Endothelial Function in a Mouse Model of Myeloperoxidase Deficiency

Veronika Golubinskaya,Li-Ming Gan,Holger Nilsson,Martin Kjerrulf,Ulla Brandt-Eliasson

doi:10.1155/2014/128046

Veronika Golubinskaya, Li-Ming Gan + Show 3 more

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https://doi.org/10.1155/2014/128046

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Abstract

Myeloperoxidase (MPO) activity is suggested to reduce the function of vascular nitric oxide, thereby contributing to endothelial dysfunction, although data in rodents are inconclusive. We examined vascular contractile and relaxant responses in MPO-deficient (MPO−/−) and wild-type mice to investigate the role for myeloperoxidase in the development of endothelial dysfunction. Carotid and saphenous arteries were taken from 8-month-old mice and studied in a myograph. Responses of carotid arteries to phenylephrine, high potassium, or acetylcholine (Ach) were statistically not different from controls. Treatment with lipopolysaccharide (LPS; to enhance endothelial dysfunction) reduced responses to Ach in MPO−/− but did not affect responses in wild-type. In response to high concentrations of Ach, carotid arteries responded with transient contractions, which were not different between the groups and not affected by LPS treatment. Saphenous arteries from MPO−/− had smaller normalized diameters and developed less contractile force. Vessels from MPO−/− were less sensitive to Ach than controls. These data suggest that mature MPO-deficient mice do not show enhanced endothelial function compared to wild-type mice, even when provoked with LPS treatment. The EDHF response appears to be reduced in MPO deficiency.

Highlights

Endothelium-dependent vasodilatation in response to, for example, elevations of blood flow is considered a hallmark of normal vascular function [1]
Most of the C57BL/6 mice neutrophils expressed MPO (96.1 ± 2.5%) while neutrophils of MPO−/− mice were deficient for MPO (0.52 ± 0.51%)
Liberated MPO may penetrate the endothelium and accumulate extracellularly in the subintimal space, where the activity of MPO will reduce the half-life of nitric oxide, released from the endothelium, and counteract NO-dependent vasodilator mechanisms and contribute to endothelial dysfunction

Summary

Introduction

Endothelium-dependent vasodilatation in response to, for example, elevations of blood flow is considered a hallmark of normal vascular function [1]. Atherosclerosis affects predominantly the large arteries, endothelial dysfunction is probably a general feature of the endothelium in most parts of the vasculature of the atherosclerotic patient [3]. MPO catalyses the conversion of hydrogen peroxide to hypochlorous acid. This product may react with nitric oxide, creating peroxynitrite, which has detrimental effects on effector cell function. MPO may directly catalyse the elimination of nitric oxide. MPO may increase oxidative stress and oxidise [5, 6] or carbamylate [7] lipoproteins. In these ways, myeloperoxidase activity may directly and indirectly antagonise endothelial function

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