients undergoing elective percutaneous coronary intervention, bivalirudin, in contrast to heparin, exhibited a significant decrease in plasma MPO levels (p = 0.03) accompanied by a deterioration of flow-mediated dilation (p = 0.02), a surrogate for endothelial NO bioavailability. In vitro experiments revealed avid binding of bivalirudin to both bovine aortic endothelial cells (BAEC) and MPO. Methylation of bivalirudin carboxyl groups at the carboxyl-terminal end revealed the specific binding site of bivalirudin to MPO. Bivalirudin-facilitated binding of MPO to BAEC resulted also in functional changes in terms of increased NO consumption as well as enhanced MPO-mediated redox modifications. These results illustrate dichotomous extracoagulant properties of heparins and thrombin inhibitors and suggest that bivalirudin acutely impairs endothelial NO bioavailability, thereby underscoring the potentially critical role of MPO as a mediator of vascular function.
AB - Bivalirudin, a direct thrombin inhibitor, has emerged as an important alternative to heparin in patients undergoing percutaneous coronary intervention. However, it remains elusive if potentially adverse extracoagulant properties are responsible for the fact that its favorable effects in clinical studies are mainly driven by a reduction in bleeding events. The aim of the current study was to determine the effects and mechanisms of acute treatment with bivalirudin in comparison to heparin on NO bioavailability, an important factor for the pathogenesis of ischemic events. In particular, we studied the interaction between bivalirudin and myeloperoxidase (MPO), a leukocyte-derived enzyme that consumes endothelial-derived nitric oxide (NO), modifies a variety of biological targets, and thus affects the integrity of the vessel wall. In patients undergoing elective percutaneous coronary intervention, bivalirudin, in contrast to heparin, exhibited a significant decrease in plasma MPO levels (p = 0.03) accompanied by a deterioration of flow-mediated dilation (p = 0.02), a surrogate for endothelial NO bioavailability. In vitro experiments revealed avid binding of bivalirudin to both bovine aortic endothelial cells (BAEC) and MPO. Methylation of bivalirudin carboxyl groups at the carboxyl-terminal end revealed the specific binding site of bivalirudin to MPO. Bivalirudin-facilitated binding of MPO to BAEC resulted also in functional changes in terms of increased NO consumption as well as enhanced MPO-mediated redox modifications. These results illustrate dichotomous extracoagulant properties of heparins and thrombin inhibitors and suggest that bivalirudin acutely impairs endothelial NO bioavailability, thereby underscoring the potentially critical role of MPO as a mediator of vascular function.
KW - Aged
KW - Animals
KW - Antithrombins/pharmacology
KW - Biological Availability
KW - Cattle
KW - Female
KW - Fluorescent Antibody Technique
KW - Hirudins/metabolism
KW - Humans
KW - Male
KW - Methylation
KW - Middle Aged
KW - Nitric Oxide/metabolism
KW - Peptide Fragments/metabolism
KW - Peroxidase/blood
KW - Recombinant Proteins/metabolism
KW - Spectrometry, Mass, Electrospray Ionization
KW - Tyrosine/analogs & derivatives
KW - Vasodilation
U2 - 10.1124/jpet.108.142414
DO - 10.1124/jpet.108.142414
M3 - SCORING: Journal article
C2 - 18701766
VL - 327
SP - 324
EP - 331
JO - J PHARMACOL EXP THER
JF - J PHARMACOL EXP THER
SN - 0022-3565
IS - 2
ER -