Jin Shang

Tongji Hospital, Wu-han-shih, Hubei, China

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Publications (11)17.66 Total impact

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    ABSTRACT: Obstructive sleep apnea syndrome (OSAS) is usually associated with multiple cardiovascular disorders, including myocardial hypertrophy. Melatonin protects the heart from damaging conditions. However, whether melatonin alleviates heart damage induced by chronic intermittent hypoxia (CIH) is unknown. We investigated the melatonin-induced protective role of AMPK-regulated autophagy in the myocardium by exposing rats to CIH and treating them with melatonin or saline daily for six weeks. In vivo, CIH induced significant myocardial hypertrophy; this trend was strikingly reversed by melatonin. Moreover, AMPK activation and autophagy was enhanced, and the number of autophagosomes increased. CIH induced apoptosis of cardiomyocytes; this was significantly mitigated by melatonin. In vitro, CIH induced hypertrophic changes in cardiomyocytes; this effect was significantly reversed by melatonin. Autophagy decreased after AMPK inhibition, and we found that autophagy was required for the protective function of melatonin. Our results suggest that melatonin ameliorates cardiac hypertrophy caused by CIH by inducing autophagy via the AMPK pathway and by autophagy-regulated apoptosis. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 07/2015; DOI:10.1016/j.bbrc.2015.06.149 · 2.28 Impact Factor
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    ABSTRACT: Obstructive sleep apnea, characterized by recurrent episodes of hypoxia [intermittent hypoxia (IH)], has been identified as a risk factor for cardiovascular diseases. The O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) of proteins has important regulatory implications on the pathophysiology of cardiovascular disorders. In this study, we examined the role of O-GlcNAcylation in cardiac architecture and left ventricular function following IH. Rats were randomly assigned to a normoxia and IH group (2 min 21% O2; 2 min 6-8% O2). Left ventricular function, myocardial morphology and the levels of signaling molecules were then measured. IH induced a significant increase in blood pressure, associated with a gradually abnormal myocardial architecture. The rats exposed to 2 or 3 weeks of IH presented with augmented left ventricular systolic and diastolic function, which declined at week 4. Consistently, the O-GlcNAc protein and O-GlcNAcase (OGA) levels in the left ventricular tissues steadily increased following IH, reaching peak levels at week 3. The O-GlcNAc transferase (OGT), extracellular signal-regulated kinase 1/2 (ERK1/2) and the p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation levels were affected in an opposite manner. The phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) remained unaltered. In parallel, compared with exposure to normoxia, 4 weeks of IH augmented the O-GlcNAc protein, OGT, phosphorylated ERK1/2 and p38 MAPK levels, accompanied by a decrease in OGA levels and an increase in the levels of myocardial nuclear factor-κB (NF-κB), inflammatory cytokines, caspase-3 and cardiomyocyte apoptosis. Taken together, our suggest a possible involvement of O-GlcNAc protein and MAPK signaling in the alterations of left ventricular function and cardiac injury following IH.
    International Journal of Molecular Medicine 04/2015; DOI:10.3892/ijmm.2015.2198 · 1.88 Impact Factor
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    ABSTRACT: Obstructive sleep apnea syndrome (OSAS) plays a critical role in the initiation and progression of Alzheimer׳s disease (AD), but little is known about the precise mechanism of OSAS-induced AD. Nitric oxide synthase (NOS) and nitric oxide (NO) are known to play key roles in the development of AD. Several studies have confirmed that an angiotensin II type 1 receptor blocker, telmisartan, beneficially regulates NOS and NO. Here, we examined the neuroprotective effects of telmisartan against hippocampal apoptosis induced by chronic intermittent hypoxia (CIH), the most characteristic pathophysiological change of OSAS. Adult male Sprague Dawley rats were subjected to 8 h of intermittent hypoxia per day with or without telmisartan for eight weeks. Neuronal apoptosis in the hippocampal CA1 region, NOS activity, NO content, and the presence of inflammatory agents and radical oxygen species in the hippocampus were determined. The results showed that CIH activated inducible nitric oxide synthase (iNOS), increased NO content, and enhanced lipid peroxidation and inflammatory responses in the hippocampus. Treatment with telmisartan inhibited excessive iNOS and NO generation and reduced lipid peroxidation and inflammatory responses. In addition, telmisartan significantly ameliorated the hippocampal apoptosis induced by CIH. In conclusion, Pre-CIH telmisartan administration attenuated CIH-induced hippocampal apoptosis partly by regulating NOS activity, inhibiting excessive NO generation, and reducing lipid peroxidation and inflammatory responses.
