Globular adiponectin protects hepatocytes against intermittent hypoxia-induced injury via Pink1/Parkin-mediated mitophagy induction.

PURPOSE: This study sought to determine the effect of Pink1/Parkin-mediated mitophagy on liver cells exposed to intermittent hypoxia (IH) and the roles of globular adiponectin (gAPN). METHODS: The hepatocyte model of IH was established. Cell apoptosis was assessed using flow cytometry. Mitochondrial membrane potential (MMP) level was determined using JC-1, and mitophagy was assessed using a confocal laser. Mitochondrial injury associated protein levels of bax and bcl-2, and protein levels of Pink1 and Parkin were evaluated via western blotting. We downregulated Parkin expression by transfecting the cells with Parkin siRNA. RESULTS: Pink1 and Parkin protein levels, mitophagy, and cell apoptosis rate were high, while the MMP level and protein level ratio of bcl-2/bax were low in IH-treated hepatocyte. gAPN upregulated Pink1 and Parkin protein levels, MMP level, protein level ratio of bcl-2/bax, and mitophagy while it reduced the rate of cell apoptosis in IH-treated hepatocytes. Inhibiting Parkin expression significantly reduced mitophagy and increased mitochondrial injury and the rate of hepatocyte apoptosis under IH or IH with gAPN. CONCLUSION: gAPN alleviated IH-induced mitochondrial injury and hepatocyte apoptosis by upregulating Pink1/Parkin-mediated mitophagy.

Adiponectin Ameliorated Pancreatic Islet Injury Induced by Chronic Intermittent Hypoxia through Inhibiting the Imbalance in Mitochondrial Fusion and Division.

Objective This study aimed to assess the protective value of adiponectin (APN) in pancreatic islet injury induced by chronic intermittent hypoxia (CIH). Methods Sixty rats were randomly divided into three groups: normal control (NC) group, CIH group, and CIH with APN supplement (CIH+APN) group. After 5 weeks of CIH exposure, we conducted oral glucose tolerance tests (OGTT) and insulin released test (IRT), examined and compared the adenosine triphosphate (ATP) levels, mitochondrial membrane potential (MMP) levels, reactive oxygen species (ROS) levels, enzymes gene expression levels of Ant1, Cs, Hmox1, and Cox4i1 which represented mitochondrial tricarboxylic acid cycle function, the protein and gene expression levels of DRP1, FIS1, MFN1, and OPA1 which represented mitochondrial fusion and division, and the protein expression levels of BAX, BCL-2, cleaved Caspase-3, and cleaved PARP which represented mitochondrial associated apoptosis pathway of pancreatic islet. Results OGTT and IRT showed blood glucose and insulin levels had no differences among the NC, CIH and CIH+APN groups (both P>0.05) at 0 min, 20 min, 30 min, 60 min, 120 min. However, we found that compared to NC group, CIH increased the ROS level, reduced ATP level and MMP level. The islets of CIH exposed rats showed reduced gene expression levels of Ant1, Cs, Hmox1, and Cox4i1, decreased protein and gene expression levels of MFN1 and OPA1, increased protein and gene expression levels of DRP1 and FIS1, increased protein expression levels of cleaved Caspase-3 and cleaved PARP, with lower ratio of BCL-2/BAX at protein expression level. All the differences among three groups were statistically significant. APN treated CIH rats showed mitigated changes in the above measurements associated with islet injuries. Conclusion APN may ameliorate the pancreatic islet injury induced by CIH via inhibiting the imbalance in mitochondrial fusion and division.

Klotho alleviates chronic intermittent hypoxia-induced genioglossus myocyte apoptosis by inhibiting endoplasmic reticulum stress.

