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The Proceedings of the American Thoracic Society 5:820-823 (2008)
© 2008 The American Thoracic Society
doi: 10.1513/pats.200807-063TH
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Contribution of Myeloperoxidase to Smoking-dependent Vascular Inflammation

Tanja K. Rudolph1, Volker Rudolph1 and Stephan Baldus1

1 Department of Cardiology/Angiology, University Hospital Heart Center, Hamburg, Germany

Correspondence and requests for reprints should be addressed to Tanja K. Rudolph, M.D., University Hospital Heart Center, Department of Cardiology/Angiology, 20246 Hamburg, Germany. E-mail: t.rudolph{at}uke.de

ABSTRACT

Smoking remains the leading cause of cardiovascular disease, accounting for almost one third of cardiac deaths in the Western industrialized countries. Atherosclerosis in general, and coronary disease in particular, is now considered an inflammatory disease. Recent research has tried to better characterize the subcellular mechanisms of smoke and nicotine on the vessel wall and circulating mediators of disease. Whereas nicotine-dependent receptor activation on endothelial cells has long been considered to elicit antiinflammatory actions, recent observations reveal that nicotine evokes close interactions between the endothelium and proinflammatory cells: namely, leukocytes. Besides monocytes and macrophages, nicotine has been shown to stimulate neutrophils, a cell species long been considered irrelevant for the progression of atherosclerotic disease. Being stimulated by nicotine, neutrophils generate reactive oxygen species and release prooxidant enzymes like myeloperoxidase, which are capable of entering the vessel wall independently. Central mechanisms by which these enzymes can modulate the structural and functional integrity of the vessel wall have been characterized and increased our understanding of neutrophil-derived changes in vascular homeostasis in response to smoking and nicotine, respectively.

Key Words: myeloperoxidase • smoking • leukocytes

Smoking is the most important risk factor for the initiation and progression of coronary artery disease. A total of 40% of all smoking related deaths are caused by ischemic heart disease. Different epidemiological studies have shown that smokers have a two- to threefold increased risk of developing coronary artery disease, peripheral artery disease, aortic aneurysm, or ischemic and hemorrhagic stroke. In addition, smoking correlates dose dependently with sudden cardiac death. Cessation of smoking significantly improves outcome; for example, the risk for nonfatal and fatal myocardial infarction was reduced within 5 years.

The mechanism by which smoking may influence cardiovascular events is not fully understood. However, different smoking-induced pathophysiological pathways that accelerate the initiation and progression of atherosclerosis have been identified. Smoking increases blood pressure (1), increases low-density lipoprotein (LDL) cholesterol levels (2), facilitates its oxidation (3, 4), enhances platelet aggregation (5, 6), and increases the expression of cell adhesion molecules in the vessel wall, resulting in increased monocyte and neutrophil adhesion (7–9). Of importance, smoking has also been shown to reduce bioavailability of vascular nitric oxide (NO). This has been mostly attributed to the formation of superoxide by cigarette smoke, which, in turn, can oxidize NO to peroxynitrite (10, 11).

As a consequence, endothelial function has been found to be impaired in otherwise healthy smokers compared with nonsmokers (12, 13). Even previous smokers still reveal impaired endothelial function (13). Nicotine itself seems to contribute at least acutely to the impairment of endothelial function (14). Evidence has been provided that endothelial function has prognostic implications on cardiac events in patients with preserved function, but also in patients with early-stage heart failure (15, 16). Thus, smoking-related impairment of endothelial function can be seen as one important cause for an increase in cardiovascular events in smokers.

Of note, smokers exhibit elevated white cell counts; however, the reason for this observation has not been fully understood (17–19). However, an elevated white blood cell count is closely associated with an increased risk of subsequent cardiovascular events (20, 21). Additionally, it has been shown that not only the number of leukocytes is increased in smokers but leukocytes, and in particular neutrophils, are also significantly activated in smokers, suggesting a systemic inflammatory state (13). In turn, chronic vascular inflammation has emerged to be closely linked to the pathogenesis of coronary artery disease. It seems likely that this smoking-induced inflammatory state is in part responsible for the impact of smoking on the initiation and progression of coronary artery disease in smokers.

