Chronic Hypobaric Hypoxia Research Articles

Astaxanthin Supplementation Effects in Right Ventricle of Rats Exposed to Chronic Intermittent Hypobaric Hypoxia.

Thirty two male Wistar rats were randomly assigned to the following groups (n = 8 per group): the normoxia with vehicle (NX), normoxia with astaxanthin (NX + AS), chronic intermittent hypobaric hypoxia with vehicle (CIHH), and chronic intermittent hypobaric hypoxia with astaxanthin (CIHH + AS) groups. CIHH was simulated by 2 days in a hypobaric chamber followed by 2 days at sea level for 29 days. Exposure to CIHH induced RVH and increased lipid peroxidation (MDA), Nox2 expression, and SOD activity, however, it decreased pro-IL-1β expression. Astaxanthin restored oxidative stress markers (Nox2 and MDA), increased GPx activity, and decreased RVH compared to CIHH. Astaxanthin alleviates RVH and reduces Nox2 and MDA levels while increasing GPx activity in rats subjected to CIHH. These findings provide new insights of astaxanthin as a new nutraceutical against high-altitude effects.

Oral antioxidant edaravone protects against cognitive deficits induced by chronic hypobaric hypoxia at high altitudes

Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.

A prospective study on the cardiorespiratory effects of air pollution among residents of the Tibetan Plateau

The Tibetan Plateau is characterized by high ozone concentration which poses a significant public health concern. However, the causal evidence linking ozone pollution to adverse cardiopulmonary health impacts, as well as the understanding of its underlying biological mechanisms, remains limited. Additionally, exposure levels to particulate and other gaseous air pollutants along with their associated health effects in this region are largely unknown. To address these gaps, we conducted a prospective follow-up study in Tibet from May 2021 to November 2021. In consideration of the potential synergistic effects of chronic hypobaric hypoxia, two Tibetan cities with different altitudes, Lhasa (3650 m) and Nyingchi (3000 m), were chosen to implement atmospheric monitoring and health measurement. We employed cutting-edge, high-precision instruments at stationary monitoring sites to measure ambient air pollution and collected particle samples. Portable devices were used to monitor personal exposure levels of ozone and black carbon. A total of 212 healthy Tibetan college students participated in up to four clinical visits, yielding 774 visits in total, during which functional endpoints were measured and biological samples were collected. The primary aim of this study is to evaluate the cardiorespiratory effects of ambient ozone under hypoxic conditions, where its impact may be amplified due to the region's unique environmental characteristics. The secondary aim is to provide a comprehensive assessment of other air pollutants, including their exposure levels, sources, and health effects. By addressing these aims, the study offers valuable insights into air quality and its health implications in this unique high-altitude setting. This paper outlines the research motivation, measurement framework, and preliminary findings.

The burden of suicide across different altitudes: 11-year geodemographic analysis conducted in 221 cantons in Ecuador ranging from 0 to 4300 m of elevation.

The World Health Organization and the Global Burden of Disease study estimate that almost 800 000 people die from suicide yearly. The role of non-traditional risk factors such as climate and high-altitude exposure are poorly understood. This study aims to determine a potential relationship between altitude exposure and suicide rates among 221 cantons located at different altitudes ranging from 0 to 4300 m. We conducted an 11-year, country-wide, population-based analysis on age- and gender-standardised suicide rates in Ecuador, based on the official data from the National Institute of Statistics, using all available self-harm death codes (ICD-10 codes X60-X84). A total of 11 280 cases of suicide were reported during 2011-2021. Suicide rates were higher among men (11.48/100 000). In terms of elevation, suicide rates were significantly higher among people from high-altitude cantons (3.7/100 000) versus those from low-altitude cantons. When applying the International Society Mountain Medicine categorisation, suicide rates were significantly higher at moderate- (4.3/100 000), high- (3.6/100 000) and very-high-altitude cantons (4.4/100 000) when compared with low-altitude locations (2.5/100 000). Ecuador is one of the few countries that has a vast range of cantons located at different altitudes. We found that living at higher elevations is positively associated with greater suicide rates. Although the rates are significantly greater as elevation increases, a clear linear relationship is not apparent, likely because of the interplay of socioeconomic factors, including urbanicity. The effect of chronic hypobaric hypoxia on mood cannot be ruled out, although the existence of causal mechanisms remains to be elucidated.

