Liberation of vessel adherent myeloperoxidase by enoxaparin improves endothelial function.

BACKGROUND: Myeloperoxidase (MPO), a leukocyte-derived heme enzyme binds to the endothelium and depletes vascular nitric oxide (NO) bioavailability in animal models. Unfractionated heparins release vessel-bound MPO and increase endothelial NO bioavailability. Whether low molecular weight heparins also affect circulating MPO levels and NO dependent vasoreactivity however remains elusive. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled trial patients with stable coronary artery disease received either 1 mg/kg enoxaparin or an equivalent volume of sodium chloride (NaCl) subcutaneously. Enoxaparin led to a significant improvement of FMD (5.51+/-0.53% vs. 6.55+/-0.58%, p=0.01) accompanied by a significant increase in plasma MPO levels (2.51 [IR: 2.04-3.62] ng/ml vs. 3.70 [IR: 2.80-5.50] ng/ml; p<0.001) whereas NaCl revealed neither a change in FMD (5.56+/-0.67% vs. 5.34+/-0.61%, p=ns) nor in plasma MPO levels (3.04 [IR: 2.22-4.67] ng/ml vs. 2.90 [IR: 1.95-4.32] ng/ml; p=ns). The extent of enoxaparin-induced MPO release and the improvement in endothelial function showed a good correlation (r=0.67, p<0.001). DISCUSSION: This study confirms the concept that heparins improve endothelial function, an established read-out of vascular NO bioavailability, by mobilizing vessel bound MPO. These data not only support the notion of extracoagulant, anti-inflammatory properties of heparins but reinforce the concept of MPO-dependent NO oxidation as a central mechanism for regulation of vascular tone in inflammatory vascular disease. (Eudra-CT number: 2005-006113-40).

Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation.

Observational clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here we provide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation. MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation. In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our data demonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation.