| Obstructive sleep apnea syndrome (OSAS) is a highly prevalent disease and is recognized as an independent risk factor for the development of various cardiovascular disorders. The pathogenesis of cardiovascular complications in OS AS is not completely understood but a multifactorial aetiology is likely. Current evidence suggests that inflammatory processes leading to endothelial dysfunction play a pivotal role in the pathogenesis. The unique form of hypoxia occurring in OS AS, termed intermittent hypoxia (IH), is likely to be a major factor in the initiation of the inflammatory process. The basic mechanisms underlying the inflammatory process initiated by IH remain unclear. The association between hypoxia degree and inflammatory processes are incompletely understood. So we developed an animal model of IH that involved exposing rats to different degree of IH, then investigating both the serum levels of various circulating markers of inflammation and the activation profiles of inflammatory transcription factors in cardiovascular systerm compared with sustained hypoxia. Our goal was to understand the possible mechanisms of endothelial dysfunction induced by IH.Contents:1. Developed an animal model of IH that involved exposing rats to different degree of IH.2. The research about serum levels of various circulating markers of inflammation in different degree of CIH.3. The research about activation profiles of inflammatory transcription factors and CIH in cardiovascular systerm.Methods:The first part: Developed an animal model of IH that involved exposing rats to different degree of IH. One hundred and sixty male Wistar rats were divided randomly into the five groups:5%,7.5%,10%of the intermittent hypoxia group (IH-1,2,3),10%sustained hypoxia group (CH) and the normal oxygen control group (SC). At the second, fourth, sixth, and eighth weeks, eight rats under different environmental stimulation hypoxia in each group were sacrificed to collect serum, endothelia cells and myocardial tissue.The second part: ELISA assay were used to detect the concentration of serum TNF-a, IL-8, IL-6, CRP and IL-10.The last part: ELISA assay were used to detect the concentration of ICAM-1in myocardial tissuses. Real-time PCR were used to detect the expression levels of c-fos and VEGF mRNA in aortic vascular endothelial and myocardial tissue. Western blot were used to detect the protein levels of inflammatory transcription factors NF-κB P65and HIF-la.Results:The first part:1. Blood gas analysis show us the minimum PO2in IH-1,2,3groups were35.6mmHg,40.3mmHg and48.8mmHg separately; CH group maintained at37.4-39.6mmHg while SC group at98-102mmHg.2. The systolic blood pressure was significantly increased in all three IH groups. At the fouth week, SBP was higher than before. At the sixth week, it was higher than CH and SC group (P<0.05).The second part:1. Serum levels of TNF-a, IL-8, IL-6and CRP were significantly increased in all three IH groups, while levels of IL-10were significantly decreased (F=14.637,6.42,43.814,3.642and5.787, P<0.001).2. We find the peak point of serum levels with TNF-a, IL-8and IL-10at the sixth week in all three IH groups, while the IL-6and CRP levels continued to rise over time.3. In the sixth week which has the most severe inflammatory response, the TNF-a, IL-8and IL-6levels in IH groups were significantly higher than the SC group P<0.001) and the CH group (P<0.05). The IL-10levels were significantly lower than the SC group and CH group (P<0.01and0.05).4. Levels of TNF-a and IL-8in IH-1group were significantly higher than those in IH-3group at the sixth week (F=1.20,34.68; P=0.049,0.046).The third part:1. The concentration of ICAM-1in myocardial tissuses was higher in IH-1 group than CH and SC group (P=0.009,0.000). We find the peak point in the six week and than decreased slowly.2. Protein levels of NF-κB P65in endothelia cells in all three IH groups and CH group were significantly higher than SC group (P<0.01). We find the peak point of protein levels at the sixth week in IH groups.3. In the sixth week, protein levels of NF-κB P65in IH-1,2,3group were significantly higher than CH group (P=0.000,0.002,0.012).4. Protein levels of NF-κB P65in IH-1group were significantly higher than IH-3group (P=0.003) at the sixth week.5. We did not find any band of HIF-lα protein. But its downstream gene VEGF mRNA expression levels in endothelial and myocardial tissues were significantly increased in IH-1and CH group, which higher than the SC group (P<0.05).6. Myocardial expression of c-fos mRNA in IH-1group and the CH group was significantly increased. At the eight weeks was significantly higher than SC group (P=0.001,0.018).Conclusions:1. Rat model of different degree intermittent hypoxia can mimic the pattern of sleep hypoxia experienced by patients with sleep apnea.2. The systolic blood pressure in rats was significantly increased in intermittent hypoxia groups.3. Intermittent hypoxia and sustained hypoxia can also cause systemic and cardiovascular inflammatory response.4. Inflammatory injury induced by intermittent hypoxia was more serious than sustained hypoxia.5. Inflammatory injury induced by intermittent hypoxia was dependent with desaturation levels.6. Inflammatory reaction induced by intermittent hypoxia increased at first and then decreased, which indicated there were compensatory mechanisms and adaptive response in the body.7. Transcription factors NF-κB, HIF-1and AP-1were activated by intermittent hypoxia and sustained hypoxia.8. CIH indeced new balance between inflammatary and protective reaction.9. NF-κB activated by IH leading to inflammatory reaction which caused endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular disease in patients with OSAS. |
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