|Year : 2020 | Volume
| Issue : 2 | Page : 252-257
Is there a correlation between obstructive sleep-apnea syndrome severity and prolidase activity as an oxidative stress marker?
H Gunbatar1, HS Kaplan2, S Yildiz3
1 Department of Pulmonary and Critical Care, Yuzuncu Yil University Medical Faculty, Kampüsü, 65090 Tusba/Van, Turkey
2 Anaesthesia and Reanimations, Yuzuncu Yil University Medical Faculty, Kampüsü, 65090 Tusba/Van, Turkey
3 Endocrinology, Yuzuncu Yil University Medical Faculty, Kampüsü, 65090 Tusba/Van, Turkey
|Date of Submission||02-Aug-2018|
|Date of Acceptance||21-Nov-2019|
|Date of Web Publication||7-Feb-2020|
Dr. H S Kaplan
Anaesthesia and Reanimations, Yuzuncu Yil University Medical Faculty, Kampüsü, 65090 Tusba/Van
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: Obstructive sleep apnea syndrome (OSAS) is a highly prevalent breathing disorder in sleep. The aim of this study was to evaluate the relationship between OSAS and prolidase activity, the oxidative stress index (OSI), total antioxidative capacity (TAC), total oxidative capacity (TOC) and the carotid intima media thickness (CIMT). Method: After night polysomnography, 74 people were diagnosed with OSAS and simple snoring. Plasma prolidase activities, TAC and TOC were measured in blood samples taken in the morning after the sleep study. The patients' bilateral common carotid arteries were scanned. Results: In total, 56 patients were in OSAS group [13 subjects 23.2% mild, 19 subjects 33.9% moderate, 24 subjects 42.8% severe] and 18 in simple snoring control group. The mean Prolidase, TOC, TAC and OSI levels were 744.7 ± 156.8, 59.2 ± 19.2, 2.12 ± 0.41, 3.12 ± 1.03, in the mild OSAS group, 761.6 ± 114.4, 57.9 ± 18.3, 2.03 ± 0.37, 3.15 ± 0.8, in the moderate OSAS group, 754.08 ± 133.9, 51.15 ± 12.1, 1.97 ± 0.27, 2.8 ± 0.82, in the severe OSAS group, and 711.9 ± 139, 52.3 ± 15.1, 1.83 ± 0.32, 3.06 ± 0.92 in the control group, respectively. Mean CIMT measurements were 0.71(±0,13) in the OSAS group and 0.76(±0.07) in the control group. Conclusion: There was no difference between the control and OSAS groups in terms of the parameters studied. Further studies should be undertaken in order to clarify the relation.
Keywords: Carotid intima media, obstructive sleep apnea, prolidase
|How to cite this article:|
Gunbatar H, Kaplan H S, Yildiz S. Is there a correlation between obstructive sleep-apnea syndrome severity and prolidase activity as an oxidative stress marker?. Niger J Clin Pract 2020;23:252-7
|How to cite this URL:|
Gunbatar H, Kaplan H S, Yildiz S. Is there a correlation between obstructive sleep-apnea syndrome severity and prolidase activity as an oxidative stress marker?. Niger J Clin Pract [serial online] 2020 [cited 2020 Oct 1];23:252-7. Available from: http://www.njcponline.com/text.asp?2020/23/2/252/277868
| Introduction|| |
Obstructive sleep apnea syndrome (OSAS) is characterized by the collapse of the upper respiratory tract during sleep, recurrent apnea, intermittent hypoxemia, difficult airway and daytime sleep, poor daytime performance and impaired quality of life. It is a common disorder in middle-aged adults, affecting 4% of males and 2% of females.
Recent studies have indicated that OSAS is associated with multiple causal factors of endothelial damage and atherosclerosis due to oxidative stress, systemic inflammation, complement elements and increased levels of soluble adhesion molecules and coagulation factors.,
Prolidase is a cytosolic and multifunctional exopeptidase that possesses the unique ability to degrade iminodipeptidase, which releases carboxy-terminal proline or hydroxyproline from oligopeptides.
