| ObjectivesObstructive sleep apnea hypopnea syndrome, characterized by chronic intermittent hypoxia (CIH), is closely correlated to genioglossus dysfunction. CIH has been identified to mediate mitochondrial damage in genioglossus. It has been reported that endoplasmic reticulum stress (ERS) could be induced by outcomes of mitochondrial dysfunction. This study aimed to investigate the role of ERS in CⅢ-induced genioglossus injury, as well as the systemic inflammation in rats. Additionally, the possible intervention effect of adiponectin (Ad) supplement was explored.MethodsForty-five male Sprague-Dawly rats were randomly divided into three groups and submitted to room air (group A, n=15) as a control or CIH (groups B and C, n= 15, respectively). Throughout the exposure period, group C were given intravenous adiponectin; meanwhile groups A and B were given intravenous normal saline. At the end of the 35-days exposure, genioglossus samples were obtained from the pentobarbital-anaesthetized rats via surgical dissection, following blood sampling. Western blotting was applied to detect expressions of ERS signals and associated apoptotic pathways in genioglossus. Terminal Deoxynucleotidyl Transferase-mediated dUTP Nick-End Labeling (TUNEL) assay was applied to identify the cellular apoptosis in genioglossus. Enzyme linked immunosorbent assay (ELISA) was also used to estimate the levels of malondialdehyde (MDA), myeloperoxidase (MPO) and Superoxide dismutase (SOD) activity in genioglossus, as well as tumor necrosis factor , interleukin (IL)1β , IL-6, C reactive protein (CRP) and adiponectin in serum. The level of reactive oxygen spieces (ROS) in genioglossus was detected via fluorescence microscope. The transcription level of nuclear factor (NF) κB, adiponectin receptor (AdR) 1 and AdR2 in genioglossus were assessed by means of Real time Quantified Polymerase Chain Reaction (RT-qPCR). Additionally, the ultrastructure of genioglossus was observed by scanning electron microscope.ResultsSignificant hypoadiponectinemia was revealed in group B only (P< 0.05). Compared to those in groups A and C, expressions of markers involved in ERS, such as GRP78, p-PERK, p-eIF2a, p-IRE1α, XPB1s and ATF6, were significantly enhanced in group B (all P<0.01); while no significant difference was shown between groups A and C (all P> 0.05). ERS-associated apoptotic pathways were remarkably activated in group B. The involved markers such as CHOP, BAX and caspase-12 were significantly elevated expressed (all P< 0.01). The percentage of apoptotic cells in genioglossus tissue in group B ((28.2±21.3)%) was significantly higher than those in groups A ((11.5±3.7)%, PBA=0.002) and C ((15.9±10.3)%, PBc=0.019);.while no significant difference was shown between groups A and C (PAC=0.390). The genioglossus level of MDA in group B ((8.05±4.53) nmol/mg prot) was significantly elevated than those in groups A ((5.18±3.03) nmol/mg prot, PBA=0.001) and C (5.74±3.06) nmol/mg prot, PBC=0.002); while no significant difference was shown between groups A and C (PAC=0.691). In group C, the level of SOD activity ((42.42 ±23.17) U/mg prot) was significantly higher than that in group A((18.62±11.67) U/mg prot, PCA=0.009) but lower than that in group B ((61.77±36.38) U/mg prot, PCB=0.015). Similarly, the relative level of total ROS in genioglossus of group C (1.94±1.01) was significantly lower than that in group B (3.31±1.56, PCB=0.001), meanwhile higher than that in group A (1.08±0.38, PCA=0.038)。The transcription of NF-κB was significantly enhanced in genioglossus of group B than those in groups A and C, which was contrary to those of AdR1 and AdR2 (all P<0.05); while no significant difference was shown between groups A and C (all P> 0.05). The level of MPO in both groups B ((0.40±0.29)μlU/mg prot) and C ((0.31±0.17) μIU/mg prot) were significantly higher than that in group A ((0.17±0.08)μIU/mg prot, PBA= 0.002, PCA=0.047); however, no significace was detected between groups B and C (PBC= 0.240). In serum, the TNF-a level in group B ((70.87±35.16) pg/mL) was significantly higher than those in groups A ((26.54±20.32) pg/mL, PBA<0.01) and C ((29.50±22.54) pg/mL, PBc<0.01); while no significance existed between groups A and C. The level of serum IL-6 was shown significantly elevated in groups B ((30.54±12.25) pg/mL) and C ((23.04±13.85) pg/mL) compared to that in group A ((14.10±8.83) pg/mL, PBA<0.01, PCA=0.045), but no significance was shown between groups B and C.ConclusionsBeyond hypoadiponectinemia, CIH could also enhance ERS and induce ERS-associated apoptosis in genioglossus, as well as oxidative stress and inflammation, which jointly result in the ultrastructural damage. Additionally, systemic inflammation was also induced by CIH. Meanwhile, supplement of adiponectin could attenuate the genioglossus injury and partly improve the systemic inflammation. |
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