The Plasminogen System and Transforming Growth Factor-β in Subjects With Obstructive Sleep Apnea Syndrome: Effects of CPAP Treatment

Abstract

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) has emerged as a risk factor for cardiovascular disease. A prothrombotic state may affect coagulation and participate in the atherosclerotic process in subjects with OSAS. These alterations in coagulation seem to involve the plasminogen activation system. We evaluated the imbalances of the plasminogen activation system related to OSAS, and we assessed the effects of CPAP on the plasminogen activation system. METHODS: Thirty-nine subjects were submitted to a home-based cardiorespiratory sleep study, and 14 healthy subjects (apnea-hypopnea index < 5) were used as controls. Serum levels of urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and active transforming growth factor-␤ (TGF-␤) were measured. These molecules were reassessed in only 17 of the subjects after 1 month of CPAP. RESULTS: PAI-1 and tPA were significantly higher in the subjects with OSAS compared with the controls, whereas TGF-␤ and uPA levels were lower. PAI-1 showed a significant positive correlation with the apnea-hypopnea index, percentage of time spent at O 2 saturation < 90%, and oxygen desaturation index, whereas TGF-␤ was inversely related to all 3 of these parameters. After the CPAP therapy, PAI-1 significantly decreased, whereas TGF-␤ showed a significant increase, although the values did not reach those of the controls. uPA and tPA did not show significant differences after the treatment. CONCLUSIONS: Our results suggest an imbalance of fibrinolysis related to OSAS and an improvement of the prothrombotic state after the CPAP treatment.

Circulating Soluble Urokinase-Type Plasminogen Activator Receptor in Obstructive Sleep Apnoea

“…Obstructive sleep apnoea is associated with heightened systemic inflammation, theoretically contributing to higher uPAR expression [11,[13][14][15]. However, the cleavage of uPAR may be slower in OSA due to decreased levels of uPA [8] and plasmin [5,6,23]. The expression of uPA is induced by female sexual hormones [20] and the proto-oncogenic survivin [27], which presented decreased expressions in OSA [3,28].…”

“…Plasmin is formed by plasminogen, and this reaction is blocked by plasminogen activator-inhibitors (PAI), shown to be upregulated in OSA [5,6,23]. In addition, OSA is associated with decreased levels of transforming growth factor-β [8], an inducer of uPAR transcription [29,30]. These studies suggest that although uPAR expression may be upregulated by systemic inflammation in OSA [11,[13][14][15]; this is counterbalanced by the reduced cleavage.…”

“…Chronic intermittent hypoxia and increased sympathetic tone induce production of pro-inflammatory molecules, such as interleukin (IL)-6, IL-1β, tumour necrosis factor-α [1] or complement elements [2] and suppresses the release of anti-inflammatory [3,4] molecules. Linked to inflammation and sympathetic activity, OSA is characterised by a hypercoagulation state [5][6][7][8][9]. Accelerated systemic inflammation and increased coagulation may contribute to the development of cardiovascular disease and acute cardiovascular events [10].…”

Interactions between and Shared Molecular Mechanisms of Diabetic Peripheral Neuropathy and Obstructive Sleep Apnea in Type 2 Diabetes Patients

“…Increased PAI-1 activity was associated with sleep-disordered breathing, possibly contributing to increased vascular risk [ 167 ]. A previous study indicated that PAI-1 levels were significantly higher in OSA subjects than controls and PAI-1 positively correlated with AHI index [ 168 ]. CPAP therapy could significantly reduce PAI-1 levels.…”

The Relationship of Stroke and Sleep-A Review

“…OUAS olan 39 hastanın 1 aylık CPAP tedavisi alarak kontrol grubu ile karşılaştırıldığı başka bir çalışmada PAİ-1 anlamlı olarak düşerken, transforming büyüme faktörü-beta artmıştır. Her ne kadar bu artış kontrol grubu kadar olmasa da bu çalışma OUAS'a bağlı fibrinolizis dengesizliğinin ve protrombotik durumun CPAP tedavisinden sonra düzeldiğini düşündürmektedir (49). Fibrinojenin OUAS ile inme arasında patolojik bir bağlantı oluşturduğunu gösteren bir çalışmada, etkin CPAP tedavisinin plazma fibrinojen düzeylerinde düşme sağladığı gösterilmiştir (17).…”