Chronic intermittent hypoxia (CIH) has been shown to induce cell apoptosis in multiple organs of the human body. The present study aimed to assess the effects of exogenous klotho on CIH-induced genioglossus muscle injury, as well as the involvement of endoplasmic reticulum stress (ERS) in this process. A total of 36 adult C57BL/6 male mice were assigned to normoxia control (NC), CIH and CIH + klotho groups (n=12 mice/group). ELISA was performed to detect the level of klotho protein in the serum and in the genioglossus muscle tissue samples. Apoptosis was evaluated using the TUNEL assay. Reactive oxygen species (ROS) levels were quantified using a dihydroethidium assay kit, and the protein and mRNA levels of ERS-associated proteins (namely, glucoseregulated protein 78, C/EBP homologous protein, cleaved caspase-12 and cleaved caspase-3) in genioglossus samples were assessed using immunoblot assay and reverse transcription-quantitative PCR, respectively. Compared with the NC group, the quantities of klotho protein in the serum and genioglossus muscle tissue samples in the CIH group were significantly decreased, whereas the apoptotic rate, ROS levels and protein and mRNA levels of the ERS-associated proteins in the genioglossus muscle were significantly increased. Following supplementation with exogenous klotho protein, the klotho protein levels in the serum and genioglossus muscle tissue of mice were found to be markedly increased, and the apoptotic rate, ROS levels and protein and mRNA levels of the ERS-associated proteins in the genioglossus muscle were decreased compared with those in the CIH group. Taken together, the results of the present study have demonstrated that exogenous klotho may inhibit apoptosis of genioglossus myocytes in mice by inhibiting ROS-associated ERS.

Adiponectin ameliorates lung injury induced by intermittent hypoxia through inhibition of ROS-associated pulmonary cell apoptosis.

PURPOSE: Obstructive sleep apnea hypopnea syndrome has been reported to be associated with pulmonary hypertension (PH). Adiponectin (Ad) has many protective roles in the human body, including its function as an anti-inflammatory and an anti-oxidant, as well as its role in preventing insulin resistance and atherosclerosis. This study aimed to investigate the molecular mechanism of chronic intermittent hypoxia (CIH)-induced pulmonary injury and the protective role of Ad in experimental rats. METHODS: Thirty male Sprague-Dawley rats were randomly divided into three groups with 10 rats in each group: normal control (NC) group, CIH group, and CIH + Ad group. Rats in the NC group were kept breathing room air for 12 weeks. Rats in the CIH group were intermittently exposed to a hypoxic environment for 8 h/day for 12 weeks. Rats in the CIH + Ad group received 10 µg Ad twice weekly via intravenous injection. After 12 weeks of CIH exposure, we detected the pulmonary function, pulmonary artery pressure, lung histology, pulmonary cell apoptosis, pulmonary artery endothelial cell apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) level. We also analyzed expression proteins involved in the mitochondria-, endoplasmic reticulum (ER) stress-, and Fas receptor-associated pulmonary apoptosis pathways, as well as the SIRT3/SOD2 pathway. RESULTS: CIH exposure for 12 weeks did not lead to abnormal pulmonary function, PH, or pulmonary artery endothelial cell apoptosis. However, we observed a significant increase in the rate of pulmonary cell apoptosis, the expression of proteins involved in mitochondria-, ER stress-, and Fas receptor-associated pulmonary apoptosis pathways, and the generation of ROS in the CIH group compared with the NC group. In contrast, the MMP and protein expressions of SIRT3/SOD2 pathway were significantly decreased in the CIH group compared with the NC group. Ad supplementation in the CIH + Ad group partially improved these changes induced by CIH. CONCLUSION: Even though CIH did not cause abnormal pulmonary function or PH, early lung injury was detected at the molecular level in rats exposed to CIH. Treatment with Ad ameliorated the pulmonary injury by activating the SIRT3/SOD2 pathway, reducing ROS generation, and inhibiting ROS-associated lung cell apoptosis.

The role of mitophagy in the mechanism of genioglossal dysfunction caused by chronic intermittent hypoxia and the protective effect of adiponectin.