Collagen is an important substrate of prolidase due to its high contents of amino acids. It has been shown that serum prolidase enzyme activity is elevated in conditions that are characterized by chronic inflammation of the tissue and/or increased turnover of collagen. Prolidase has been described in various tissues, including the plasma, hearth, thymus, brain and uterus. Elevated serum levels of prolidase have been associated with oxidative stress in some organic diseases such as mitral stenosis, helicobacterpylori infection and ovarian cancer., Previous studies have investigated prolidase activity in bronchial asthma and chronic obstructive pulmonary disease, Several studies have indicated the presence of higher levels of oxidative stress,,,, or decreased activity of the antioxidant system,, in OSAS patients in comparison to non-OSAS controls. However, to the best of our knowledge, there are no studies in the medical literature focused on prolidase activity in OSAS. Carotid atherosclerosis strongly correlates with coronary atherosclerosis and carotid intima-media thickness (CIMT) measured by carotid doppler ultrasound is an effective, validated method for evaluating carotid atherosclerosis.,
The aim of this study was to determine whether the serum prolidase levels were associated with OSAS severity, and whether there was a relationship among prolidase activity and oxidative parameters with CIMT in OSAS.
| Patients and Methods|| |
This prospective study was approved by Van Yuzuncuyil University's Faculty of Medicine Review Board in accordance with the Helsinki Declaration, and it was also registered on www. ClinicalTrials.gov. (NCT03563118). Written informed consent was received from the OSAS subjects and controls before enrolment in the study. The patients and control group were recruited from the Pulmonary Medicine and department of Anaesthesia, where the patients come for pre-operative examination, Medical Faculty, Yuzuncu Yil University.
The subjects selected from patients who were diagnosed with OSAS after night polysomnography (PSG) recording between January 2014 and June 2014 consecutively. They were enrolled in the study following receipt of their written informed consent. The exclusion criteria for the OSAS subjects were as follows: no history of ischaemic cardiovascular diseases, chronic obstructive pulmonary diseases, ischaemic cerebral diseases, chronic inflammatory diseases, or chronic and acute systemic infections at the time of the study. Sleep-disordered breathing events were scored manually by the same examiner, according to the 2012 American Academy of Sleep Medicine criteria. Subjects were diagnosed with OSAS when the apnoea-hypopnoea index (AHI) was ≥5. The grading was scored as follows: mild OSAS, AHI ≥5 and <15; moderate OSAS, AHI ≥15 and <30; and severe OSAS, AHI ≥30. The subjects in the OSAS group were divided into three subgroups according to the severity of the disease: 13 mild OSAS, 19 moderate OSA and 24 severe OSAS subjects. In total, 18 simple snoring subjects were selected for the control group.
Overnight polysomnography was performed with 16 channel Embla (Medcare Inc., Iceland) continuous sleep technician monitoring. The system consists of four channels of EEG (with electrode placements at C4-A1, C3-A2, O2-A1 and O1-A2) and two channels of EOG, recording submental EMG, oronasal air flow, thoracic and abdominal movements, pulse oximeter oxygen saturation, tibial EMG, body position, electrocardiogram readings and tracheal sound. Apnea was defined as the complete cessation of airflow lasting more than 10 s. Hypopnea was defined as a reduction >30% in airflow lasting more than 10 s accompanied by >4% desaturation and/or arousal. The average number of episodes of apnea and hypopnea per hour of sleep were measured as AHI. The OSAS diagnosis was made on the basis of an apnea/hypopnea index (AHI) >5. Sleep stages were scored according to standard criteria with 30-s epochs and were reviewed and verified by a certified sleep physician.
Determination of CIMT
Bilateral common carotid arteries of the patients were scanned longitudinally with a 7-MHz transducer attached to the available machine (Vivid 3, General Electric). Images were obtained from the distal portion of the common carotid artery, 1–2 cm proximal to the carotid bulb. The two bright echogenic lines in the arterial wall were identified as the intima and media lines. Intima media thickness was measured as the distance from the main edge of the first echogenic line to the main edge of the second. All examinations were performed by the same physician who was not involved in the study. Images showing the maximum intima media thickness were digitally stored, and CIMT measurements were made offline. The intima media thickness of the distal wall of the right common carotid artery on the lengthwise axis was calculated according to the method described by Pign P. et al. Each measurement was repeated three times, and the mean of the left and right common carotid arteries was used for analysis. Plaques, defined as >50% localized thickening of the intima compared to the rest of the wall or as an endoluminal protrusion of the arterial lumen of >0.5 mm, were not included in the measurement of CIMT.
Fasting blood samples were drawn into heparinized-tubes and centrifuged at 3,000 rpm for 10 min to separate the plasma. The samples were stored at -80°C until analysis.
Measurement of the total oxidant and anti-oxidant status
TAC and TOS levels were measured by using an automated measurement method developed by Erel., TAC measurement method involves the production of a potent biological hydroxyl radical. Ferrous ion solution is mixed with hydrogen peroxide. Thus, it is possible to measure the anti-oxidative effect of the sample against the potent free radical reactions initiated by the production of the hydroxyl radical. TOS method is based on the oxidation of ferrous ion to ferric ion in the presence of various oxidant species in acidic medium and the measurement of the ferric ion by xylenol orange. Results were expressed in mmol Trolox equivalent (equiv)/L, mmol H2O2/L and mg/dL, respectively, and the assay is characterized by excellent precision values of less than 3%.
