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Increased Levels and Activity of Matrix Metalloproteinase-9 in Obstructive Sleep Apnea Syndrome

First Department of Internal Medicine, Showa University, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Kenji Minoguchi, M.D., Ph.D., First Department of Internal Medicine, Showa University, School of Medicine, 1–5–8 Hatanodai, Shinagawa-ku, Tokyo 142–8666, Japan. E-mail: minochan{at}fn.catv.ne.jp

	ABSTRACT

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Matrix metalloproteinases (MMPs) are involved in the pathogenesis of cardiovascular diseases. We examined serum levels of MMP-9 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), activity of MMP-9, and the effect of nasal continuous positive airway pressure (nCPAP) in patients with obstructive sleep apnea syndrome (OSAS). After polysomnography, venous blood was collected at 5:00 A.M. from 44 patients with OSAS and 18 control subjects who were obese, and serum levels of MMP-9, TIMP-1, and enzymatic activity of MMP-9 were measured. In addition, the effects of 1 month of treatment with nCPAP were studied in patients with moderate to severe OSAS. Although serum levels of MMP-9 (p < 0.03) and MMP-9 activity (p < 0.01) were higher in patients with OSAS than in control subjects who were obese, TIMP-1 levels did not differ significantly. In patients with OSAS, the severity of OSAS was the primary factor influencing levels (p < 0.01) and activity (p < 0.01) of MMP-9. nCPAP significantly decreased serum levels (p < 0.01) and activity (p < 0.001) of MMP-9 but did not affect TIMP-1 levels. Therefore, OSAS may increase risks of cardiovascular morbidity, and nCPAP might be useful for decreasing these risks.

Key Words: atherosclerosis • cardiovascular disease • cytokine • metalloproteinase • sleep apnea

Obstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular morbidity and mortality (1, 2). Repeated apnea-related hypoxia significantly increases superoxide production by neutrophils and monocytes in patients with OSAS (3, 4). We and others have reported that levels of C-reactive protein, interleukin (IL)-6, tumor necrosis factor- (TNF-), and circulating soluble adhesion molecules are elevated in patients with OSAS (5–8). In addition, the intracellular content of the proinflammatory cytokines TNF- and IL-8 was greater, and that of the antiinflammatory cytokine IL-10 in T cells was less in patients with sleep apnea than in control subjects; these differences may lead to endothelial injury and adverse cardiovascular function in patients with sleep apnea (9). Moreover, plasma levels of vascular endothelial growth factor, which is a potent angiogenic cytokine but also contributes for the progression of atherosclerosis, are increased in patients with OSAS (10, 11). Therefore, these results suggest that OSAS may affect the progression of atherosclerosis.

Matrix metalloproteinases (MMPs) are a family of zinc-containing endoproteases that share structural domains but differ in substrate specificity, cellular sources, and inducibility (12). The expression of MMPs is generally low but is increased in the remodeling processes of atherosclerosis and myocardial infarction (13–18). MMPs regulate the degradation of the extracellular matrix and play an important role in cardiac and vascular remodeling (19, 20). Overexpression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MMP-14, and MMP-17 has been observed in atherosclerotic tissues (21). Of these MMPs, MMP-2 and MMP-9 are elevated in the peripheral blood of patients with coronary artery disease, and MMP-9 is a predictor of cardiovascular mortality in these patients (22, 23). MMP-9 degrades the basement membrane to promote both monocyte infiltration into the plaque and smooth muscle cell migration into the fibrous cap. An increase in MMP-9 activity results in degradation of the fibrous cap, plaque instability, and plaque rupture (24). Therefore, MMP-9 plays important roles in cardiovascular events. In addition, production of MMP-9 is stimulated by hypoxia and by several cytokines, such as IL-6 and TNF- (25–27). Although these cytokines are increased and hypoxia is induced by apnea and hypopnea during sleep in patients with OSAS, serum levels and activity of MMP-9 and levels of its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), have not been examined in patients with OSAS.

The purpose of this study in patients with OSAS was to evaluate whether serum levels and activity of MMP-9 and levels of TIMP-1 are elevated, to identify factors that are independent variables for serum levels and activity of MMP-9, and to determine whether treatment with nasal continuous positive airway pressure (nCPAP) decreases serum levels and activity of MMP-9 and levels of TIMP-1. Some of the results of these studies have been previously reported in the form of an abstract (28).