It has been shown that nicotine, per se, activates polymorphonuclear neutrophils (PMNs)–nicotine treatment ex vivo resulted in an increased production of IL-8 by neutrophils, and also induced nicotinamide adenine dinucleotide phosphate reduced oxidase activity leading to an enhanced superoxide production (22). In addition, it has also been shown that the levels of myeloperoxidase (MPO), a neutrophil-derived enzyme, are significantly elevated in smokers compared with nonsmokers (13). Even previous smokers were indicative of higher circulating levels of MPO than never-smokers. MPO, a heme enzyme, is primarily expressed in PMNs—and presenting 5% of total protein—is one of the most abundant proteins in PMN. PMNs are responsible for 95% of the circulating MPO pool in humans (23, 24). To a far lesser extent, MPO is also expressed by monocytes, macrophages, Kupffer cells, and microglia cells (24–26). MPO is stored in the azurophilic granules of PMN. Upon activation and degranulation, MPO is released into phagocytic vacuoles, into the extracellular space, and, in the case of PMN activation within the circulatory system, MPO can also be released into the blood stream.

In the presence of its substrates, hydrogen peroxide and chloride MPO catalyzes the formation of hypochloric acid, a powerful chlorinating oxidant, which is believed to be critically important for the microbicidal and viricidal properties of neutrophils (27, 28). For many years, MPO has been only viewed as an important enzyme involved in immune defense. However, over the last decade, evidence is growing that MPO not only plays a role in bacterial and viral immune defense, but also contributes to the initiation and progression of vascular inflammatory diseases (29–31).

An important prerequisite for the effect of MPO on vascular inflammatory diseases is its ability to oxidize NO to nitrite, leading to a reduced vascular NO bioavailability (Figure 1) (32, 33). MPO, which is highly cationic, is able to interact with the anionic-charged heparansulfate-glycosaminoglycans of the surface of endothelial cells (34). Upon binding to endothelial cells, catalytically active MPO reaches the subendothelial layer by transcytosis, and sequestrates in the layer between endothelial cells and smooth muscle cells (35). Considering the antiinflammatory properties of endothelial-derived NO, as evidenced by relaxation of smooth muscle cells, inhibition of smooth muscle cell proliferation, adhesion molecule expression, as well as platelet aggregation, MPO likely affects homeostasis and antiinflammatory properties of the vessel wall.


Figure 1
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  		Figure 1. Activation of polymorphonuclear neutrophils by nicotine/smoke condensate and its consequences in the vessel wall. MPO = myeloperoxidase; MPO-I = myeloperoxidase compound I; MPO-II = myeloperoxidase compound II; NO = nitric oxide; H2O2 = hydrogen peroxide; NO2– = nitrite;·NO2 = nitrogen dioxide; O2– = superoxide.

 
In addition, in the presence of its principal substrate, hydrogen peroxide, MPO is able to oxidize nitrite to the highly reactive radical, nitrogen dioxide, which in turn nitrates free and protein associated tyrosine residues to 3-nitro-tyrosine (27, 35). Nitrotyrosine has been considered to represent a marker of oxidative stress, but, furthermore, it is also linked to altered protein structure and, consequently, function during inflammatory conditions (36). For example, the matrix protein, fibronectin, has been identified to be modified by MPO. Its oxidative modification leads to a significant alteration of its biological function, which includes regulation of motility, growth, and adherence of various cell types (37).