Redefining chronic mountain sickness: insights from high-altitude research and clinical experience

Abstract Chronic Mountain Sickness (CMS), characterized by increased red blood cells above average values traditionally attributed to chronic hypobaric hypoxia exposure, is being redefined in light of recent research and clinical experience. We propose a shift in perspective, viewing CMS not as a singular entity but as Poly-erythrocythemia (PEH), as the Hematocrit/Hemoglobin/Red Blood Cells (Ht/Hb/RBCs) increase constitutes a sign, not a disease reflecting a spectrum of oxygen transport alterations in multiple diseases in the chronic hypoxia environment in high-altitude populations. Drawing on over five decades of experience at the High Altitude Pulmonary and Pathology Institute (HAPPI-IPPA) in Bolivia, we advocate for altitude-specific blood parameter norms and emphasize the importance of correct etiological diagnosis for effective management. This updated understanding not only aids in managing chronically hypoxemic patients at various altitudes but also offers valuable insights into global health challenges, including the recovery from COVID-19.

Interleukins expression by lymphocytes of rats exposed to chronic intermittent normobaric hypoxia

Hypoxia acute and chronic modulates the expression of inflammatory mediators such as cytokines. However, studies in chronic and intermittent hypobaric or normobaric hypoxia similar to described in miner’s population are scares o absent. In regards with this we propose evaluated the effect of chronic intermittent normobaric hypoxia (CINH) on the hematological, cardiovascular response and expression of lymphocyte’s cytokines such as IL-1b, IL-2, IL6 and IL-10 in rats. A total of 20 Sprague-Dawley rats were divided in two groups: a) CINH of FiO2 10% (n=10) and normoxic rats (n=10) were used as controls. Blood samples were obtained from both groups for hematological studies, systolic arterial pressure and heart rate was measured in tail-cuff sensor, and expression of cytokines obtained from lymphocytes was determined by RT-PCR. Hematocrit, hemoglobin, platelet count and hematological constant are elevated however leucocyte count decrease. A significant increase of systolic arterial pressure (over 50%). In vitro expression of cytokines from lymphocytes shown that IL-10, IL-2 and IL6 increase 35%, 64% and 16% respectively, while that of IL-1bdecreases by 18%. CINH could be activate an inflammatory response mediated by IL-2, however this response could be attenuated due to the increase in the expression of IL-10, a known anti-inflammatory cytokine, and the decrease in the expression of IL-1β and IL6 suggesting a mechanism of adaptation to CINH. Innova-Corfo Project 07CN13ISM-152. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Transcutaneous evaluation of hemoconcentration response to hypoxia simulated and hypobaric hypoxia of 5050 m

Objective: To evaluate the effect of normobaric and hypobaric hypoxia of 5050 m on hemoconcentration response in population without experience to hypoxia and acclimatized population to chronic intermittent hypobaric hypoxia (CIHH). Materials and Methods: 16 subjects without experience to altitudes over 1500 m (9 women/7 men) and 39 subjects acclimatized workers to CIHH at high altitude (5050 m, 9 women/32 men) were recruited. Normobaric hypoxia were performed in 3 steps: 5 min breathing ambient air, 20 min breathing hypoxic air (11,5% O2, equivalent to 5050 m) and 5 min of recovery breathing ambient air. CIHH condition represents a normal exposure characterized by 8 days working at high altitude and 6 days resting at low altitude (<1500 m). Subjects were evaluated at sea level and 5-6th day of exposure to CIHH at 5050 m. In each condition, Hemoglobin concentration (Hb), Carboxyhemoglobin (COHb), Methemoglobin (MetHb), Pulse oximetry (SPO2), heart rate (HR) were measured using a transcutaneous sensor (Rad 67 pulse Co-Oximeter, Masimo). Results: In evaluations performed at sea level, both groups of hypoxia (normobaric and CIHH) exhibited a lower hemoglobin concentration in women in comparison with men. During exposure to simulated hypoxia, a significative increase in hemoglobin concentration was showed, associated to decrease in SpO2 and increase in HR. However, an increased level of MetHb in women and men and only increased level of COHb in women were observed. During hypobaric exposure, Hb concentration increased, with reduced SpO2, and increased HR in comparison to sea level. Lower HR was observed in men respect of women. Lower level of COHb was observed in men respect of women. In addition, in women was observed an increase of level COHb related with time of exposure, in contrast, a tendency to reduction in level of COHb and MetHb in men was observed. Conclusion: The use of transcutaneous sensor to measure SpO2 and Hb showed an increase in hemoglobin concentration in normobaric and hypobaric hypoxia, in agreement with previous results from our laboratory. In addition, we reported new information about level of COHb and MetHb in two different model of exposure simulated hypoxia and hypobaric hypoxia at extreme altitude. SUSESO ACHS 279-2022. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Chronic Intermittent Hypobaric Hypoxia Reduces Hypothalamic N-Methyl-d-Aspartate Receptor Activity and Sympathetic Outflow in Spontaneously Hypertensive Rats.

