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. 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 (Pϭ0.01). Heparin treatment also improved endothelial NO bioavailability, as evidenced by flow-mediated dilation (PϽ0.01) and by acetylcholine-induced changes in forearm blood flow (PϽ0.01). The extent of heparin-induced MPO release was correlated with improvement in endothelial function (rϭ0.69, PϽ0.01). 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

Increased Myeloperoxidase in the Placenta and Circulation of Women With Preeclampsia

“…Functional significance of the vascular-associated MPO has been shown in patients undergoing coronary angiography for treatment of coronary artery disease. Baldus et al 30 found no significant difference in baseline plasma MPO levels, but on heparin infusion to release MPO from heparin glycosaminoglycan binding sites, circulating MPO levels were significantly higher in patients with coronary artery disease. Heparin infusion was also associated with improved NO-mediated endothelial function using flow-mediated dilation and responsiveness to acetylcholine.…”

Free Fatty Acid Causes Leukocyte Activation and Resultant Endothelial Dysfunction Through Enhanced Angiotensin II Production in Mononuclear and Polymorphonuclear Cells

“…Immediately after blood sampling at 120 minutes, bolus heparin (70 U/kg of body weight) was injected to release vessel wall-immobilized MPO into the circulating blood. [22][23][24] Each subject received 160-mg oral doses of valsartan (Novartis Pharmaceutical Co, Ltd) or placebo at 28 and 4 hours before the experiment in a double-blind crossover design on study day 2 or 3. The order of the pretreatment was randomized.…”

Old and new applications of non-anticoagulant heparin

“…A recent systematic review with meta-analysis showed the beneficial effects of heparin treatment in asthmatic patients [13]. In normal subjects, heparin can inhibit reactive oxygen species (ROS) generation [14], supporting the observed cardiovascular protective effects, and also increases nitric oxide bioavailability through the release of vessel immobilized myeloperoxidase [15]. The role of neutrophil elastase, a highly aggressive endopeptidase, seems to be crucial and is provoked by imbalances of natural inhibitors leading to degradation of connective and tissue components as observed in emphysema, cystic fibrosis, rheumatoid arthritis, psoriasis, perodontitis, mucopolysaccharidosis, wound healing and tumour invasion.…”

“…Experimental and clinical studies in patients with proteinuric glomerulonephritis showed benefit by oral treatment with sulodexide, a mixture of LMW heparin and dermatan sulfate in a Acute respiratory distress syndrome* [5,42] Allergic rhinitis [43] Antimalaric a [44] Antiphospholipid syndrome [45] Asthma and bronchial constriction [5,13] Cardioversion of atrial fibrillation [46] Cardiopathies [47] Chronic obstructive pulmonary diseases [5] Cystic fibrosis [18,48] Glomerulonephritis [26] Hyperlipemias [49] Inflammatory bowel diseases [5,29,50] Mucolytic agent (Inhaled) [51] Nervous system protection by radiation [52] Rheumatoid arthritis [5,53] Severe sepsis [54] Tissue repair and wound healing [5] Vasoprotection [55] a Heparin, inhibiting and reversing cytoadherence and rosetting of Plasmodium falciparium infected erythrocytes "in vitro". Tested from 1967 in severe malaria clinical trials, after some overall promising outcomes, were discontinued due to severe intracranial bleeding [44] 4:1 weight ratio [26].…”