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Obstructive sleep apnea syndrome (OSAS) is a clinic syndrome characters with repeated apnea, intermittent hypoxia, frequent arousals during sleeping at night whether companied with hypercapnia or not. Studies suggest that OSAS is being considered as an independent risk factor for cardiovascular diseases, leading to increased multi-morbidity and mortality. Chronic intermittent hypoxia is the most important feature of OSAHS. Chronic intermittent hypoxia promoted the formation of atherosclerosis and plaque rupture, however its mechanism is not yet clear. Matrix metalloproteinases (MMPs) and cysteine protease (Cathepsins) participates in the formation of atherosclerosis through promoting inflammation and extracellular matrix degradation. Endoplasmic reticulum stress signaling pathway participates in the development of atherosclerosis formation.
To observe the role of endoplasmic reticulum stress in chronic intermittent hypoxia induced protease expression in macrophage.
Human macrophages cells (THP-1) were exposed to chronic intermittent hypoxia (2%∼21% FiO2 60min/cycle) respectively 24h, 48h, 72h. The cells were divided into three groups: control group, chronic intermittent hypoxia group, chronic intermittent hypoxia and endoplasmic reticulum stress inhibitors (TUDCA) group in different doses (2.5uL and 5uL, 500umol/L). Cells morphological changes were detected by optical microscope. Cells viability was detected by MTT. The expression of endoplasmic reticulum stress related protein glucose-regulated protein 78 (GRP78), protein kinase-like ER kinase (PERK), phosphorylation eukaryotic initiation factor 2 alpha (P-EIF2 alpha), activating transcription factor 4 (ATF4), and the expression of MMP-9 and Cathepsis S level were detect by Western Blot.
Chronic intermittent hypoxia increased the expression of MMP-9 and cathepsin S significantly compared with control group in a time-dependent manner (p < 0.05). Chronic intermittent hypoxia also increased GRP78, PERK, P-EIF2 alpha and ATF4 expression in 48h and 72h significantly compared with control group (p < 0.05). TUDCA (5 uL) group abolished chronic intermittent hypoxia induced MMP-9 protein expression significantly (p < 0.05). TUDCA (5 uL) group significant inhibited the expression of P-EIF2 alpha (p < 0.05).
Chronic intermittent hypoxia promoted the protein expression of MMP-9, Cathepsin S and endoplasmic reticulum stress related protein expression in THP-1 cells. TUDCA inhibited the expression of MMP-9 induced by chronic intermittent hypoxia in THP-1 cells may through endoplasmic reticulum stress pathway. This may provide a new target for the prevention and treatment of atherosclerosis combined with OSAS.