PURPOSE: Dysfunction of the genioglossus muscle is important in the pathogenesis of obstructive sleep apnea due to chronic intermittent hypoxia (CIH). Mitochondrial impairment resulting from hypoxia is mitigated by mitophagy to avoid cell apoptosis in cardiomyocytes. This project was designed to explore the effects of CIH on mitophagy in the genioglossus muscle and the impact of adiponectin (Ad). METHODS: One hundred eighty male SD rats were randomly divided into 3 groups (normal control [NC], CIH, and CIH + Ad groups), with 60 rats in each group observed for 5 weeks. Comparisons of serum Ad levels, mitochondrial structure and function, mitophagy, and cell apoptosis in the genioglossus were made at different time points. RESULTS: (1) The CIH group was significantly different from the NC group as follows: During the first 3 weeks, serum Ad levels, the reactive oxygen species (ROS), relative proteins and mRNA of mitophagy, autophagy biomarker LC3-II, and autophagosomes increased, while during the last 2 weeks, most parameters decreased. (2) There was no difference among the 3 groups in mitochondrial structure and function-associated mRNA during the first 3 weeks, while damaged mitochondrial structures were growing during the last 2 weeks. Exacerbation of apoptosis was also detected in the last 2 weeks. (3) All of the damage was partially alleviated in the CIH + Ad group in contrast to CIH group at the end of this study. CONCLUSION: Disturbances of genioglossal mitophagy could be related to damaged mitochondrial structure and function induced by CIH, which could be alleviated by supplementation of exogenous Ad via increasing mitophagy.

Globular adiponectin alleviates chronic intermittent hypoxia-induced H9C2 cardiomyocytes apoptosis via ER-phagy induction.

This study evaluated the effects of endoplasmic reticulum autophagy (ER-phagy) and globular adiponectin (gAPN) on chronic intermittent hypoxia (CIH)-induced H9C2 cardiomyocytes injury while investigating potential mechanisms of action. The CIH model of H9C2 cardiomyocytes was established in this study. CCK-8 assay was used to determine cell viability post-exposure to various CIH times and gAPN concentrations. Flow cytometry was used to observe H9C2 cardiomyocytes apoptosis and immunofluorescence was used to measure ER-phagy and SEC62 activation. Western blot was used to observe ER stress and AMPK pathway. Results indicated that ER stress was activated in H9C2 cardiomyocytes exposed to CIH. Inhibition of ER stress reduced CIH-induced cell apoptosis. gAPN attenuated CIH-induced ER stress and H9C2 cardiomyocytes apoptosis. ER-phagy and SEC62 protein level were induced by CIH, while gAPN highly enhanced these changes. Inhibition of SEC62 expression reduced ER-phagy and increased ER stress and H9C2 cardiomyocytes apoptosis. Moreover, gAPN induced AMPK expression. Inhibition of AMPK expression reduced SEC62-mediated ER-phagy and increased the H9C2 cardiomyocytes apoptosis. Altogether, our study suggested that gAPN upregulated SEC62-mediated ER-phagy to extenuate ER stress, and mitigated H9C2 cardiomyocytes apoptosis induced by CIH through AMPK activation.

Globular Adiponectin Attenuated H2O2-Induced Apoptosis in Rat Chondrocytes by Inducing Autophagy Through the AMPK/ mTOR Pathway.

BACKGROUND/AIMS: Chondrocyte apoptosis is closely related to the development and progression of osteoarthritis. Global adiponectin (gAPN), secreted from adipose tissue, possesses potent anti-inflammatory and antiapoptotic properties in various cell types. This study aimed to investigate the role of autophagy induced by gAPN in the suppression of H2O2-induced apoptosis and the potential mechanism of gAPN-induced autophagy in chondrocytes. METHODS: H2O2 was used to induce apoptotic injury in rat chondrocytes. CCK-8 assay was performed to determine the viability of cells treated with different concentrations of gAPN with or without H2O2. Cell apoptosis was detected by flow cytometry and TUNEL staining. Mitochondrial membrane potential was examined using JC-1 fluorescence staining assay. The autophagy inhibitors 3-MA and Bafilomycin A1 were used to treat cells and then evaluate the effect of gAPN-induced autophagy. To determine the downstream pathway, chondrocytes were preincubated with the AMPK inhibitor Compound C. Beclin-1, LC3B, P62 and apoptosis-related proteins were identified by Western blot analysis. RESULTS: H2O2 (400 µM)-induced chondrocytes apoptosis and caspase-3 activation were attenuated by gAPN (0.5 µg/mL). gAPN increased Bcl-2 expression and decreased Bax expression. The loss of mitochondrial membrane potential induced by H2O2 was also abolished by gAPN. Furthermore, the antiapoptotic effect of gAPN was related to gAPN-induced autophagy by increased formation of Beclin-1 and LC3B and P62 degradation. In particular, the inhibition of gAPN-induced autophagy by 3-MA prevented the protective effect of gAPN on apoptosis induced by H2O2. Moreover, gAPN increased p-AMPK expression and decreased p-mTOR expression. Compound C partly suppressed the expression of autophagy-related proteins and restored the expression of p-mTOR suppressed by gAPN. Thus, the AMPK/mTOR pathway played an important role in the induction of autophagy and protection of H2O2-induced chondrocytes apoptosis by gAPN. CONCLUSIONS: gAPN protected chondrocytes from H2O2-induced apoptosis by inducing autophagy possibly associated with AMPK/mTOR signal-pathway activation.

