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Am J Physiol Regul Integr Comp Physiol 287: R284-R287, 2004. First published May 13, 2004; doi:10.1152/ajpregu.00241.2004
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Oxidative Stress

Circulating free nitrotyrosine in obstructive sleep apnea

Anna Svatikova, Robert Wolk, Hui H. Wang, Maria E. Otto, Kevin A. Bybee, Ravinder J. Singh, and Virend K. Somers

Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905

Submitted 9 April 2004 ; accepted in final form 11 May 2004


   ABSTRACT
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 ABSTRACT
METHODS
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 DISCUSSION
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Obstructive sleep apnea (OSA) has been increasingly linked to cardiovascular disease, endothelial dysfunction, and oxidative stress, generated by repetitive nocturnal hypoxemia and reperfusion. Circulating free nitrotyrosine has been reported as a novel biomarker of nitric oxide (NO)-induced oxidative/nitrosative stress. Nitrosative stress has been implicated as a possible mechanism for development of cardiovascular diseases. We tested the hypothesis that repetitive severe hypoxemia resulting from OSA would increase NO-mediated oxidative stress. We studied 10 men with newly diagnosed moderate to severe OSA who were free of other diseases, had never been treated for OSA, and were taking no medications. Nitrotyrosine measurements, performed by liquid chromatography-tandem mass spectrometry, were made before and after untreated apneic sleep. We compared free nitrotyrosine levels in these patients with those obtained at similar times in 10 healthy male control subjects without OSA, with similar age and body mass index. Evening baseline nitrotyrosine levels were similar before sleep in the control and OSA groups [0.16 ± 0.01 and 0.15 ± 0.01 ng/ml, respectively, P = not significant (NS)]. Neither normal nor disturbed apneic sleep led to significant changes of plasma nitrotyrosine (morning levels: control group 0.14 ± 0.01 ng/ml; OSA group 0.15 ± 0.01 ng/ml, P = NS). OSA was not accompanied by increased circulating free nitrotyrosine either at baseline or after sleep. This observation suggests that repetitive hypoxemia during OSA does not result in increased NO-mediated oxidative/nitrosative stress in otherwise healthy subjects with OSA.

nitric oxide; cardiovascular diseases

OBSTRUCTIVE SLEEP APNEA (OSA) has been linked to increased prevalence of cardiovascular and cerebrovascular morbidity (43). OSA is characterized by repetitive episodes of apnea and hypopnea that lead to surges in arterial blood pressure and increased sympathetic nerve activity (37, 45). More recently, OSA has also been associated with inflammation (35, 39, 44), endothelial dysfunction (19, 22) and increased oxidative stress (6, 9, 23, 32), generated by repetitive nocturnal hypoxemia and reoxygenation. However, the mechanisms for increased cardiovascular disease in OSA are not fully understood.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the most important free radicals in the human body causing increased oxidative/nitrosative stress and tissue injury under pathological conditions (20, 31). Emerging evidence suggests that ROS are involved in the development and progression of a wide range of cardiovascular diseases (1, 14, 27, 30). Recent studies also indicate that RNS may likewise contribute to cardiovascular disease, including vascular inflammation, endothelial dysfunction, coronary artherosclerosis, hypertension, and heart failure (2, 3, 7, 15, 36, 41). OSA has been strongly linked to oxidative stress (6, 9, 23, 32); however, the effects of OSA on RNS have not been evaluated.

Peroxynitrite (ONNO–) and other RNS are generated by the reaction of superoxide (O2–·) and nitric oxide (NO), which is a ubiquitous signaling molecule (17, 26, 28). OSA is associated with increased release of ROS, including superoxide (32) and hence the possibility that OSA would also be accompanied by increased production of RNS. The reaction of RNS with protein-bound tyrosine residues causes formation of 3-nitrotyrosine, which has been implicated as a possible mechanism for development of cardiovascular diseases (2, 10, 16, 25, 36, 38). Thus increased levels of circulating free plasma nitrotyrosine in OSA might help explain any associations between OSA and cardiovascular diseases.

We therefore tested the hypothesis that repetitive hypoxemia resulting from OSA would increase systemic NO-mediated oxidative/nitrosative burden. We performed quantitative analysis of the fluctuation of free nitrotyrosine concentrations in OSA patients compared with healthy controls, using a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, so as to evaluate for direct in vivo evidence for NO-mediated oxidative/nitrosative tissue injury.


   METHODS
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 METHODS
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We compared subjects with moderate to severe OSA [apnea-hypopnea index (AHI) > 20] with those without OSA (AHI < 5). We studied 10 male patients with newly diagnosed OSA who were free of other diseases, had never been treated for OSA, and were taking no medications and 10 healthy male control subjects with similar age and body mass index (BMI), in whom occult OSA was excluded by overnight polysomnography. OSA patients without concomitant disease were recruited by obtaining a detailed medical history, medical records, detailed physical exam, blood pressure check, electrocardiogram, and blood tests (glucose, creatinine, and lipid levels). All participants were nonsmokers. The study protocol was approved by the Human Subjects Review Committee, and all subjects signed an informed written consent.

The presence and severity of OSA were determined by standard overnight polysomnography. AHI was calculated as the total number of apneas and hypopneas per hour of sleep. Plasma levels of nitrotyrosine were measured in all subjects at baseline before sleep at 9:00 PM and immediately after waking in the morning at 6:00 AM. Blood pressure measurements reported in Table 1 were taken using an automatic device (Dinamap) in the evening, before the sleep study started. All subjects remained in the supine position and rested for at least 15 min before the measurement.


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  		Table 1. Baseline characteristics of OSA patients and healthy control subjects

 
Circulating free nitrotyrosine concentration in each plasma sample was measured by LC-MS/MS method (12, 42), using a HPLC reverse-phase column, followed by a Triple Quadrupole Mass Spectrometer (API 3000), using electrospray ionization and a positive ion mode with multiple-reaction monitoring.