    Brain Research 11/2014; 1596. DOI:10.1016/j.brainres.2014.11.035 · 2.83 Impact Factor
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    ABSTRACT: NO and NO synthase (NOS) are known to play key roles in the development of myocardial apoptosis induced by ischemia/hypoxia. Current evidence suggests that angiotensin II type 1 receptor blockers, such as telmisartan, lower blood pressure and produce beneficial regulatory effects on NO and NOS. Here, we examined the protective role of telmisartan in myocardial apoptosis induced by chronic intermittent hypoxia (CIH). Adult male Sprague-Dawley rats were subjected to 8 h of intermittent hypoxia/day, with/without telmisartan for 8 weeks. Myocardial apoptosis, NO and NOS activity, and levels of inflammatory mediators and radical oxygen species were determined. Treatment with telmisartan preserved endothelial NOS expression and inhibited inducible NOS and excessive NO generation, while reducing oxidation/nitration stress and inflammatory responses. Administration of telmisartan before CIH significantly ameliorated the CIH-induced myocardial apoptosis. This study show that pre-CIH telmisartan administration ameliorated myocardial injury following CIH by attenuating CIH-induced myocardial apoptosis via regulation of NOS activity and inhibition of excessive NO generation, oxidation/nitration stress, and inflammatory responses.
    Sleep And Breathing 11/2014; 19(2). DOI:10.1007/s11325-014-1081-y · 2.87 Impact Factor
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    ABSTRACT: Inflammatory processes and oxidative stress are known to play a key role in the development of cardiovascular complications such as cardiac hypertrophy induced by chronic intermittent hypoxia (CIH), the most characteristic pathophysiological change of obstructive sleep apnea syndrome (OSAS). Current evidence suggests that competitive inhibitors of 3-hydroxy-3-methylglutaryl-CoA coenzyme A reductase, such as atorvastatin, not only reduce blood lipids but also have anti-inflammatory and inhibit oxidative stress benefits. This study examined the protective role of atorvastatin in CIH- induced cardiac hypertrophy. Adult male wistar rats were subjected to 8 hours of intermittent hypoxia/day, with/without atorvastatin for 6 weeks. Ventricular remodeling, toll-like receptor 4 (TLR-4), myeloid differentiation primary response protein 88 (MYD88), inflammatory agents and radical oxygen species were determined. As a result, we found that treatment with atorvastatin markedly inhibited the mRNA and protein expressions of TLR4, MYD88 and the downstream inflammatory agents and radical oxygen species. Administration of atorvastatin following CIH significantly ameliorated the myocardial injury, such as cardiac hypertrophy. In conclusion, Pre-CIH atorvastatin administration may attenuate TLR-4/MYD88 mediated inflammatory processes and oxidative stress in the injured rat myocardium, and this may be one mechanism by which atorvastatin ameliorated myocardial injury following CIH.