Adiponectin protects the rats liver against chronic intermittent hypoxia induced injury through AMP-activated protein kinase pathway.

This study was performed to assess the effect of chronic intermittent hypoxia (CIH) on the liver, the associated mechanisms and the potential therapeutic roles of adiponectin (Ad). Sixty rats were randomly assigned to four groups: the normal control (NC), NC and Ad supplement (NC + Ad), CIH, and CIH and Ad supplement (CIH + Ad) groups. The rats in the CIH and CIH + Ad groups were exposed to a hypoxic environment for 4 months. Rats in the NC + Ad and CIH + Ad groups were also treated with an intravenous injection of Ad (10 ug), twice a week. The plasma levels of hepatic enzymes, serum triglyceride, liver triglyceride, fasting blood glucose and hepatic cell apoptosis in hepatic tissue, were higher in the CIH group than in the NC and NC + Ad groups. However, the Ad supplementation in the CIH + Ad group rescued the hepatic tissue insult by activating the AMP-activated protein kinase (AMPK) pathway. In conclusion, Ad could protect against CIH-induced hepatic injury partly through the AMPK pathway.

Obstructive Sleep Apnea Increases the Perioperative Risk of Cardiac Valve Replacement Surgery: A Prospective Single-Center Study.

STUDY OBJECTIVES: Sleep apnea is common in patients referred for cardiac valve replacement (CVR). We aimed to determine the association of obstructive sleep apnea (OSA) and central sleep apnea (CSA) with perioperative events in CVR surgery in patients with rheumatic valvular heart disease (RVHD). METHODS: Between April 2010 and April 2014, 290 patients with RVHD undergoing CVR were screened for sleep apnea 1 to 7 days before CVR. Baseline medications, cardiac function, sleep parameters, perioperative events, and related risk factors were evaluated. RESULTS: OSA patients had longer duration of intensive care unit (ICU) stay and mechanical ventilation compared with no sleep-disordered breathing and CSA patients. Patients with CSA had a higher rate of pacemaker use and higher first dose of dobutamine in ICU. NYHA Class and the presence of OSA were independently associated with overall worsening of postoperative recovery (ICU stay ≥ 25 h). Age, NYHA class, and the presence of OSA were independently associated with postoperative respiratory insufficiency (mechanical ventilation ≥ 20 h). Preoperative atrial fibrillation, pulmonary hypertension, and OSA were independently associated with postoperative pacemaker use. CONCLUSIONS: RVHD patients with OSA have an increased incidence of perioperative adverse events. OSA was independently associated with overall postoperative recovery, respiratory insufficiency, and higher rate of postoperative pacemaker use, while CSA was not associated with postoperative events.

Adiponectin protects the kidney against chronic intermittent hypoxia-induced injury through inhibiting endoplasmic reticulum stress.

PURPOSE: The current study was carried out to assess the effects of chronic intermittent hypoxia (CIH) on the kidney, the intervention roles of adiponectin (Ad), and the associated mechanisms. METHODS: Sixty Wistar rats were randomly divided into four groups: the normal control (NC), normal control plus Ad supplement (NC + Ad), CIH, and CIH plus Ad supplement (CIH + Ad) groups. The rats in both CIH and CIH + Ad groups were submitted to a CIH environment for 4 months, while the rats in NC and NC + Ad groups were housed with the normal air for 4 months. In addition, the rats in NC + Ad and CIH + Ad groups were treated with an intravenous injection of Ad at a dosage of 10 µg per injection, twice a week, for four successive months. RESULTS: The production level of reactive oxygen species (ROS) and the protein levels of endoplasmic reticulum (ER) stress, as well as the cell apoptosis level in kidney, were all higher in the CIH group than in the NC and NC + Ad groups (all p < 0.05). However, the ROS production, the protein of ER stress, and cell apoptosis levels in kidney were all lower in the CIH + Ad group than those in the CIH group (all p < 0.05). CONCLUSION: Ad could protect against CIH-induced renal cell apoptosis through inhibiting ROS-related ER stress.

