Serum Myeloperoxidase Levels Independently Predict Endothelial Dysfunction in Humans

Joseph Vita

Marie Brennan

Noyan Gokce

Shirley Mann

From the Departments of Cell Biology (M.-L.B., S.A.M., M.H.S., M.S.P., S.L.H.) and Cardiovascular Medicine (M.S.P., M.G., S.L.H.) and Center for Cardiovascular Diagnostics and Prevention (M.-L.B., S.A.M., M.H.S., M.S.P., S.L.H.), Cleveland Clinic Foundation, Cleveland, Ohio, and the Evans Department of Medicine and Whitaker Cardiovascular Institute (N.G., J.F.K., J.A.V.), Boston University School of Medicine, Boston, Mass.

Correspondence to Stanley L. Hazen, MD, PhD, Preventive Cardiology, Cleveland Clinic Foundation, 9500 Euclid Ave, C51, Cleveland, OH 44195. E-mail gro.fcc@snezah

Abstract

Background

In vitro and animal studies demonstrate that myeloperoxidase catalytically consumes nitric oxide as a substrate, limiting its bioavailability and function. We therefore hypothesized that circulating levels of myeloperoxidase would predict risk of endothelial dysfunction in human subjects.

Methods and Results

Serum myeloperoxidase was measured by enzyme-linked immunoassay, and brachial artery flow–mediated dilation and nitroglycerin-mediated dilation were determined by ultrasound in a hospital-based population of 298 subjects participating in an ongoing study of the clinical correlates of endothelial dysfunction (age, 51±16; 61% men, 51% with cardiovascular disease). A strong inverse relation between brachial artery flow–mediated dilation and increasing quartile of serum myeloperoxidase level was observed (11.0±6.0%, 9.4±5.3%, 8.6±5.8%, and 6.4±4.5% for quartiles 1 through 4, respectively; P<0.001 for trend). Using the median as a cut point to define endothelial dysfunction, increasing quartile of myeloperoxidase predicted endothelial dysfunction after adjustment for classic cardiovascular disease risk factors, C-reactive protein levels, prevalence of cardiovascular disease, and ongoing treatment with cardiovascular medications (OR, 6.4; 95% CI, 2.6 to 16; P=0.001 for highest versus lowest quartile).

Conclusions

Serum myeloperoxidase levels serve as a strong and independent predictor of endothelial dysfunction in human subjects. Myeloperoxidase-mediated endothelial dysfunction may be an important mechanistic link between oxidation, inflammation, and cardiovascular disease.

Keywords: atherosclerosis, free radicals, inflammation, peroxidase, nitric oxide

Abstract

Recent studies have emphasized the importance of myeloperoxidase for cardiovascular disease.¹4 Myeloperoxidase levels are higher in patients with coronary artery disease¹ and predict future cardiovascular events after risk factors and C-reactive protein are controlled for.²3 Myeloperoxidase-derived oxidants, including hypochlorous acid, play a physiological role in innate host defenses. However, the enzyme and products of myeloperoxidase-catalyzed oxidation reactions (tyrosylation, nitration, halogenation) have been identified in human atherosclerotic lesions, further suggesting that myeloperoxidase may play a pathophysiological role in atherogenesis.⁵8

Another potentially important consequence of myeloperoxidase activity is consumption of nitric oxide and induction of endothelial dysfunction. Kinetic studies first showed that myeloperoxidase can serve as a catalytic sink for nitric oxide.⁹ Consistent with such an effect, myeloperoxidase impairs nitric oxide–dependent vasodilation in isolated arterial and tracheal rings and decreases nitric oxide bioavailability in cultured cells.¹⁰12 Myeloperoxidase is rapidly taken up by endothelial cells by a transcytotic process and accumulates within the subendothelial space, positioning it anatomically to interfere with the effects of nitric oxide in the vessel wall.¹²13

The purpose of the present study was to seek evidence that myeloperoxidase impairs the biological activity of endothelium-derived nitric oxide in human subjects. We hypothesized that serum myeloperoxidase levels would correlate inversely with nitric oxide–dependent flow-mediated dilation of the brachial artery.¹⁴ Given the important antiatherogenic effects of endothelium-derived nitric oxide,¹⁵ this finding would provide insight into the causes of endothelial dysfunction and additional evidence that myeloperoxidase may play a pathogenic role in cardiovascular disease.

Footnotes

Disclosure

Dr Hazen is named as a co-inventor on pending patents filed by the Cleveland Clinic Foundation that relate to the use of biomarkers for inflammatory and cardiovascular diseases.

Footnotes

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