Results are reported as means ± SE. Continuous variables were compared between groups using paired or unpaired t-tests, as appropriate. Statistical significance was defined as P < 0.05.


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Baseline demographics, hemodynamics, and metabolic characteristics of study participants are shown in Table 1. OSA patients suffered a high nocturnal hypoxic burden with a mean AHI of 56 events/h and lowest nocturnal oxygen saturation averaging 76 ± 4%.

Evening baseline free nitrotyrosine levels were similar before sleep in the control and OSA groups [0.16 ± 0.01 and 0.15 ± 0.01 ng/ml, respectively, P = not significant (NS)]. Neither normal sleep nor disturbed apneic sleep led to significant changes of plasma nitrotyrosine levels (morning levels: control group 0.14 ± 0.01 ng/ml; OSA group 0.15 ± 0.01 ng/ml, P = NS) (Fig. 1).



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  		Fig. 1. Plasma free nitrotyrosine levels in 10 obstructive sleep apnea (OSA) patients and 10 healthy control subjects before sleep (9:00 PM) and in the morning, after awakening (6:00 AM). Data are shown as scatterplot with horizontal bars representing the means. P = not significant.

 

   DISCUSSION
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The present study was undertaken to test the hypothesis that circulating free nitrotyrosine levels, a specific marker for NO-mediated oxidative injury to proteins, are affected either acutely or chronically by repetitive severe hypoxemia resulting from OSA.

Our hypothesis was based on the fact that OSA has been shown to be associated with increased generation of superoxide and other ROS (9, 32), which react with NO and lead to the production of peroxynitrite. Peroxynitrite is a potent oxidizing and nitrating agent that may be implicated in the pathogenesis of cardiovascular disease and formation of atherosclerotic lesions by increasing lipid peroxidation, depleting antioxidant defenses, and injuring endothelial cells (2, 3, 15, 17). Decreased NO synthase activity, which may be also due to hypoxia or due to increased NO synthase inhibitors (34), may contribute to the lower NO levels that have been reported in OSA patients (18, 24, 33). Reduced biological effects of NO and increased nitrosative stress might therefore help explain the development of cardiovascular complications in OSA.

Peroxynitrite is very short-lived and therefore cannot be readily measured in plasma. However, it can nitrate tyrosine residues in proteins (2, 10, 16), leaving longer-lasting footprints of its transient production in vivo. Animal studies demonstrate that nitrotyrosine has a half-life of ~1–1.5 h in vivo (21, 40). Therefore, circulating free nitrotyrosine can be considered as an indirect index of peroxynitrite production. Furthermore, the half-life of nitrotyrosine suggests that it should be useful in detecting not only chronic but also acute (i.e., overnight) effects of OSA on RNS production. Nevertheless, nitrotyrosine can be generated also through other pathways, such as myeloperoxidase (10, 13, 29). Therefore, rather than being a specific marker for peroxynitrite formation, nitrotyrosine should be considered as a marker of overall nitrosative stress.

Our results demonstrate that in otherwise disease-free subjects, moderate to severe OSA is not accompanied by chronically elevated nitrotyrosine. In addition, plasma nitrotyrosine levels do not change acutely even after severe oxidative stress, such as that induced by overnight apneic sleep with significant nocturnal hypoxic stress. Furthermore, nitrotyrosine concentrations do not exhibit diurnal variation in normal healthy subjects.

Our negative results are important for understanding the pathophysiology of hypoxemia/reoxygenation in OSA. Despite prior studies describing the presence of oxidative stress and increased production of ROS in OSA (6, 9, 23, 32), we have found no evidence that RNS generation is affected by OSA. This might indicate that RNS are not involved in OSA pathophysiology or that OSA may activate some defense mechanisms protecting the body from any deleterious effects of RNS.

Important strengths of our study are first, that we included only normotensive, nonsmoking, otherwise healthy OSA patients, on no medications. Second, our healthy control subjects were very similar with respect to age and BMI, and the presence of occult sleep apnea in the control group was excluded by overnight polysomnography. Because obesity may itself be linked to increased nitrotyrosine (4, 5, 8, 11), matching for BMI is critical to differentiate between effects of obesity and effects of OSA on nitrotyrosine. Overt cardiovascular diseases may also be accompanied by increased nitrotyrosine (2, 3, 15, 36, 41). Exclusion of subjects with any other comorbidities and exclusion of occult OSA in the control subjects minimize any likelihood that our results were affected by the presence of other comorbidities or occult OSA in the control group. Third, our OSA patient group had an AHI level averaging in the severe range and lowest nocturnal oxygen desaturation averaging 76%, indicating profound nocturnal hypoxic stress. Hence, any clinically significant effects of OSA on nitrotyrosine should have been evident from our studies. Limitations of our study include the modest sample size. Furthermore, we measured free nitrotyrosine, and we cannot exclude the possibility that protein-bound or intracellular nitrotyrosine may be affected by OSA.

In conclusion, in otherwise healthy individuals, OSA is not accompanied by increased circulating free nitrotyrosine. This observation suggests that repetitive hypoxemia alone does not result in increased nitrosative stress in OSA. Thus nitrosative stress is unlikely to explain the increased prevalence of cardiovascular and cerebrovascular dysfunction reported in OSA patients.


   GRANTS
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This research was supported by National Institutes of Health Grants HL-65176, HL-61560, HL-70602, and M01-RR-00585.


   FOOTNOTES
 

Address for reprint requests and other correspondence: V. K. Somers, Mayo Clinic, Rochester, MN 55905 (E-mail: somers.virend{at}mayo.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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