	METHODS

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Patients
Forty-eight men with newly diagnosed OSAS and 18 male obese snoring control subjects were enrolled in this study (Table 1). They underwent polysomnography (PSG) and were classified as control subjects or patients with OSAS. All subjects who were free from other diseases and were taking no medications were enrolled into this study. Subjects who smoked or had systemic infections at the time of the study or within 2 weeks before the study were also excluded. The study was approved by the ethics committee of Showa University, and all patients gave written informed consent.

Measurement of MMP-9, TIMP-1, IL-6, and TNF-
All subjects went to bed at 9:00 P.M. and were awakened at 5:00 A.M. Samples of peripheral venous blood were collected at 5:00 A.M. Samples were stored at –80°C until assay. Serum levels of MMP-9 (Amersham Biosciences, Piscataway, NJ), TIMP-1 (Daiichi Fine Chemical Co. Ltd., Tokyo, Japan), IL-6 (Biosource International, Camarillo, CA), and TNF- (Biosource International) were measured with an ELISA.

Zymography
To assess the activity of MMP-9, gelatin zymography was performed according to the same method as described previously (30). Briefly, specimens of serum were diluted (1:20) and subjected to electrophoresis on 10% polyacrylamide sodium dodecyl sulfate gels containing 1 mg/ml of porcine skin gelatin (Sigma Chemical Co., St. Louis, MO). After electrophoresis, the gels were fixed and then stained with 0.05% Coomassie brilliant blue. Areas of gelatin digestion were identified as clear zones of lysis against a blue background. An area of 92-kD enzymatic activity was expressed as ratios relative to the activity of known amounts of control recombinant human MMP-9 (160 pg). The zone of enzymatic activity was quantified with National Institutes of Health Image 1.62.

nCPAP Treatment
Twenty-four patients with moderate to severe OSAS were treated with nCPAP using the S6 CPAP device (ResMed, North Ryde, Australia). At 1 month after nCPAP was started, PSG was performed again as the patient received nCPAP. Samples of venous blood were obtained at 5:00 A.M., and serum levels of MMP-9, TIMP-1, IL-6, and TNF- and activity of MMP-9 were measured as described previously.

Statistical Analysis
The significance of differences between two groups was analyzed with Student's t test. To compare three groups, we first analyzed the data with analysis of variance and then checked with Student's t test with Bonferroni correction. Correlations were analyzed with Spearman's rank correlation. To assess the relative strength of association of serum levels or activity of MMP-9, stepwise multiple regression analysis was applied to patients with OSAS as a single group. Data are expressed as mean ± SEM, and a probability of less than 0.05 was considered to indicate significance.

	RESULTS

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Serum Levels of MMP-9, TIMP-1, IL-6, and TNF-
Serum levels of MMP-9, IL-6, and TNF- were significantly higher in all patients with OSAS (144.2 ± 10.7 ng/ml, 1.90 ± 0.33 pg/ml, and 2.31 ± 0.20 pg/ml; Figure 1A) than in control subjects who were obese (91.9 ± 9.8 ng/ml, p < 0.03, 0.69 ± 0.12 pg/ml, p < 0.01, and 1.16 ± 0.11 pg/ml, p < 0.01; Figure 1A). Serum levels of TIMP-1 were not differ significantly between all patients with OSAS (202.4 ± 6.6 ng/ml) and control subjects who were obese (187.7 ± 13.8 ng/ml; Figure 1B). Levels of MMP-9, IL-6, and TNF- were significantly higher in patients with moderate to severe OSAS than in control subjects who were obese and in patients with mild OSAS (Table 1). However, levels of TIMP-1 did not differ significantly between patients with moderate to severe OSAS and control subjects who were obese or patients with mild OSAS (Table 1). Serum levels of MMP-9 were still significantly higher in patients with OSAS than in control subjects after adjusting for body mass index (p < 0.05), waist circumference (p < 0.03), or waist/hip ratio (p < 0.03).

View larger version (10K): [in this window] [in a new window]   Figure 1. Serum levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1), and serum activity of MMP-9. (A) Serum levels of MMP-9 in control subjects who were obese (n = 18) and in patients with obstructive sleep apnea syndrome (OSAS) (n = 48). (B) Serum levels of TIMP-1 in control subjects who were obese (n = 18) and in patients with OSAS (n = 48). (C) Serum activity of MMP-9 in control subjects who were obese (n = 18) and in patients with OSAS (n = 48).

