Letter Regarding Article by Vita et al, “Serum Myeloperoxidase Levels Independently Predict Endothelial Dysfunction in Humans”
To the Editor:
We read with great interest the article by Vita and coworkers1 that described serum myeloperoxidase levels as a strong and independent predictor of endothelial dysfunction in a hospital-based population. Recently, we retrospectively analyzed concentrations of serum myeloperoxidase levels by enzyme-linked immunosorbent assay (ELISA; Calbiochem/EMD Biosciences) in 22 patients (18 men, 4 women; 11 smokers; mean age±SD: 64.8±13.3 years) who underwent elective coronary or peripheral arterial angiography2 and compared them with neopterin (determined by ELISA; BRAHMS Diagnostica) and homocysteine levels (measured by HPLC), 2 parameters that have been identified individually as prognostic markers for adverse events in patients with atherosclerotic disease.3,4 We found significant associations between myeloperoxidase and neopterin (Spearman rank correlation coefficient rs 0.594, P<0.01) and between myeloperoxidase and homocysteine (rs 0.490, P<0.05) concentrations; in addition, neopterin and homocysteine concentrations were significantly related (rs 0.604, P<0.001).
Neopterin is released by macrophages on stimulation with interferon-γ; thus, increased neopterin concentrations are found in diseases that involve the activation of cellular immunity. Therefore, the concurrent increase of serum myeloperoxidase, neopterin, and homocysteine concentrations points to an association between myeloperoxidase production and specific immune activation. The finding in patients is strengthened by the recent observation that neopterin interferes with the generation of reactive species by myeloperoxidase in human neutrophils.5 Nevertheless, the association among these 3 risk factors has not been appreciated before in vivo. From the data it appears that the immunoregulatory pathway that leads to cellular immune activation, increased production of Th1-type cytokine interferon-γ, and macrophage stimulation offers a potential link between the immunopathogenesis of atherosclerosis and elevated levels not only of neopterin but also of myeloperoxidase and homocysteine. Of note, Vita et al did not find an association between C-reactive protein and myeloperoxidase concentrations1; likewise, our analysis showed no correlation between C-reactive protein and myeloperoxidase, neopterin, and homocysteine, suggesting that activation of this immunoregulatory pathway does not necessarily lead to easily detectable increases of other markers of systemic inflammation.
Our preliminary data suggest a relationship between myeloperoxidase production and immune system activation pathways and may therefore question the independence of myeloperoxidase as a predictive marker for endothelial dysfunction and adverse events in patients with cardiovascular disease. Further studies are necessary to confirm the associations found in our limited number of patients and to firmly establish a causal relationship.
We thank Drs Walter, Schroecksnadel, and Fuchs for their interest in our article.1 Their preliminary findings of correlations among myeloperoxidase, homocysteine, and neopterin are intriguing and deserve further examination with larger numbers of patients. An association between serum myeloperoxidase levels and activation of cellular immunity, as monitored by neopterin, may be rationalized by interferon-γ–dependent activation of monocyte/macrophages, a cell source of myeloperoxidase. Biochemical pathways that may account for correlations between elevated levels of homocysteine and myeloperoxidase are less clear, however.
We agree that our clinical studies do not establish a cause-and-effect relationship between myeloperoxidase and the development of endothelial dysfunction in humans. We note, however, that the rationale for examining the relationship between myeloperoxidase and endothelial dysfunction has its genesis in basic biochemical and kinetic studies that identify nitric oxide as a physiological substrate of myeloperoxidase.2 Subsequent cellular, organ chamber, and animal model studies that use myeloperoxidase knockout mice similarly point toward the conclusion that myeloperoxidase may both function as a catalytic sink for nitric oxide and limit its synthesis, reducing its bioavailability and function at sites of inflammation.3–5 The observed robustness of the association between myeloperoxidase levels and endothelial dysfunction in subjects despite adjustments for multiple factors such as prevalent cardiovascular disease, cardiovascular medications, C-reactive protein, and Framingham risk factors is consistent with the notion that myeloperoxidase may limit nitric oxide bioavailability in the subendothelial compartment of atherosclerotic plaque, where the enzyme is enriched.
Vita JA, Brennan ML, Gokce N, Mann SA, Goormastic M, Shishehbor MH, Penn MS, Keaney JF Jr, Hazen SL. Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation. 2004; 110: 1134–1139.
Abu-Soud HM, Hazen SL. Nitric oxide is a physiological substrate for mammalian peroxidases. J Biol Chem. 2000; 275: 37524–37532.
Zhang C, Patel R, Eiserich JP, Zhou F, Kelpke S, Ma W, Parks DA, Darley-Usmar V, White CR. Endothelial dysfunction is induced by proinflammatory oxidant hypochlorous acid. Am J Physiol Heart Circ Physiol. 2001; 281: H1469–H1475.
Eiserich JP, Baldus S, Brennan ML, Ma W, Zhang C, Tousson A, Castro L, Lusis AJ, Nauseef WM, White CR, Freeman BA. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science. 2002; 296: 2391–2394.