    Biochemical and Biophysical Research Communications 02/2014; 446(1). DOI:10.1016/j.bbrc.2014.02.091 · 2.28 Impact Factor
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    ABSTRACT: Accumulated evidence shows that hypoxia can induce endothelial apoptosis, however the mechanism is still unknown. We hypothesized whether intermittent or persistent hypoxia could induce endoplasmic reticular stress, leading to endothelial apoptosis. Twenty-four 8-week male Sprague Dawley (SD) rats were divided into three groups: normoxia (NC) group, intermittent hypoxia (IH) group and persistent hypoxia (PH) group. TUNEL staining was performed to detect aortic arch endotheliar apoptosis, and immunohistochemistry for BIP, CHOP and caspase12 to test protein expression; human umbilical vein endothelial cells (HUVECs) of the line ECV304 were cultured (with or without taurodeoxycholic acid (TUDCA) 10 mmol/L, 100 mmol/L) and divided into four groups: NC group (20.8% O2 for 4 hours), PH1 group (5% O2 for 4 hours), PH2 group (5% O2 for 12 hours) and IH group (20.8% O2 and 5% O2 alternatively for 8 hours). Annexin V-fluorescein-isothiocyanate/propidium iodide flow cytometry was used to assess apoptosis in each group. The expressions of GRP78, CHOP and caspase12 were detected by real-time quantitative reverse-transcription PCR. Result Intermittent and persistent hypoxia could increase the rate of endothelium apoptosis and the expressions of GRP78, CHOP and caspase12 compared with the control, induction by intermittent hypoxia was slightly higher than persistent hypoxia. In the HUVEC experiment, TUDCA significantly reduced apoptosis and the expressions of GRP78, CHOP and caspase12. Hypoxia, especially intermittent, can induce endothelial cell apoptosis possibly through endoplasmic reticulum stress pathway, which can be attenuated by taurodeoxycholic acid.
    Chinese medical journal 12/2013; 126(23):4517-23. · 1.02 Impact Factor
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    ABSTRACT: Obstructive sleep apnea (OSA) has been recognized as an independent risk factor for systemic hypertension. The study investigated the functional consequences of chronic intermittent hypoxia (CIH) on aortic constriction induced by angiotensin II (Ang II) and the possible signaling involving ERK1/2 and contractile proteins such as myosin light chain kinase (MLCK), myosin phosphatase targeting subunit (MYPT1) and myosin light chain (MLC). Male Wistar rats were randomly divided into CIH group and normoxia group and exposed to either CIH procedure or air-air cycles. Phosphorylation of ERK1/2, MYPT1 and MLC was assessed by Western blotting following constrictor studies in the presence or absence of PD98059 (10 µmol/L). CIH-exposure resulted in more body weight gain and elevated blood pressure, which could be attenuated by pretreatment with PD98059. Endothelium-removed aortic rings from CIH rats exhibited higher constrictor sensitivity to Ang II (Emax: (138.56±5.78)% versus (98.45±5.31)% of KCl; pD2: 7.98±0.14 versus 8.14±0.05, respectively). CIH procedure exerted complex effects on ERK expressions (total ERK1/2 decreased whereas the ratio of phosphorylated to total ERK1/2 increased). CIH aortas had higher MLCK mRNA and basal phosphorylation of MYPT1 and MLC. In parallel to greater increases in phosphorylation of ERK1/2, MYPT1 and MLC, Ang II-induced aortic constriction was significantly enhanced in CIH rats, which was largely reversed by PD98059. However vascular constriction of normoxia rats remained unchanged despite similar but smaller changing tendency of proteins phosphorylation. These data suggest that CIH exposure results in aortic hyperresponsiveness to Ang II, presumably owing to more activated ERK1/2 signaling pathway.
