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chronic intermittent hypoxia aggravates cardiomyocyte apoptosis in rat ovariectomized model

Chinese Medical Journal 2012年第17期125卷 3087-3092页

作者： GAO Ying-hui CHEN Lin MA Yan-liang HE Quan-ying Department of Pneumology Peking University People's HospitalBeijing 100044China

Background The prevalence of obstructive sleep apnea （OSA） increases after menopause in women, but remains under diagnosed because of social or lifestyle factors. It is important to evaluate the hazards of OSA on cardiovascular disease in menopausal women. We tested the hypothesis that chronic intermittent hypoxia （CIH） may aggravate cardiomyocyte apoptosis in ovariectomized （OVX） Sprague Dawley （SD） rats; the changes of anti-oxidation ability in cardiac muscles may be one of the reasons for cardiomyocyte apoptosis. Methods Forty-eight 60-day old female SD rats were randomly divided into a CIH group, OVX group, OVX±CIH （OC） group, and handled control （HC） group, and the rats were exposed either to CIH （nadir 02 6%） or handled normoxic controls. The changes of body weight and whole heart weight were measured. Super oxide dismutase （SOD） and malonaldehyde （MDA） were used to evaluate the level of oxidative stress. TdT-mediated dUTP nick end labeling （TUNEL） was used to measure apoptosis in each rat. Western blotting was used to measure apoptosis associated proteins in cardiac muscle samples from each rat. Results When compared with the HC and CIH groups, the levels of oxidative stress in the OC and OVX groups were significantly higher. The levels of SOD in the HC, CIH, OC, and OVX groups were （47.99±4.89）, （53.60±4.47）, （20.99±2.72）, and （30.64±3.79） mmol/mg protein; significantly increased in the CIH group （P 〈0.05） and significantly decreased in the OC （P 〈0.01） and OVX （P 〈0.05） groups. The levels of MDA in the HC, CIH, OVX, and OC groups were （1.63±0.20）, （1.93±0.77）, （3.30±0.39）, and （1.95_±0.20） mmol/mg protein; it significantly increased in the CIH （P 〈0.05）, OC （P 〈0.01）, and OVX （P 〈0.05） groups compared with the HC group. Bax protein expression was significantly increased and bcl-2 protein expression was significantly reduced after CIH compared with HC rats （P 〈0.05）. The protein expression of bax and bcl-2 in the OC group was not significantly different from

关键词： sleep apnea obstructive chronic intermittent hypoxia apoptosis myocardium ovariectomy

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Ginsenoside Rb1 alleviates chronic intermittent hypoxia-induced diabetic cardiomyopathy in db/db mice by regulating the adenosine monophosphate-activated protein kinase/Nrf2/heme oxygenase-1 signaling pathway

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Journal of Traditional Chinese Medicine 2023年第5期43卷 906-914页

作者： LIU Bingbing LI Jieru SI Jianchao CHEN Qi YANG Shengchang JI Ensheng Department of Physiology Hebei University of Chinese MedicineShijiazhuang 050200China Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine Shijiazhuang 050200China

OBJECTIVE:To examine the protective effect of ginsenoside Rb1(Rb1),the main component of Renshen(Radix Ginseng),on cardiomyopathy in db/db mice exposed to chronic intermittent hypoxia(CIH)and explore the potential underlying mechanism of Rb1 in treating diabetic cardiomyopathy(DCM).METHODS:The db/db mice were randomly separated into five groups:normal control group,model group,Rb120 mg/kg group,Rb140 mg/kg group,and glucagon-like peptide-1(GLP-1)*** were exposed to aircondition or CIH for 8 weeks,and Rb1 and GLP-1 were administrated before CIH exposure every *** glucose tolerance test(OGTT),intraperitoneal insulin tolerance test(IPITT),total cholesterol(TC),triglyceride(TG),and high-density lipoprotein cholesterol(HDL-C)were detected to evaluate glycolipid *** level of insulin was detected by a mouse enzyme-linked immunosorbent assay(ELISA).Cardiac function was detected by echocardiography,and myocardial pathology was observed by hematoxylin-eosin and Masson *** expression of collagenⅠand collagenⅢwas detected by *** monophosphate-activated protein kinase(AMPK)/Nrf2/heme oxygenase-1(HO-1)signaling pathway was detected by Western blot and ***:Rb1 treatment could improve glucose tolerance and the level of cardiac function indexes,and inhibit the level of oxidative stress indexes and the expression of collagenⅠand collagenⅢ.Moreover,Rb1 treatment enhanced AMPK phosphorylation and increased Nrf2 and HO-1 ***:Rb1 treatment alleviated CIH-induced diabetic cardiomyopathy and glycolipid metabolism disorders in db/db mice by inhibiting oxidative stress and regulating the AMPK/Nrf2/HO-1 signaling pathway.