Guo, Xinqi, Hongyu Ma, Ziye Cui, Qiyue Zhao, Ying Zhang, Lu Jia, Liping Zhang, Hui Guo, Xiangjian Zhang, Yi Zhang, Yue Guan, and Huijie Ma. Chronic intermittent hypobaric hypoxia reduces hypothalamic N-Methyl-d-Aspartate Receptor activity and sympathetic outflow in spontaneously hypertensive rats. High Alt Med Biol. 25:77-88, 2024. Objective: This study aims to determine the role of hypothalamic renin-angiotensin system (RAS) in the antihypertensive effect of chronic intermittent hypobaric hypoxia (CIHH). Methods: Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) received 35 days of hypobaric hypoxia simulating an altitude of 4,000 m, 5 h/day. The levels of RAS, blood pressure, and N-methyl-d-aspartate receptor (NMDAR) activities of hypothalamic paraventricular nucleus (PVN) presympathetic neurons from each group of rats were determined. Results: The systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure (MAP) of SHRs significantly decreased from the third week of CIHH treatment. This blood pressure reduction effect could be maintained for at least 2 weeks after stopping the CIHH treatment. CIHH treatment also attenuated the decrease in MAP and renal sympathetic nerve activity induced by hexamethonium administration in SHRs, but not in WKY rats. Furthermore, CIHH reversed the increase in serum angiotensin (Ang)II concentration and the expression of PVN angiotensin-converting enzyme (ACE) and AngII type 1 (AT1) receptors, as well as the decrease in serum Ang1-7 concentration and the expression of PVN ACE2 and Mas receptors in SHRs. In addition, the administration of CIHH resulted in a reduction in the frequency of miniature excitatory postsynaptic currents and amplitude of NMDAR current in PVN presympathetic neurons of SHRs, which means that CIHH decreased the pre- and postsynaptic NMDAR activity of PVN presympathetic neurons in SHRs. However, pretreatment with A779 (a Mas receptor blocker) or AngII abrogated the above effects. Meanwhile, Ang1-7 pretreatment mimicked the CIHH effect on pre- and postsynaptic NMDAR activity of presympathetic neurons in SHRs. Conclusions: Our data indicate that CIHH reduces pre- and postsynaptic NMDAR activity of PVN presympathetic neurons, sympathetic outflow, and blood pressure by decreasing the activity of the ACE/AngII/AT1 axis and increasing the activity of ACE2/Ang1-7/Mas axis in the hypothalamus in hypertension.

Emerging Evidence for Association of Transsulfuration Pathway with Hypoxia Responses

When people ascend to a high altitude (HA), the body’s oxygen (O2) sensing mechanisms can sense perturbation in partial pressure and trigger adaptive responses. Rapid ascending to HA without ample time for acclimatization culminates in high-altitude illnesses, which can derail the body functioning of lowlanders moving to HA. High-altitude native populations have undergone positive natural selection to efficiently overcome the challenges of chronic hypobaric hypoxia (HH) and thus offer a unique model to understand physiological and genetic adaptations at high altitudes. In addition, evolutionary shreds of evidence propose that sulfur belonging to the same periodic table family can mimic oxygen to bypass its metabolic oxygen demand and modulate energy production.Intriguingly, our group has identified a strong association between diminished hydrogen sulfide (H2S)levels and HH-induced pathological responses. We have recently presented experimental evidence of cysteine deficit, which functionally regulates both lowered levels of endogenous H2S and HH-induced neuropathological responses. In this review, we sought to understand the role of H2S and the transsulfuration pathway at HA.

Expedition 5300: limits of human adaptations in the highest city in the world.