[Effects of chronic intermittent hypoxia on oxidative stress and inflammatory response and the interventional roles of adiponectin].

OBJECTIVE: To explore the effects of chronic intermittent hypoxia (CIH) on oxidative stress and inflammatory response and the interventional roles of adiponectin (Ad). METHODS: A total of 45 male Wistar rats were randomly divided into three groups of control group, CIH and CIH+Ad (n = 15 each). The control group breathed room air while the CIH and CIH+Ad groups received CIH 8 h/d for 5 successive weeks. The CIH+Ad group Ad had an injection of 10 µg once a week through tail vein. At the end of experiment (Day 35), comparison was performed among three groups about Ad, tumor necrosis factor α (TNF-α), C-reactive protein (CRP) and interleukin (IL) 6 from serum as well as malondialdehyde, superoxide dismutase (SOD), myeloperoxidase (MPO), reactive oxygen spieces (ROS) and nuclear factor (NF) κB from genioglossus. RESULTS: Serum Ad level in CIH group was lower than those in control and CIH+Ad groups ((4 208 ± 2 239) vs (7 051 ± 2 432) and (6 405 ± 2 384) ng/ml, all P < 0.05) with no statistic difference between control and CIH+Ad groups. Both serum levels of TNF-α and CRP were higher in CIH group than those in control and CIH+Ad groups ((70.87 ± 35.16) vs (26.54 ± 20.32) and (29.50 ± 22.54) pg/ml, as well as (31.84 ± 11.48) vs (22.68 ± 9.63), (25.32 ± 8.34) mg/L, all P < 0.05)with no significant difference between control and CIH+Ad groups. Serum IL-6 levels were all higher in CIH group and CIH+Ad group than that in control group ((30.54 ± 12.25) and (23.04 ± 13.) vs (14.10 ± 8.83) pg/ml, all P < 0.05) with no significant difference between CIH and CIH+Ad groups. Genioglossal malondialdehyde level was significantly elevated in CIH group than those in control and CIH+Ad groups ((8.05 ± 4.53) vs (5.18 ± 3.03) and ((5.74 ± 3.06) nmol/mg, all P < 0.01) with no significant difference between control and CIH+Ad groups. Genioglossal SOD activity was lower in CIH+Ad group than that in CIH group but higher than that in control group ((42.42 ± 23.17) vs (61.77 ± 36.38) and (18.62 ± 11.67) U/mg, all P < 0.05). Genioglossal MPO levels were significantly higher in both CIH and CIH+Ad groups than that in control group ((0.40 ± 0.29) and (0.31 ± 0.17) vs (0.17 ± 0.08) µU/mg, all P < 0.01), with no significance between CIH and CIH+Ad groups. The relative level of total reactive oxygen species (ROS) in genioglossus of CIH+Ad group was significantly lower than that in CIH group but higher than that in control group (1.94 ± 1.01 vs 3.31 ± 1.56 and 1.08 ± 0.38 all P < 0.05). The transcription of NF-κB was significantly higher in CIH group than that in control and CIH+Ad groups (2.24 ± 0.34 vs 0.78 ± 0.21, P < 0.05), but there was no statistical difference with CIH+Ad group (1.04 ± 0.27). CONCLUSION: CIH may induce oxidative stress and inflammation possibly through NF κB pathway while a supplement of Ad attenuates the above CIH-induced responses.

Adiponectin protects rat heart from left ventricular remodeling induced by chronic intermittent hypoxia via inhibition of TGF-ß/smad2/3 pathway.

OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) is associated with many cardiovascular disorders. Chronic intermittent hypoxia (CIH) is the primary player in OSAS of the many associated factors. This study was in order to investigate the effects of the Adiponectin (Ad) on left ventricular remodeling induced by CIH. METHODS: Forty-five rats were randomly divided into three groups: normal control (NC) group, CIH group and CIH plus Ad supplemented (CIH + Ad) group. After 35 days' CIH exposure, masson analysis was used to detect the left ventricular fibrosis and western blot was used to measure the protein expression of collagen I, collagen III and TGF-ß/smad2/3 pathway. Gene analysis by RT-PCR was used to study the MMP2 and TIMP2. RESULTS: After CIH exposure, the fibrosis of left ventricular in CIH group was significantly remarkable than that in both NC and CIH + Ad groups (P<0.05), although statistical difference existed between NC and CIH + Ad groups (P<0.05). In addition, the protein expression of collagen I as well as collagen III and the ratio of mRNA levels of MMP2/TIMP2 were the highest in CIH group but the lowest in NC group, with CIH + Ad group in between. There was a significant difference among three groups (all P<0.05). The TGF-ß/smad2/3 pathway was activated obviously in CIH group, but less noticeably in CIH + Ad group (P<0.05) with a significant difference in the two groups. CONCLUSIONS: The present study showed that Ad could ameliorate the left ventricular remodeling induced by CIH via inhibition of the expression of TGF-ß/smad2/3 pathway.

Adiponectin protects rat myocardium against chronic intermittent hypoxia-induced injury via inhibition of endoplasmic reticulum stress.

Obstructive sleep apnea syndrome (OSAS) is associated with many cardiovascular disorders such as heart failure, hypertension, atherosclerosis, and arrhythmia and so on. Of the many associated factors, chronic intermittent hypoxia (CIH) in particular is the primary player in OSAS. To assess the effects of CIH on cardiac function secondary to OSAS, we established a model to study the effects of CIH on Wistar rats. Specifically, we examined the possible underlying cellular mechanisms of hypoxic tissue damage and the possible protective role of adiponectin against hypoxic insults. In the first treatment group, rats were exposed to CIH conditions (nadir O2, 5-6%) for 8 hours/day, for 5 weeks. Subsequent CIH-induced cardiac dysfunction was measured by echocardiograph. Compared with the normal control (NC) group, rats in the CIH-exposed group experienced elevated levels of left ventricular end-systolic dimension and left ventricular end-systolic volume and depressed levels of left ventricular ejection fraction and left ventricular fractional shortening (p<0.05). However, when adiponectin (Ad) was added in CIH + Ad group, we saw a rescue in the elevations of the aforementioned left ventricular function (p<0.05). To assess critical cardiac injury, we detected myocardial apoptosis by Terminal deoxynucleotidyl transfer-mediated dUTP nick end-labeling (TUNEL) analysis. It was showed that the apoptosis percentage in CIH group (2.948%) was significantly higher than that in NC group (0.4167%) and CIH + Ad group (1.219%) (p<0.05). Protein expressions of cleaved caspase-3, cleaved caspase-9, and cleaved-caspase-12 validated our TUNEL results (p<0.05). Mechanistically, our results demonstrated that the proteins expressed with endoplasmic reticulum stress and the expression of reactive oxygen species (ROS) were significantly elevated under CIH conditions, whereas Ad supplementation partially decreased them. Overall, our results suggested that Ad augmentation could improve CIH-induced left ventricular dysfunction and associated myocardial apoptosis by inhibition of ROS-dependent ER stress.

[A study on rat cardiovascular injury induced by intermittent hypoxia and the protective role of adiponectin].