关键词： ginsenosides diabetic cardiomyopathies oxidative stress AMP-activated protein kinases heme oxygenase-1 signal transduction chronic intermittent hypoxia

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Shengmaisan combined with Liuwei Dihuang Decoction alleviates chronic intermittent hypoxia-induced cognitive impairment by activating the EPO/EPOR/JAK2 signaling pathway

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Chinese Journal of Natural Medicines 2024年第5期22卷 426-440页

作者： SI Jianchao CHEN Xue QI Kerong LI Dongli LIU Bingbing ZHENG Yuying JI Ensheng YANG Shengchang Department of Physiology Hebei University of Chinese MedicineShijiazhuang 050000China Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine Shijiazhuang 050000China Department of Geriatrics First People’s Hospital of XiaoganXiaogan 432000China

chronic intermittent hypoxia(CIH),a principal pathophysiological aspect of obstructive sleep apnea(OSA),is associated with cognitive *** evidence suggests that a combination of Shengmaisan and Liuwei Dihuang Decoctions(SMS-LD)can enhance cognitive function by nourishing yin and strengthening the *** study aimed to assess the efficacy and underlying mechanisms of SMS-LD in addressing cognitive impairments induced by *** exposed C57BL/6N mice to CIH for five weeks(20%-5%O_(2),5 min/cycle,8 h/day)and administered SMS-LD intragastrically(15.0 or 30 g·kg^(-1)·day)30 min before each CIH ***,AG490,a JJanus kinase 2(JAK2)inhibitor,was administered via intracerebroventricular *** function was evaluated using the Morris water maze,while synaptic and mitochondrial structures were examined by transmission electron *** stress levels were determined using DHE staining,and the activation of the erythropoietin(ER)/ER receptor(EPOR)/JAK2 signaling pathway was analyzed through immunohistochemistry and Western *** further investigate molecular mechanisms,HT22 cells were treated in vitro with either SMS-LD medicated serum alone or in combination with AG490 and then exposed to CIH for 48 *** results indicate that SMS-LD significantly mitigated CIH-induced cognitive impairments in ***,SMS-LD treatment enhanced dendritic spine density,ameliorated mitochondrial dysfunction,reduced oxidative stress,and activated the EPO/EPOR/JAK2 signaling ***,AG490 negated SMS-LD’s neuroprotective and cognitive improvement effects under CIH *** findings suggest that SMS-LD’s beneficial impact on cognitive impairment and synaptic and mitochondrial integrity under CIH conditions may predominantly be attributed to the activation of the EPO/EPOR/JAK2 signaling pathway.

关键词： chronic intermittent hypoxia Cognitive impairment Shengmaisan Liuwei Dihuang Decoction Oxidative stress EPO/EPOR/JAK2 signaling pathway

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chronic intermittent hypoxia and Hypertension:A Review of Systemic Inflammation and Chinese Medicine

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Chinese Journal of Integrative Medicine 2013年第5期19卷 394-400页

作者：邬春晓刘玥张京春 Department of Cardiovascular Disease Xiyuan HospitalChina Academy of Chinese Medical Sciences

Obstructive sleep apnea syndrome （OSAS） and hypertension commonly coexist. Clinical studies indicate that OSAS plays a key role in increasing the risk of prevalent hypertension. chronic intermittent hypoxia （CIH） is the core pathological mechanism of OSAS, and has a close relationship with systemic inflammation. Growing evidence shows that CIH and hypertension are strongly related, involving markers or pathways indicative of systemic inflammation, such as high-sensitivity C-reactive protein （hs-CRP）, interteukin-6, nuclear factor-kappa B, tumor necrosis factor-α, interleukin-8 and p38 mitogen-activated protein kinase （MAPK）dependent pathways. Oxidative stress also plays an important role in this process, including in the activation of polymorphonuclear neutrophils. However, the pathophysiological and clinical significance of systemic inflammation in CIH and hypertension is not proven. This review article highlights the relationship between CIH and hypertension through systemic inflammation and the current interventions available in Chinese medicine, to offer a background for the future treatment of OSAS-related hypertension with integrative medicine.