Exposure to chronic hypobaric hypoxia imposes a significant physiological burden to more than 80 million humans living above 2500m throughout the world. Among them, 50000 live in the world's highest city, La Rinconada, located at 5000-5300m in southern Peru. Expedition 5300 is the first scientific and medical programme led in La Rinconada to investigate the physiological adaptations and altitude-related health issues in this unique population. Dwellers from La Rinconada have very high haemoglobin concentration (20.3±2.4g/dL; n=57) and those with chronic mountain sickness (CMS) exhibit even higher concentrations (23.1±1.7g/dL; n=150). These values are associated with large total haemoglobin mass and blood volume, without an associated iron deficit. These changes in intravascular volumes lead to a substantial increase in blood viscosity, which is even larger in CMS patients. Despite these large haematological changes, 24h blood pressure monitoring is essentially normal in La Rinconada, but some results suggest impaired vascular reactivity. Echocardiography revealed large right heart dilatation and high pulmonary arterial pressure as well as left ventricle concentric remodelling and grade I diastolic dysfunction. These changes in heart dimension and function tend to be more severe in highlanders with CMS. Polygraphy evaluations revealed a large reduction in nocturnal pulse oxygen saturation (median SpO2 =79%), which is even more severe in CMS patients who also tended to show a higher oxygen desaturation index. The population of La Rinconada offers a unique opportunity to investigate the human responses to chronic severe hypoxia, at an altitude that is probably close to the maximum altitude human beings can permanently tolerate without presenting major health issues.

Transcriptional Profiling in the Intestinal of Rats under Hypobaric Hypoxia

High-altitude ascent induces various physiological changes, with Gastrointestinal (GI) disorders being a prevalent occurrence. The gut plays a pivotal role in maintaining overall body homeostasis during normal physiological adaptation. The molecular and pathophysiological mechanisms underlying gastrointestinal injury resulting from exposure to a hypoxic environment remain largely unknown. To comprehensively explore the potential physiological changes associated with intestinal disorders after exposure to a hypobaric hypoxic environment, we employed genome-wide transcriptional profiling to examine gene expression alterations in the small intestine of rats. Our study involved RNA-Sequencing (RNA-Seq) of the intestinal tissues of rats exposed to simulated hypobaric hypoxia for 2 weeks (W2Z) and 4 weeks (W4Z), allowing us to investigate the transcriptional profile during both acute and chronic hypobaric hypoxic conditions in this animal model. We identified differentially expressed genes among the three groups. A principal component analysis revealed substantial distinctions between the acute and chronic hypobaric hypoxia groups when compared to the control group. Furthermore, pathway analysis indicated that the differentially expressed genes were associated with the interaction of neuroactive ligands and receptors. This suggests that the adaptation of rats to hypobaric hypoxia involves, at least partially, the regulation of the neuroactive ligand-receptor interaction pathway.

Histological and cytochemical analysis of the brain under conditions of hypobaric hypoxia-induced oxygen deficiency in albino rats

High altitude sickness is a life-threatening disease that occurs among acclimatized individuals working or living at a high altitude accompanied by hypobaric hypoxia exposure. The prolonged influence of hypobaric hypoxia on the brain may trigger neuronal damage and cell death due to an oxygen deficiency. The purpose of the current study was to investigate the histomorphological changes in the hippocampus, cerebral cortex, cerebellar cortex, and striatum of the rat’s brain following chronic hypobaric hypoxia. Fourteen albino rats were used for this investigation. The animals were exposed to chronic hypobaric hypoxia in the special decompression chamber at an altitude of 7000 m for 7 days. The histological analysis was conducted via toluidine staining and silver impregnation. DNA damage and cell apoptosis were assessed via Feulgen staining. The histochemical assessment revealed increased dark neurons in the hippocampus with cell swelling. Silver impregnation showed increased argyrophilic neurons in the cerebellar cortex, striatum, CA1 subfield of the hippocampus, and cerebral cortex. The cytochemical analysis determined the increased apoptotic cells with hyperchromatic condensation and pyknosis in the hippocampus subfields and cerebral cortex. In addition, it has been observed that hypoxia has resulted in small hemorrhages and perivascular edema within the cerebellar and cerebral cortex.The results indicate brain injury observed in the various parts of the brain towards hypobaric hypoxia, however, the hippocampus showed greater vulnerability against hypoxic exposure in comparison to the striatum, cerebellum, and cerebral cortex. These changes support our insights regarding brain intolerance under conditions of hypoxia-induced oxygen deficiency and its histomorphological manifestations.