    Chinese medical journal 09/2013; 126(17):3251-8. · 1.02 Impact Factor
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    ABSTRACT: Obstructive sleep apnea is a frequent medical condition consisting of repetitive sleep-related episodes of upper air ways obstruction and can lead to hypertension. Ang II type 1 receptor (AT1R) played important roles in hypertension since it binds with Ang II, controlling salt-water and blood pressure homeostasis. This study explores rat aorta AT1R expression during intermittent hypoxia (IH) and the signaling pathways involved. A rat model and a cell model used a BioSpherix-OxyCycler A84 system and a ProOx C21 system respectively. The arterial blood pressure was recorded by a Nihon Kohden Polygraph System. Immunohistochemic was used to focus and analyze the expression of AT1R in rat aorta. Real-time PCR and Western blotting were used to explore the signaling pathways that participated in AT1R expression. In this study, we found that chronic intermittent hypoxia (CIH) induced AT1R transcription which increased the blood pressure in rat aorta compared to normoxia and to sustained hypoxia. The AT1R protein expression in the aorta was similar to the real-time PCR results. We explored the signaling mechanisms involved in the AT1R induction in both rat aorta and the aortic endothelial cells by real-time PCR and Western blotting. Compared to normoxia, CIH increased ERK1 mRNA transcription but not ERK2 or p38MAPK in the aorta; whereas sustained hypoxia (SH) upregulated ERK2 but not ERK1 or p38MAPK mRNA. In cells, IH induced AT1R expression with ERK1/2 phosphorylation but reduced p38MAPKs phosphorylation, whereas SH induced only ERK1/2 phosphorylation. The ERK1/2 inhibitor PD98059 attenuated the IHinduced AT1R increase but the p38MAPK inhibitor SB203580 did not. Our results indicate that CIH induced the elevation of rat blood pressure and aorta AT1R expression. Moreover, AT1R expression in IH and sustained hypoxia might be regulated by different signal transduction pathways, highlighting a novel regulatory function through ERK1/2 signaling in IH.
    Chinese medical journal 09/2013; 126(17):3264-9. · 1.02 Impact Factor
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    ABSTRACT: The effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin on the enhanced hypoxia induced factor-1α (HIF-1α) and endothelin-1 (ET-1) expression, elevated systolic blood pressure under chronic intermittent hypoxia (CIH) condition and its action mechanism were investigated. Thirty healthy 8-week old Sprague-Dawley (SD) male rats were randomly divided into three groups (n=10 each): sham group, CIH group, and apocynin-treated CIH group. Tail artery systolic blood pressure was measured by tail-cuff method. Real-time fluorescence quantitative polymerase chain reaction (PCR) was used to detect the mRNA expression of HIF-1α and ET-1 in the carotid body, and the HIF-1α protein expression was examined by using Western blotting. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by using colorimetric method. In addition, the plasma ET-1 and HIF-1α levels were measured by using enzyme-linked immunosorbent assay. It was found that CIH exposure was associated with increased MDA levels, and apocynin-treated CIH animals showed reduction in MDA levels. Apocynin treatment prevented CIH-induced hypertension as well as CIH-induced decrease in SOD. The increases of HIF-1α and ET-1 mRNA along with HIF-1α protein expression in the carotid body, and elevated circulating HIF-1α and ET-1 levels were observed in CIH-exposed animals. Treatment with apocynin significantly decreased the ET-1 mRNA, HIF-1α protein expression and circulating HIF-1α level in CIH-exposed animals, and there was no statistically significant difference in the HIF-1α mRNA expression between CIH group and apocynin-treated group. These results indicated that apocynin alleviated CIH-induced hypertension by inhibiting NADPH oxidase, further leading to the reduced vasoconstrictor ET-1 level and oxidative stress. HIF-1α/ET-1 system signal pathway may interact with CIH-induced NADPH oxidase-dependent oxidative stress. Inhibition of NADPH oxidase activity may hopefully serve as a useful strategy for prevention and treatment of obstructive sleep apnea hypopnea syndrome-induced hypertension.