View larger version (16K): [in this window] [in a new window]   Figure 2. Correlation between serum levels of MMP-9 and gelatinolytic activity of MMP-9. The 92-kD enzymatic activity of MMP-9 is expressed as relative ratios as 160 pg of recombinant human MMP-9 quantified with National Institutes of Health Image 1.62. A correlation between serum levels of MMP-9 and gelatinolytic activity of MMP-9 was demonstrated. (A) Control subjects who were obese (n = 18). (B) Patients with mild OSAS (n = 24). (C) Patients with moderate to severe OSAS (n = 24).

Correlation Between Levels or Activity of MMP-9 and PSG Variables, Metabolic Variables, Epworth Sleepiness Scale, and Levels of IL-6 and TNF- in Patients with OSAS

Effects of nCPAP on Levels of MMP-9 and TIMP-1 and Activity of MMP-9 in Patients with Moderate to Severe OSAS
In patients with moderate to severe OSAS, BMI did not change significantly, and no new cardiovascular diseases or infectious diseases were detected during 1 month of treatment with nCPAP. Treatment with nCPAP significantly decreased AHI (60.5 ± 2.9 to 2.8 ± 0.4, p < 0.0001); increased the lowest nocturnal Sa_O2 (68.4 ± 2.2 to 92.3 ± 1.3, p < 0.0001) and total sleep time (346.7 ± 23.8 to 428.1 ± 12.9, p < 0.01); and decreased percentage of time with Sa_O2 less than 90% (34.5 ± 4.5 to 0.1 ± 0.1, p < 0.0001), the arousal index (56.1 ± 3.9 to 20.0 ± 2.2, p < 0.0001), and the Epworth Sleepiness Scale (13.3 ± 0.8 to 5.3 ± 0.7, p < 0.0005). In addition, nCPAP significantly decreased serum levels of MMP-9 (168.0 ± 18.9 to 99.6 ± 10.8 ng/ml, p < 0.01; Figure 3A) and MMP-9 activity (2.46 ± 0.15 to 1.29 ± 0.10, p < 0.001; Figure 3B) but had no significant effect on TIMP-1 levels (207.0 ± 10.9 to 203.3 ± 8.4 ng/ml; Figure 3A). Levels of IL-6 (2.69 ± 0.25 to 0.97 ± 0.11 pg/ml, p < 0.001) and TNF- (2.80 ± 0.13 to 1.49 ± 0.13 pg/ml, p < 0.01) were also significantly decreased by nCPAP. Changes in AHI after treatment with nCPAP for 1 month were positively correlated with changes in MMP-9 levels (r = 0.52, p < 0.01) and MMP-9 activity (r = 0.60, p < 0.01). Moreover, changes in serum levels of MMP-9 were significantly correlated with changes in levels of IL-6 (r = 0.57, p < 0.005) and TNF- (r = 0.52, p < 0.01).

View larger version (13K): [in this window] [in a new window]   Figure 3. Effect of nasal continuous positive airway pressure (nCPAP) on serum levels of MMP-9 and TIMP-1 and activity of MMP-9. Patients with moderate to severe OSAS were treated with nCPAP for 1 month (n = 24). (A) Serum levels of MMP-9 and TIMP-1. (B) Serum activity of MMP-9.

	DISCUSSION

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MMPs and TIMPs regulate degradation of the extracellular matrix and thus play important roles in cardiac and vascular remodeling (19, 20). An excess of MMPs may be responsible for structural degradation of tissues, whereas an excess of TIMPs may promote excessive tissue repair processes and fibrosis. Studies of collagenolysis indicate that levels of active forms of interstitial collagenases, including MMP-9 over the TIMPs, are abnormally high in human atherosclerotic plaques (31). The importance of MMP-9 in vascular remodeling is also supported by a study in mouse carotid artery that showed that targeted disruption of the MMP-9 gene impairs smooth muscle cell migration and geometric arterial remodeling (32). Furthermore, MMP-9 is critical for the regulation of smooth muscle cell replication and migration after arterial injury (33). In addition, in patients with cardiovascular diseases, cancer, rheumatoid arthritis, or bronchial asthma, expression of MMP-9 is increased in both the affected organs and the peripheral blood (22, 23, 34, 35). In this study, we have found that activity of MMP-9 but not TIMP-1 levels in serum are significantly elevated in patients with OSAS. Furthermore, the finding that treatment with nCPAP significantly decreased serum levels of MMP-9 and activity of MMP-9 in patients with moderate to severe OSAS suggests that vascular remodeling by degradation of the extracellular matrix may be accelerated in patients with OSAS and that nCPAP might be useful for inhibiting vascular remodeling.