关键词： chronic intermittent hypoxia obstructive sleep apnea syndrome hypertension systemic inflammation Chinese medicine

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Atorvastatin Attenuates Myocardial Hypertrophy Induced by chronic intermittent hypoxia In Vitro Partly through miR-31/PKCε Pathway

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Current Medical Science 2018年第3期38卷 405-412页

作者： Jie REN Wei LIU Guang-cai LI Meng JIN Zhen-xi YOU Hui-guo LIU Yi HU Department of Respiratory and Critical Care Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China Department of Respiratory and Critical Care Medicine The Central Hospital of Wuhan Tongji Medical College Huazhong University of Science and Technology Wuhan 430010 China

Atorvastatin is proven to ameliorate cardiac hypertrophy induced by chronic intermittent hypoxia （CIH）. However, little is known about the mechanism by which atorvastatin modulates CIH-induced cardiac hypertrophy, and whether specific hypertrophyrelated microRNAs are involved in the modulation. MiR-31 plays key roles in the development of cardiac hypertrophy induced by ischemia/hypoxia. This study examined whether miR-31 was involved in the protective role of atorvastatin against CIH-induced myocardial hypertrophy. H9c2 cells were subjected to 8-h intermittent hypoxia per day in the presence or absence of atorvastatin for 5 days. The size of cardiomyocytes, and the expression of caspase 3 and miR-31 were determined by Western blotting and RT-PCR, respectively. MiR-31 mimic or Ro 31-8220, a specific inhibitor of protein kinase C epsilon （PKCε）, was used to determine the role of miR-31 in the anti-hypertrophic effect of atorvastatin on cardiomyocytes. PKCε in the cardiomyocytes with miR-31 upregulation or downregulation was detected using RT-PCR and Western blotting. The results showed that CIH induced obvious enlargement of cardiomyocytes, which was paralleled with increased atrial natriuretic peptide （ANP）, brain natriuretic peptide （BNP）, and slow/beta cardiac myosin heavy-chain （MYHT） mRNA levels. All these changes were reversed by the treatment with atorvastatin. Meanwhile, miR-31 was increased by CIH in vitro. Of note, the atorvastatin pretreatment significantly increased the mRNA and protein expression of PKCε and decreased that of miR-31. Moreover, overexpression of miR-31 abolished the anti-hypertrophic effect of atorvastatin on cardiomyocytes. Upregulation and downregulation of miR-31 respectively decreased and increased the mRNA and protein expression of PKCε. These results suggest that atorvastatin provides the cardioprotective effects against CIH probably via up-regulating PKCε and down-regulating miR-31.

关键词： atorvastatin chronic intermittent hypoxia myocardial remodeling miR-31 protein kinase C epsilon

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chronic intermittent hypoxia increases ROS/HIF-1a related oxidative stress and worsen bleomycin-induced pulmonary fibrosis in adult male C57BL/6J mice

Chronic intermittent hypoxia increases ROS/HIF-1a related ox...

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中国睡眠研究会第十四届全国学术年会

作者： Mengqing Xiong ke hu Renmin Hospital Of Wuhan University

Obstructive sleep apnea(OSA) has been increasingly recognized as a risk factor for idiopathic pulmonary fibrosis(IPF), however, the potential mechanism of hypoxia-related oxidative stress underlying this phenomenon remains ***, C57BL/6J mice were administered intratracheal injection injected of Bleomycin(BLM) or saline and then exposed to IH to mimic OSA or intermittent air(IA).This study found that pulmonary fibrosis in the four experimental mice was not observed at day 4, while pulmonary fibrosis in BLM+IH mice was more severe than that in BLM+IA group at day 8 and 21. Besides, ROS and HIF-1a in BLM+IA mice were higher than normal saline + IA group, and IH increased these above indexes in BLM-treated mice from day 4 to day 21. A positive linear correlation between the HIF-1a related oxidative stress and HYP was observed. Some inflammatory cells in bronchoalveolar lavage fluid also were increased significantly from day 4 to 21. There was a positive correlation between lung inflammation and ROS *** results demonstrated that CIH aggravated BLM-induced pulmonary fibrosis, and ROS/HIF-1a related oxidative stress was involved.