Oxidative stress index (OSI)
The percent ratio of TOS to TAC yields the OSI, an indicator of the degree of oxidative stress. For calculation, the resulting unit of TAC was changed to mmol/L, and the OSI value was calculated according to the following formula: OSI (arbitrary unit) = TOS (mmol H2O2Equiv./L)/TAC (mmol Trolox Eq/L)
Determination of prolidase activity
Prolidase activity was determined by a photometric method based on the measurement of the proline levels produced by prolidase. Plasma samples (100 ml) were blended with 100 ml of serum physiological. A total of 25 ml of the mixture was preincubated with 75 ml of the preincubation solution (50 mmol/l Tris HCl buffer pH 7.0 containing 1 mmol/l glutathion, 50 mmol/l MnCl2) at 37°C for 30 min. The reaction mixture containing 144 mmol/l gly-pro, pH 7.8 (100 ml) was incubated with 100 ml of preincubated sample at 37°C for 5 min. To stop the incubation reaction, 1-ml glacial acetic acid was added. After adding 300-ml Tris HCl buffer, pH 7.8 and 1 ml of ninhydrin solution (3 g/dl ninhydrin was melted in 0.5 mol/l orthophosphoric acid), the mixture was incubated at 90°C for 20 min and cooled with ice and subsequently its absorbance was measured at a wavelength of 515 nm for determining proline level as proposed by Myara., This method is a modification of Chinard's method. Intra- and interassay CVs of the assay were lower than 10%. Blood samples were analyzed at the Biochemistry Laboratory of Harran University Medical Faculty.
Statistical analysis was performed using SPSS 21 software. Continuous data were expressed as means ± standard deviation (SD). Statistical comparisons were performed using one-way ANOVA, posthoc test. To determine the relationships between these variables in each group separately, Pearson's correlation coefficients were calculated. AHI, TOC, body mass index (BMI), TAC and prolidasevariables in the patient and control groups were assessed. Results were considered statistically significant when P value was <0.05. A previous study by Hopps et al. revealed a mean TAC level of 1.370 ± 0.162 in patients with high grade OSA. Assuming a 10% decrease in TAC levels in mild OSA with a two-sided type I error of 0.05, and a power of 0.90, 58 subjects were required to find a significant difference. We then increase the sample size for possible missing values by 20% and concluded that a total of 70 patients should be enrolled in the study.
| Results|| |
We included a total of 74 subjects: 56 in the OSAS group (mild disease, 13 subjects [23.2%], moderate disease, 19 subjects [33.9%], severe disease, 24 subjects [42.8%]) and 18 in the simple snoring group as control cases. The mean age of the mild OSAS subjects was 49.78 ± 10.7 years, that of the moderate OSAS subjects was 51.4 ± 10.7 years, that of the severe OSAS subjects was 51.3 ± 9.3 years and that of the control group was 52.8 ± 11.7 years; 57.8% of the subjects were male. The demographic data (age, sex, etc.) of the patients and their controls showed homogeneity, and there were no significant differences between the groups (P > 0.05). The parameters in the OSAS and control subjects groups are shown in [Table 1]. There was a positive correlation between the OSI levels and TAC or TOC levels (P = 0.0001 or P = 0.021, respectively). The mean values of age, prolidase, BMI, TAC, TOC and OSI were similar among the three OSAS groups compared to those of the simple snoring subjects in the control group (P > 0.05). The mean prolidase levels were 744.7 ± 156.8 in the mild OSAS group, 761.6 ± 114.4 in the moderate OSAS group, 754.08 ± 133.9 in the severe OSAS group and 711.9 ± 139.1 in the control group. The mean TOC levels were 59.2 ± 19.2 in the mild OSAS group, 57.9 ± 18.3 in the moderate OSAS group, 51.15 ± 12.1 in the severe OSAS group and 52.3 ± 15.1 in the control group. The mean OSI levels were 3.12 ± 1.03 in the mild OSAS group, 3.15 ± 0.8 in the moderate OSAS group, 2.8 ± 0.82 in the severe OSAS group and 3.06 ± 0.92 in the control group. The mean TAC levels were 2.12 ± 0.41 in the mild OSAS group, 2.03 ± 0.37 in the moderate OSAS group, 1.97 ± 0.27 in the severe OSAS group and 1.83 ± 0.32 in the control group. Mean CIMT measurements were 0.71(±0, 13) in the OSAS group and 0.76 (±0.07) in the control group.
|Table 1: Mean values of mild, moderate, severe OSAS subjects' and Control group parameters|
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| Discussion|| |
We investigated the relationship among OSAS, plasma TAC, TOS, OSI, prolidase activity and carotid intima media thickness. We found a positive correlation between OSI levels and TAC or TOC levels. However, we did not find a correlation between CIMT levels and those of the other parameters.
