Matrix Metalloproteinases as Possible Biomarkers of Obstructive Sleep Apnea Severity

Abstract

Upper airway collapse in obstructive sleep apnea (OSA) is associated with intermittent hypoxia, which resembles ischemia-reperfusion (IR). Oxidative stress in IR has been shown to increase matrix metalloproteinases (MMPs) action and lead to adverse cardiovascular consequences in animal models. The results of previous studies on circulating MMP level in OSA are inconsistent. Oxidative stress in OSA might also directly contribute to kidney injury. The alteration in urinary MMP levels have been previously shown in acute and chronic renal injury, but there is no data about MMP levels in urine of OSA patients. The aim of this study is to determine if serum and urine MMPs in OSA patients are associated with OSA severity and CVD in OSA. The study is a part of a multi-center Canadian trial performed through the Canadian Sleep and Circadian Network. OSA subjects (n=124) were recruited from the Sleep Disorders Center (Saskatoon City Hospital, Saskatchewan, Canada) after in-lab polysomnography (PSG). Controls (n=26) were subjects referred to the Center who did not have OSA. Severity of OSA was categorized based on apnea/hypopnea index (AHI) according to American Academy of Sleep Medicine criteria. Level of hypoxemia was expressed as oxygen desaturation index (ODI). MMP-2 and MMP-9 activities were measured in blood and urine samples with gelatin zymography method. Albumin-to-creatinine ratio (ACR - indicator of glomerular damage) was calculated from urinary albumin and creatinine. Mann-Whitney U and Kruskal-Wallis tests were used for statistical analysis. Multivariable linear regression was used to control for potential confounders. Serum MMP-2 activity was associated with OSA severity/level of hypoxemia in OSA, even after adjustment for age, sex, body mass index (BMI), and CVD (p = 0.004). In stratified analysis, the association between serum MMP-2 and AHI remained significant only for patients with CVD (p = 0.009). Serum MMP-9 was associated with white blood cell count, after adjustment for AHI, age, sex, BMI and CVD (p < 0.001). Urinary MMPs did not show any association with OSA severity. Urinary MMP-2-to-creatinine in OSA was associated with ACR, independently of hypertension and diabetes (p = 0.022). There were no differences in MMP activities between OSA patients with CVD and without CVD. The results suggest that in future studies serum MMP-2 might be considered as biomarker of OSA severity, whereas MMP-9 may be a marker of inflammation in OSA. Urinary MMP-2 was associated with glomerular damage in OSA. Prospective studies in larger sample size are needed to confirm and delineate observed associations.