关键词： Idiopathic pulmonary fibrosis chronic intermittent hypoxia Oxidative stress ROS HIF-1α

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chronic intermittent hypoxia versus continuous hypoxia:same effects on hemorheology?

Chronic intermittent hypoxia versus continuous hypoxia:same ...

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2015年全国睡眠呼吸学术年会

作者： Jing Kang Yuanyuan Li Ke Hu Wen Lu Xiufang Zhou Shuhui Yu Lifang Xu

Although both chronic intermittent hypoxia（CIH）and chronic continuous hypoxia（CCH）have effects on hemorheology,we do not know whether their roles are the *** this study,we explored the effect of simulated-apneaCIH on hemorheology in experimental rats and compared with the effect of CCH.45adult SD rats were randomly divided into the normoxic control group,CCHand *** rats were given nitrogen and air alternately for 8 hours per day and the experiment lasted for 5 *** control group were placed in the normoxia animal chambers,and the CCH rats were housed in the same chambers which were continuously given normobaric hypoxia（FiO2=10%）.After the preparations,the blood samples were taken andthe hemorheology were *** with control group,the whole blood apparent viscosity,plasma viscosity,hematocrit,erythrocyte aggregation index and electrophoresisindex,platelet aggregation rate and fibrinogensignificantly increased in CIH group and *** whole blood viscosity,plasma viscosity,hematocrit and fibrinogen values were much higher in CCH group than in CIH ***,there was not significantly difference in RBC deformation index or rigidity index among the three groups and no significantly differenceswere found in the effects on RBC rheological property between CIH and *** results suggest that intermittent hypoxia and continuous hypoxia increasewhole blood viscosity,impair the functions of red blood cells and promote the platelet aggregation in model ***,CCH had a greatereffect on blood rheology than CIH.

关键词： chronic intermittent hypoxia continuous hypoxia hemorheology rat.

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Sheng-Mai-San attenuates contractile dysfunction and structural damage induced by chronic intermittent hypoxia in mice

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Chinese Journal of Natural Medicines 2015年第10期13卷 743-750页

作者： MO Wei-Lan CHAI Cheng-Zhi KOU Jun-Ping YAN Yong-Qing YU Bo-Yang Department of Complex Prescription of TCM China Pharmaceutical University Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research China Pharmaceutical University

Sheng-Mai-San(SMS), a well-known Chinese medicinal plant formula, is widely used for the treatment of cardiac diseases characterized by deficiency of Qi and Yin syndrome. A mouse chronic intermittent hypoxia(CIH) model was established to mimic the primary clinical features of deficiency of Qi and Yin syndrome. Mice experienced CIH for 28 days(nadir 7% to peak 8% oxygen, 20 min per day), resulting in left ventricle(LV) dysfunction and structure abnormalities. After administration of SMS(0.55, 1.1, and 5.5 g·kg-1·d-1) for four weeks, improved cardiac function was observed, as indicated by the increase in the ejection fraction from the LV on echocardiography. SMS also preserved the structural integrity of the LV against eccentric hypotrophy, tissue vacuolization, and mitochondrial injury as measured by histology, electron microscopy, and ultrasound assessments. Mechanistically, the antioxidant effects of SMS were demonstrated; SMS was able to suppress mitochondrial apoptosis as indicated by the reduction of several pro-apoptotic factors(Bax, cytochrome c, and cleaved caspase-3) and up-regulation of the anti-apoptosis factor Bcl-2. In conclusion, these results demonstrate that SMS treatment can protect the structure and function of the LV and that the protective effects of this formula are associated with the regulation of the mitochondrial apoptosis pathway.