Protective effects of epigallocatechin-3-gallate counteracting the chronic hypobaric hypoxia-induced myocardial injury in plain-grown rats at high altitude

Exposure to hypobaric hypoxia (HH) environment causes stress to the body, especially the oxygen-consuming organs. Chronic HH conditions have adverse effects on the myocardium. Thus, we conducted this experiment and aim to evaluate such adverse effects and explore the therapeutic role of epigallocatechin-3-gallate (EGCG) in rats’ heart under chronic HH conditions. For that purpose, we transported rats from plain to a real HH environment at high altitude for establishing the HH model. At high altitude, animals were treated with EGCG while the salidroside was used as the positive control. General physiological data were collected, and routine blood test results were analyzed. Cardiac magnetic resonance (CMR) was examined to assess the structural and functional changes of the heart. Serum levels of cardiac enzymes and pro-inflammatory cytokines were examined. Oxidative markers in the left ventricle (LV) were detected. Additionally, ultrastructural and histopathological changes and apoptosis of the LV were assessed. Furthermore, the antioxidant stress-relevant proteins nuclear factor E2-related factor 2 (Nrf2) and the heme oxygenase-1 (HO-1) were detected. The experiment revealed that EGCG treatment decreased HH-induced elevation of cardiac enzymes and relieved mitochondrial damage of the LV. Notably, EGCG treatment significantly alleviated oxidative stress in the LV and inflammatory response in the blood. Western blot confirmed that EGCG significantly upregulated Nrf2 and HO-1. Therefore, EGCG may be considered a promising natural compound for treating the HH-induced myocardial injuries.

The Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Preventing the Destruction of CD34+ Haematopoietic Stem Cells in Aplastic Anaemia by Modulating the Th1/Th2 Balance.

Aplastic anaemia (AA) is a haematopoietic disorder caused by immune-mediated attack on haematopoietic stem cells (HSCs). Stem cell transplantation and immunosuppressive therapy remain the major treatment choice for AA patients but have limited benefits and undesired side effects. The aim of our study was to clarify the protective role of immunity of chronic intermittent hypobaric hypoxia (CIHH) and the underlying mechanism in AA. Our integrative analysis demonstrated that CIHH pre-treatment significantly improved haematopoiesis and survival in an AA rat model. We further confirmed that CIHH pre-treatment was closely associated with the Th1/Th2 balance and a large number of negative regulatory haematopoietic factors, such as TNF-α and IFN-γ, produced by hyperactive Th1 lymphocytes released in AA rats, which induced the death program in a large number of CD34+ HSCs by activating the Fas/FasL apoptosis pathway, while CIHH pre-treatment effectively downregulated the expression of TNF-α and IFN-γ, resulting in a reduction in Fas antigen expression in CD34+ HSCs. In summary, this study provides evidence that CIHH has good protective effect against AA by modulating immune balance in Th1/Th2 cells and may provide a new therapeutic strategy.

The effect of chronic intermittent hypobaric hypoxia improving liver damage in metabolic syndrome rats through ferritinophagy.

Studies have confirmed that hepatic iron overload is one of the important factors causing liver damage in the metabolic syndrome (MS). As a special form of autophagy, ferritinophagy is involved in the regulation of iron metabolism. Our previous studies have shown that chronic intermittent hypobaric hypoxia (CIHH) can improve the iron metabolism disorder. The aim of this study was to investigate how CIHH improves liver damage through ferritinophagy in MS rats. Male Sprague-Dawley rats aged 8-10weeks were randomly divided into four groups: control (CON), CIHH (exposed to hypoxia at a simulated altitude of 5000m for 28days, 6h daily), MS model (induced by a 16-week high-fat diet and 10% fructose water feeding), and MS + CIHH (exposed to CIHH after a 16-week MS inducement) groups. Liver index, liver function, iron content, tissue morphology, oxidative stress, ferritinophagy, ferroptosis, and iron metabolism-related protein expression were measured, and the ferritinophagy flux in the liver was further analyzed. Compared with CON rats, MS rats had an increased liver index, damaged liver tissue and function, increased iron content and iron deposition, disrupted iron metabolism, significantly increased oxidative stress indicators in the liver, significantly upregulated expression of ferroptosis-related proteins, and downregulated expression of nuclear receptor coactivator 4 (NCOA4) and ferritinophagy flux. After CIHH treatment, the degree of liver damage and various abnormal indicators in MS rats were significantly improved. CIHH may improve liver damage by promoting NCOA4-mediated ferritinophagy, reducing iron overload and oxidative stress, and thereby alleviating ferroptosis in MS rats.