OSAS is an increasing major health concern in the general population. The mechanism underlying the increased risk for cardiovascular diseases in OSAS is unclear, but a multifactorial aetiology is likely to be involved. Systemic inflammation is thought to be present in many conditions and comorbidities such as atherosclerosis, vascular inflammation, endothelial dysfunction, hypertension, hyperlipidaemia, ischaemic diseases, arterial hypertension, coronary artery disease, myocardial infarction and stroke. Remarkably, all of these comorbidities are likely to be associated with OSAS., To investigate the relation between intermittent hypoxia and the severity of systemic inflammation, we performed correlation tests for AHI and minimum oxygen saturation as the indicators of disease severity, and TAC, TOC, OSI, and Prolidase as predictors of inflammation. Obesity is common in OSAS subjects. In our study, there was no difference in BMI scores between the control and OSAS subject groups. The mean scores were 30.97 ± 6.04 in the control group and 31.76 ± 5.16 in the OSAS group. Since our control group comprised individuals who had no OSAS symptoms, we believe our work is strengthened because of the lack of difference between the groups. In addition, there were no statistically significant differences between the groups regarding age. The recognition of the relation of OSAS to increased cardiovascular morbidity and mortality has increased the number of researches in the field of this relationship. Oxidative stress has been considered as a major pathogenic mechanism of atherosclerosis and cardiovascular disease. It represents an imbalance between the production of free radicals such as reactive oxygen species (ROS) and the antioxidant system activity that counteracts their harmful actions. Serum prolidase activity, TOS, TAS and OSI are recognized as oxidative stress markers. Prolidase, a member of MMPs, plays an important role in collagen metabolism and extracellular matrix remodeling.,
Prolidase enzyme activity has been researched in various diseases such as chronic liver disease, osteoporosis, osteoarthritis, uremia, hypertension, diabetic neuropathy, coronary artery disease and ovarian cancer.,,,,,,
However, there are no studies in the medical literature focused on prolidase activity in OSAS. Previous studies have suggested a significant relationship between OSAS and increased oxidative stress, but their results have been challenged. Wali et al. and Grabska-Kobylecka et al. studied catalase and glutathione peroxidase, they had found no evidence of overproduction of oxidants by studying circulating phagocytes., In the present study, prolidase activity was higher in the patient group compared to the control group, but there were no statistically significant differences. TAC levels showed a gradual decrease in parallel with increased OSAS severity; we think that the relationship between TAC levels and OSAS severity may be statistically significant as the number of cases increases. We showed no significant differences in TOC, TAC, OSI and carotis intima media thickness between OSAS and simple snorring group. In contrast, some authors have found that OSAS subjects have increased oxidative stress by demonstrating abnormal levels of oxidative stress markers, such as hydrogen peroxide, TBARS, SOD and TAC.,,,, In this respect, the question of the relationship between OSAS and oxidative stress remains open. An acceptable explanation for contradictory results reported in the literature might be because of different pathways of oxidative stress, or populations with comorbidities which augment oxidative stress, such as obesity, smoking, age, hypertension, hyperlipidemia and diabetes mellitus which are frequently found in patients with OSAS.,
According to European Society of Cardiology comments, a common carotid artery IMT > 0.9 mm can be considered as a measured estimate of actual abnormalities. Many hypotheses have been recommended on endothelial disfunction, oxidative stress seems to be one of the causes of endothelial deterioration in OSAS patients., Hypoxia is a part of the disease and causes real damage to the endothelium. Also, OSAS leads to sympathetic nervous system hiperactivity, a condition that can stimulate early alterations in the vascular morphology leading against the atherosclerotic process. Literature data suggest that carotis intima-media thickness is an evidence of early alterations in vascular morphology. This is not synonymous with atherosclerosis but because the underlying pathophysiological mechanisms are similar, the two conditions have been associated. Ciccone et al. found a positive relationship between IMT and OSAS duration. An alternative explanation obesity with OSAS and likely non-alcholic fatty liver disease is characterized by a status of chronic low-grade inflammation, of which IL-6 secreted by adipose tissue and mainly by spleen plays a main role not by an imbalance between oxidative and anti-oxidative processes. This chronic inflammation and immuno-allergic aspects impact on early atherosclerosis, evaluated as IMT. In the present study, we could not find any difference between patients and control groups about CIMT. This situation can be explained by the fact that the duration of OSAS symptoms was short.
There are several limitations of this study. First, the sample size was small. Second, we were unaware of the duration of OSAS in patients. As the last limitation, we did not measure the level of tissue prolidase activity.
In conclusion, we found no differences in the studied parameters between the control and OSAS groups. However, the low number of cases was a limiting factor. Further studies should be undertaken to clarify this trend.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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