OBJECTIVE: To observe the effect of chronic intermittent hypoxia (CIH) on rat cardiac function and blood pressure, and the protective role of adiponectin (Ad). METHODS: A total of 24 male Wistar rats were randomly and equally divided into 3 groups: normal control group (NC group), chronic intermittent hypoxygen group (CIH group) and CIH+Ad group. Normal air breathing for NC group and CHI for CIH and CIH+Ad groups were conducted for 28 days. In addition, rats in CIH+Ad group were given intravenous adiponectin at a dosage of 20 µg each time, once a week for successive 4 weeks. The results of echocardiography, blood pressure, plasma adiponectin, endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) were compared among the three groups after 28 days. RESULTS: HE stain showed that the myocardial cells of CIH rats were damaged by CIH. Compared with NC group, rats in CIH group presented with a greater heart/body weight ratio (0.070 ± 0.008 vs. 0.057 ± 0.009, P < 0.05) and systolic blood pressure [(132 ± 4) vs. (123 ± 6) mmHg(1 mmHg = 0.133 kPa), P < 0.05] and a lower LVEF [(70.3 ± 4.1)% vs. (84.1 ± 2.5)%, P < 0.05]. Plasma ET-1 was increased while NO(-)(2)/NO(-)(3) and eNOS decreased in CIH group, compared with NC group [(26.2 ± 6.9) ng/L vs. (7.7 ± 2.7) ng/L, (37 ± 9) µmol/L vs. (65 ± 10) µmol/L, (18 ± 5)µg/L vs. (27 ± 6) µg/L, respectively; P < 0.05]. The heart/body weight ratio, blood pressure and LVEF were improved in CIH+Ad group compared with those in CIH group [0.064 ± 0.009 vs. 0.070 ± 0.008, (127 ± 6) mmHg vs. (132 ± 4) mmHg, P > 0.05; (79 ± 7)% vs. (70 ± 4)%, P < 0.05; respectively]. Plasma ET-1 levels in CIH+Ad and CIH groups showed no significant difference, but were significantly lower in NC group. However, rats in CIH+Ad group had a higher NO(-)(2)/NO(-)(3) level than that in CIH group. Bivariate Correlations showed that NO(-)(2)/NO(-)(3) and eNOS were negatively correlated with systolic blood pressure while heart/body weight ratio, LVEDs, ET-1 and NO(-)(2)/NO(-)(3) were negatively correlated with left ventricular ejection fraction. CONCLUSIONS: Through xidative stress, ET-1 and NO imbalance and impaired vascular endothelial function, cardiac function could be damaged by CIH in rats, while supplement of extrinsic adiponectin could improve these damages.

Overnight fluid shifts in subjects with and without obstructive sleep apnea.

OBJECTIVE: To investigate the characteristics of baseline body fluid content and overnight fluid shifts between non-obstructive sleep apnea (non-OSA) and obstructive sleep apnea (OSA) subjects. METHODS: A case-controlled study was performed between February 2013 and January 2014, with 36 (18 OSA and 18 non-OSA) outpatients enrolled in this study. Polysomnographic parameters and results of body fluid were compared between the two groups. RESULTS: There were no differences in age, weight, and body mass index (BMI) between groups. Compared with the non-OSA group, OSA group had significantly higher neck circumference (NC) and fluid volume shift in the legs. OSA patients had higher left and right leg fluid indices than non-OSA subjects. There were significant correlations between apnoea-hypopnoea index and baseline fluid indices in both legs as well as the reduction in overnight change in both legs fluid volume. The increase in NC was also significantly correlated with the reduction in overnight change in both legs fluid volume, but not with the change in head and neck fluid volume. There were significant correlations between change in NC and increased fluid shifts in head and neck volume. CONCLUSIONS: OSA patients had a higher baseline fluid content in both legs as compared with non-OSA subjects, which may be the basic factor with regards to fluid shifts in OSA patients. The increase in head and neck fluid shift volume did not directly correlate with the severity of OSA.

Adiponectin alleviates contractile dysfunction of genioglossus in rats exposed to chronic intermittent hypoxia.

BACKGROUND: Genioglossal dysfuntion takes an important role in pathogenesis of obstructive sleep apnea hypopnea syndrome (OSAHS) in which chronic intermittent hypoxia (CIH) is the major pathological origin. Recent studies have suggested genioglossal injury induced by CIH might be improved by adiponectin. The aim of this study was to investigate the effects of adiponectin on genioglossus contractile properties in rats exposed to CIH. METHODS: Thirty-nine healthy male Wistar rats were randomly divided into three groups: normal control (NC), CIH and adiponectin supplement (CIH+Ad) with 13 rats in each. Rats in NC were kept breathing normal air, while rats in CIH and CIH+Ad experienced the same CIH environment eight hours per day for 35 successive days. Rats in CIH+Ad were given intravenous adiponectin of 10 µg twice a week for 30 successive days. Rats in the NC and CIH were injected with normal saline as a control. After 35 days' CIH exposure, the levels of serum adiponectin and genioglossus contractile properties were compared. RESULTS: Serum adiponectin level was significantly lower in CIH than in NC (1210 ng/ml vs. 2236 ng/ml). Serum adiponectin level in CIH+Ad (1844 ng/ml) was significantly higher than CIH but lower than NC. Twitch tension, time to peak tension, half relaxation time and tetanic tension were significantly lower in CIH than NC and improved in CIH+Ad. All mean tetanic fatigue indices decreased more rapidly in the first 20 seconds than during the subsequent 100 seconds. Tetanic fatigue indices in NC and CIH+Ad were significantly higher compared to CIH. CONCLUSIONS: CIH could lead to hypoadiponectinaemia, impaired genioglossus contractile properties and decreased fatigue resistance in rats. Such changes could be partially offset by supplementation of adiponectin.