It has also been demonstrated that MPO is involved in lipid peroxidation and nitration (38). Through generation of its oxidation product, nitrogen dioxide, MPO also has the ability to oxidize LDL and high-density lipoprotein (HDL), resulting in cholesterol deposition in macrophages and, finally, foam-cell formation, an important step in atherosclerotic plaque initiation and progression (39, 40). Recently, evidence has been provided that MPO-catalyzed oxidation of thiocyanate, the levels of which are significantly elevated in chronic smokers, in the presence of hydrogen dioxide also modifies LDL cholesterol, leading to carbamylation of the lipoprotein moiety, which, in turn, facilitates multiple proatherogenic activities of LDL cholesterol (41). In addition, MPO not only enhances the formation of atherosclerotic plaques, but also provokes their instability and, finally, their rupture by activation of matrix metalloproteinases via its product, hypochlorous acid (42–44).

It has also been shown that, via lipid peroxidation and nitration of different structural myocardial proteins, like plasminogen activator inhibitor-1, MPO impacts left ventricular remodeling after myocardial infarction. Investigations in MPO knockout mice have revealed that they developed less left ventricular dilation after induction of an anterior myocardial infarction, accompanied by a better restoration of left ventricular function (44).

Clinical trials during the last decade also revealed that MPO is not only an important pathophysiological factor for inflammatory vascular disease, but also a valuable diagnostic marker in patients with acute coronary syndrome. The fact that MPO plasma levels are already elevated upon plaque rupture—thus preceding myocardial necrosis—led to the hypothesis that MPO would be suitable as an early marker for acute coronary syndrome. Different studies have shown that levels of MPO increase with a sensitivity of 80–92%, much earlier, and within the first 3 hours after onset of symptoms as compared with the current diagnostic gold standard, troponin T. However, the main limitation of MPO being used as a biomarker remains its low specificity, which is between 40 and 50% (31, 45).

In contrast to its limitations as a diagnostic indicator, MPO emerged as a powerful prognostic marker in patients with acute coronary syndrome, heart failure, peripheral vascular disease, and carotid disease, as shown in Table 1 (31, 45–52). Of note, even in "healthy" subjects without a history of manifested cardiovascular disease, elevation of MPO plasma levels indicates an increased risk for the development of coronary artery disease, as evidenced by data derived from the European Prospective Investigation of Cancer Norfolk study. In this study, MPO was an independent marker to identify subjects at risk, in particular if their profile of traditional risk factors, like low LDL cholesterol levels, high HDL cholesterol levels, and low C-reactive protein levels, did not indicate an increased cardiovascular risk (30). With respect to acute coronary syndromes, two studies elucidated that elevated circulating MPO levels correspond with a 2.25- to 4.7-fold increased risk for major adverse cardiac events (31, 45).


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  		TABLE 1. MYELOPEROXIDASE AS PROGNOSTIC MARKER OF DIFFERENT CARDIOVASCULAR DISEASES

 
In summary, a growing body of evidence now suggests that MPO released by activated PMNs contributes significantly to the initiation and progression of smoking-dependent vascular inflammation and smoking-induced atherosclerosis by reducing endothelial NO bioavailability, increasing LDL and HDL oxidation, and finally enhancing atherosclerotic plaque growth and instability. Since MPO has emerged as an important contributing pathophysiological factor in atherosclerosis and heart failure, the development of pharmacological approaches to inhibit MPO activity would seem to be a promising treatment strategy in various vascular inflammatory diseases.

CONCLUSIONS

Smoking has long been known as a significant risk factor for coronary artery disease. There is growing evidence that PMNs contribute significantly to the initiation and progression of vascular inflammation in smokers. In particular, MPO emerges as a critical contributor for the development and progression of coronary artery disease in smokers, and may evolve as a novel biomarker in patients with cardiovascular disease.

FOOTNOTES

Supported by Deutsche Forschungsgemeinschaft (T.K.R., S.B.), Werner Otto-Stiftung (S.B.), and Deutsche Herzstiftung (V.R).

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form July 2, 2008; accepted in final form August 24, 2008)

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