The source of elevated levels of circulating MMP-9 in patients with OSAS is unclear. MMP-9 is expressed in atherosclerotic plaques, and elevated serum levels of MMP-9 may reflect expression of MMP-9 in the vessel walls of patients with OSAS. Another possibility is that MMP-9 is released from peripheral blood neutrophils and monocytes stimulated by such inflammatory cytokines and growth factors as IL-6, TNF-, IL-1ß, epidermal growth factors, platelet-derived growth factor, and basic fibroblast growth factor (25, 26, 36, 37). Because levels of IL-6 and TNF- are increased in patients with OSAS, these factors might increase production and serum levels of MMP-9 in patients with OSAS. In fact, this study found significant correlations between levels of MMP-9 and levels of IL-6 and TNF- in patients with OSAS and between changes in levels of MMP-9 and changes in levels of IL-6 and TNF- after treatment with nCPAP in patients with moderate to severe OSAS. Therefore, elevated levels of MMP-9 may be due in part to the elevated levels of IL-6 and TNF- in patients with OSAS.

During sleep, patients with OSAS undergo repeated cycles of arterial oxygen desaturation induced by apnea followed by oxygen resaturation induced by hyperventilation. This hypoxia/reoxygeneration cycle may alter the oxidative balance by inducing excess oxygen free radicals. Indeed, repeated apnea-related hypoxia in patients with OSAS markedly increases superoxide production by neutrophils and monocytes and increases levels of 8-isoprostane in breath condensates (3, 4, 38). Moreover, reactive oxygen species produced by macrophage-derived foam cells increase the release of MMP-9 from cultured human vascular smooth muscle cells (39). These results suggest that oxidative stress induced by repeated apnea-related hypoxia may also contribute to the elevated levels and activity of MMP-9 in patients with OSAS.

Increased levels of MMP-9 in patients with OSAS may be due to hypoxia. Studies of a cancer cell line have shown that hypoxia stimulates MMP-9 production (27). In addition, fibroblasts cultured from leptin receptor-deficient mice produced twice as much MMP-9 as did normal fibroblasts cultured under hypoxic conditions (40). Therefore, elevated levels of MMP-9 observed in patients with OSAS might be due to production of MMP-9 by cells in atherosclerotic lesions or by circulating cells because of repeated apnea-related hypoxia. In addition, our finding that serum levels and activity of MMP-9 were correlated with the duration of hypoxia during sleep (percentage of time with Sa_O2 < 90%) suggests that hypoxia may increase MMP-9 production in patients with OSAS.

A limitation of this study is that the effects of nCPAP on levels and activity of MMP-9 were not examined with a randomized and placebo-controlled design. However, we found significant correlations between changes in AHI and changes in levels and activity of MMP-9 in patients with moderate to severe OSAS after treatment with nCPAP. Therefore, nCPAP might decrease levels and activity of MMP-9 in patients with moderate to severe OSAS. The effects of nCPAP on these variables should be examined in a large-scale, placebo-controlled study. Another limitation of this study is that because we used a cutoff value of less than five events per hour to define the control subjects using thermisters instead of a cannula, we likely misclassified some patients with mild OSAS as control subjects. If some patients with mild OSAS were misclassified in this way, our results demonstrating significant differences between control subjects and those with mild OSAS would be even more powerful and convincing. Therefore, such a slight misclassification would have a minimal effect on the overall interpretation of the stratified data.

In conclusion, we have demonstrated that serum levels of MMP-9 and activity of MMP-9 are elevated in patients with OSAS but are decreased by nCPAP. Therefore, OSAS may increase risks of cardiovascular morbidity, and nCPAP might be useful for decreasing these risks.

	Acknowledgments

 
The authors thank Mrs. Hiroko Takeuchi for her skillful technical assistance and Dr. Masao Okazaki for careful review of this article.

	FOOTNOTES

 
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Conflict of Interest Statement: T.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.T.R.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; Y.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form February 16, 2004; accepted in final form September 4, 2004

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