关键词： Sheng-Mai-San chronic intermittent hypoxia Contractile dysfunction Left ventricle Mitochondrial apoptosis

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Effect of chronic intermittent hypoxia on the expression of Nip3, cell apoptosis, β-amyloid protein deposit in mice brain cortex

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Chinese Medical Journal 2009年第1期122卷 68-73页

作者： ZENG Yi-ming CAI Kai-jin CHEN Xiao-yong WU Min-xia LIN Xi Department of Pulmonary Medicine the Second Affiliated Hospital of Fujian Medical University Quanzhou Fujian 362000 China Institute of Sleep and Breath Disorders Research Fujian Medical University Quanzhou Fujian 362000 China Department of Electronic Microscope Fujian Medical University Fuzhou Fujian 350000 China

Background chronic intermittent hypoxia （CIH） is the most important pathophysiologic feature of sleep apnea syndrome （SAS）. To explore the relationship between SAS and dementia, the effects of CIH on the expression of Nip3, neuron apoptosis and β-amyloid protein deposit in the brain cortex of the frontal lobe of mice were evaluated in this study.Methods Thirty male ICRmice＇were divided into four groups： control group （A, n=-10, sham hypoxia/reoxygenation）, 2 weeks CIH group （B, n=5）, 4 weeks CIH group （C, n=-5）, and 8 weeks CIH group （D, n=10）. The ICR mice were placed in a chamber and exposed to intermittent hypoxia （oxygen concentration changed periodically from （21.72±0.55）% to （6.84±0.47）% every two minutes, eight hours per day）. Neuron apoptosis of the cortex of the frontal lobe was detected by means of terminal deoxy-nucleotidyl transferase-mediated in situ end labeling （TUNEL）. Immunohistochemical staining was performed for measuring expression of Nip3 and β-amyloid protein. The ultrastructure of neurons was observed under a transmission electron microscope.Results TUNEL positive neurons in each square millimeter in the cortex of the frontal lobe were categorized by median or Riinto group A （1, 5.5）, group B （133, 13）, group C （252, 21）, and group D （318, 24）. There were significant differences among the above four groups （P=0.000）. The significance test was performed between the control group and each CIH group respectively： group A and B （P 〉0.05）; group A and C （P 〈0.01）; and group A and D （P 〈0.005）. The number of apoptotic neurons kept increasing in the ICR mice under CIH condition, and reached the peak in the group D, but there was no significant difference between groups B and C, between groups B and D, and between groups C and D. Nip3 positive neurons in each square millimeter in the cortex of the frontal lobe in each group were calculated by median or Ri as follows： group A （2, 5.5）, group B （117, 13）, group C （227, 26.2）, and group D（479, 21.4）.

关键词： chronic intermittent hypoxia sleep apnea brain Nip3 apoptosis β-amyloidprotein

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Influence of chronic intermittent hypoxia on growth associated protein 43 expression in the hippocampus of young rats

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Neural Regeneration Research 2012年第16期7卷 1241-1246页

作者： Yan Chen Chunling Zhao Chunlai Zhang Lirong Luo Guang Yu Department of Physiology Luzhou Medical CollegeLuzhou 646000Sichuan ProvinceChina Functional Experiment Center of Luzhou Medical College Luzhou 646000Sichuan ProvinceChina

This study aimed to explore the pathological change to hippocampal neurons and the expression of growth associated protein 43 in 21-day-old young rats following chronic intermittent hypoxia. Hematoxylin-eosin staining results showed varying degrees of degeneration and necrosis in hippocampal neurons depending on the modeling time. Immunohistochemistry revealed that growth associated protein 43 expression in young rats following chronic intermittent hypoxia decreased, but that levels were still higher than those of normal rats at each time point, especially 4 weeks after modeling. During 1 5 weeks after modeling, a slow growth in rat weight was observed. Experimental findings indicate that chronic intermittent hypoxia may induce growth dysfunction and necrosis of hippocampal neurons, as well as increase the expression of growth associated protein 43 in young rats.

关键词： chronic intermittent hypoxia brain injury growth associated protein 43 obstructive sleep apneahypopnea syndrome hippocampus young rats neural regeneration

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