    Journal of Huazhong University of Science and Technology 04/2013; 33(2):178-184. DOI:10.1007/s11596-013-1093-z · 0.78 Impact Factor
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    ABSTRACT: To observe the change of the cognitive function and the serum level of advanced oxidation protein products (AOPP) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS), and then to investigate the correlation between them. Sixty seven patients with OSAHS, 20 healthy controls with matched age, BMI, and education, 15 patients with OSAHS after effective treatment of continuous positive airway pressure (CPAP) with matched age, BMI, and education were enrolled. Polysomnography (PSG), Epworth sleepiness scale (ESS), mini-mental state examination (MMSE), and clock drawing test (CDT) were performed in these groups. The serum level of AOPP, superoxide dismutase (SOD), and malondialdehyde (MDA) were measured. The MMSE and CDT scores of patients with OSAHS were decreased compared to those in healthy controls [(4.73 ± 0.81) vs (2.69 ± 1.38), (2.85 ± 0.61) vs (1.92 ± 0.62)], but the scores improved after effective CPAP treatment. The serum levels of AOPP [(78 ± 20) vs (117 ± 20) µmol/L] and MDA [(2.9 ± 1.0) vs (6.1 ± 3.0) µmol/L] in patients with OSAHS were increased compared to those in healthy controls, but the levels decreased after effective CPAP treatment. The serum SOD level in patients with OSAHS was decreased compared to that in healthy controls [(89 ± 8) vs (57 ± 9) U/ml], but it was increased after effective CPAP treatment. The MMSE and CDT scores of all the subjects including the 2 groups (the OSAHS group and the effective CPAP-treatment group) were correlated with the results of PSG (baseline SaO2, lowest SaO2, AHI, LA/HT, SLT90%). The serum levels of AOPP, MDA and SOD of all the subjects were also correlated with the results of PSG (lowest SaO2, AHI, LA/HT, SLT90%). The serum levels of AOPP, MDA and SOD of all the subjects were correlated with the MMSE and CDT scores. The serum level of AOPP of all the subjects was also correlated with the serum levels of MDA and SOD. Cognitive impairment in patients with OSAHS is correlated with the severity of the disease. AOPP is a useful marker for oxidative stress and protein injury, and closely correlated with the cognitive impairment in patients with OSAHS.
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 04/2013; 36(4):274-9.
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    ABSTRACT: Rationale: Erectile dysfunction (ED) is a frequent occurrence in male patients with obstructive sleep apnea syndrome (OSAS). Long-term intermittent hypoxia (LTIH), one of the hallmarks of OSAS, could mediate ED. Objectives: To test the hypothesis that increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity contributes to ED in rats responses to the LTIH. Methods: Healthy male Sprague-Dawley (SD) rats were randomly distributed into four groups: a LTIH group, an apocynin (a selective NADPH oxidase inhibitor)-treated LTIH group, a sham LTIH group, an apocynin-treated sham group. Erectile function was examined by measuring the mean arterial blood pressure (MAP) and intracavernosal pressure (ICP) upon electrical stimulation of the cavernous nerve. Real-time quantitavite-PCR and Western blot were used to examine mRNA and protein expression of NADPH oxidase subunit in corpus cavernosa (CC). The level of malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by colorimetric method. Nitric oxide synthase (NOS) isoforms in corpus cavernosa were also investigated. Results: LTIH markedly attenuated the erectile responses (ICP/MAP) and these were partially prevented by apocynin treatment. Promoted oxidative stress associated NADPH oxidase subunit activation was found in CC form LTIH rats. Decreased expression and activity of constitutive NOS (cNOS), including endothelial NOS (eNOS) and neuronal NOS (nNOS), associated with enhanced inducible NOS (iNOS) expression and activity were observed in LTIH rats. Apocynin prevented the decrease in cNOS activity and inhibited iNOS expression and activity in LTIH rats. Conclusions: These results indicate that NADPH oxidase activation plays an important role in the pathogenesis of LTIH-mediated ED.
    Journal of Andrology 05/2012; 33(6). DOI:10.2164/jandrol.112.016642 · 1.69 Impact Factor

Publication Stats

13 Citations
17.66 Total Impact Points


  • 2014–2015
    • Tongji Hospital
      Wu-han-shih, Hubei, China
  • 2012–2014
    • Huazhong University of Science and Technology
      • Department of Respiratory Medicine
      Wu-han-shih, Hubei, China