Adiponectin protects the genioglossus of rats against chronic intermittent hypoxia-induced injury via inhibition of endoplasmic reticulum stress.

BACKGROUND: Obstructive sleep apnea hypopnea syndrome, characterized by chronic intermittent hypoxia (CIH), is closely correlated with 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 mitochondrial dysfunction. This study aimed to investigate the role of ERS in CIH-induced genioglossus injury, as well as the possible intervention effect of adiponectin (Ad) supplement in rats. METHODS: Forty-five male Wistar 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, intravenous Ad was given in group C; while intravenous normal saline was simultaneously given in groups A and B. After 35-day 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. Serum adiponectin levels were assessed via enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant 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 glucose regulated protein 78 (GRP78), p-PERK, phosphorylated eukaryotic initiation factor 2a (p-eIF2a), phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1a (p-IRE1a), spliced X-Box binding protein 1 (XBP1s) and activating transcription factor 6 (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). ERSassociated apoptotic pathways were remarkably activated in group B. The involved markers detected as the expression of CCAAT/enhancer binding protein homologous protein (CHOP), B-cell lymphoma/leukemia associatied X protein (BAX) and caspase-12 were significantly elevated (all P < 0.01). Transvenous adiponectin supplement improved the above CIHinduced pathological changes in group C. CONCLUSION: Beyond hypoadiponectinemia, CIH could enhance ERS and induce activation of ERS-associated apoptotic pathways in genioglossus, which could be significantly improved by adiponectin supplement.

Congenital heart disease in a Chinese hospital: pre- and postnatal detection, incidence, clinical characteristics and outcomes.

BACKGROUND: The pre- and postnatal detection rate, incidence, clinical characteristics and outcomes of congenital heart disease (CHD) have been studied in developed countries for many years, but rarely have large-scale studies been reported in Chinese populations. The aim of the present study was to investigate the pre- and postnatal detection rates, incidence, clinical characteristics and outcomes of CHD in a Chinese hospital in order to improve the future screening and treatment of CHD. METHODS: Fetuses without risk factors for CHD were screened using basic cardiac ultrasound examination (BCUE). Fetuses with suspected cardiac malformation revealed by BCUE and fetuses with risk factors were screened using extended cardiac ultrasound examination. Outcomes recorded from fetal, neonatal and postmortem records over 4 years (2006-2009) included: therapeutic termination of pregnancy, spontaneous abortions or stillbirths, deaths at birth or in the neonatal period (before 28 days of age), and rate of birth and clinical characteristics of newborns. RESULTS: A total of 34,071 fetuses were screened for CHD during a period of 4 years, of which 173 fetuses were screened for CHD using BCUE and 301 fetuses were screened using extended cardiac ultrasound examination. The incidence of fetal CHD increased from 1.1% in 2006 to 2.4% in 2009 (P < 0.05), yielding an overall incidence of 1.5% (523/34,071). Of the fetuses with CHD, 48.2% (252/523) died before 28 days of age (including intra-uterine death and termination of pregnancy), 51.8% (271/523) lived more than 28 days and the incidence of live newborns with CHD was 0.80% (271/34071). CONCLUSIONS: The prevalence of CHD was quite common in this Chinese hospital. Detailed profiles of CHD suggest that, while training programs in obstetric screening at this hospital were beneficial, prenatal intervention, treatment and care of fetal CHD were inefficient and should be strengthened in China.