MFN2 deficiency promotes cardiac response to hypobaric hypoxia by reprogramming cardiomyocyte metabolism.

Under hypobaric hypoxia (HH), the heart triggers various defense mechanisms including metabolic remodeling against lack of oxygen. Mitofusin 2 (MFN2), located at the mitochondrial outer membrane, is closely involved in the regulation of mitochondrial fusion and cell metabolism. To date, however, the role of MFN2 in cardiac response to HH has not been explored. Loss- and gain-of-function approaches were used to investigate the role of MFN2 in cardiac response to HH. In vitro, the function of MFN2 in the contraction of primary neonatal rat cardiomyocytes under hypoxia was examined. Non-targeted metabolomics and mitochondrial respiration analyses, as well as functional experiments were performed to explore underlying molecular mechanisms. Our data demonstrated that, following 4 weeks of HH, cardiac-specific MFN2 knockout (MFN2 cKO) mice exhibited significantly better cardiac function than control mice. Moreover, restoring the expression of MFN2 clearly inhibited the cardiac response to HH in MFN2 cKO mice. Importantly, MFN2 knockout significantly improved cardiac metabolic reprogramming during HH, resulting in reduced capacity for fatty acid oxidation (FAO) and oxidative phosphorylation, and increased glycolysis and ATP production. In vitro data showed that down-regulation of MFN2 promoted cardiomyocyte contractility under hypoxia. Interestingly, increased FAO through palmitate treatment decreased contractility of cardiomyocyte with MFN2 knockdown under hypoxia. Furthermore, treatment with mdivi-1, an inhibitor of mitochondrial fission, disrupted HH-induced metabolic reprogramming and subsequently promoted cardiac dysfunction in MFN2-knockout hearts. Our findings provide the first evidence that down-regulation of MFN2 preserves cardiac function in chronic HH by promoting cardiac metabolic reprogramming.

Chronic intermittent hypobaric hypoxia improves iron metabolism disorders via the IL-6/JAK2/STAT3 and Epo/STAT5/ERFE signaling pathways in metabolic syndrome rats

AimOur previous study demonstrated that chronic intermittent hypobaric hypoxia (CIHH) improved iron metabolism disorder in obese rats through the downregulation of hepcidin. This study aimed to observe the molecular mechanism of CIHH in improving iron metabolism disorders, especially by Janus kinase/signal transducer and activation of the transcription (JAK/STAT) signaling pathway in metabolic syndrome (MS) rats. MethodsSix-week-old male Sprague-Dawley rats were randomly divided into four groups: CON, CIHH (subjected to hypobaric hypoxia simulating 5000-m altitude for 28 days, 6 h daily), MS (induced by high fat diet and fructose water), and MS+CIHH. The serum levels of glucose, lipid metabolism, iron metabolism, interleukin-6 (IL-6), erythropoietin (Epo) and hepcidin were measured. The protein expressions of JAK2, STAT3, STAT5, bone morphogenetic protein 6 (BMP6), small mothers against decapentaplegic 1 (SMAD1) and hepcidin were examined. The mRNA expressions of erythroferrone (ERFE) and hepcidin were analyzed. ResultsThe MS rats displayed obesity, hyperglycemia, hyperlipidemia, iron metabolism disorder, increased IL-6 and hepcidin serum levels, upregulation of JAK2/STAT3 signaling pathway, decreased Epo serum levels, downregulation of STAT5/ERFE signaling pathway in spleen, upregulation of BMP/SMAD signaling pathway in liver, and increased hepcidin mRNA and protein expression compared to CON rats. All the aforementioned abnormalities in MS rats were ameliorated in MS + CIHH rats. ConclusionsCIHH improved iron metabolism disorders, possibly by inhibiting IL-6/JAK2/STAT3 and activating Epo/STAT5/ERFE signaling pathway, thus downregulating hepcidin in MS rats.

Chronic intermittent hypobaric hypoxia ameliorates osteoporosis after spinal cord injury through balancing osteoblast and osteoclast activities in rats.

As a common complication of spinal cord injury (SCI), most SCI patients suffer from osteoporosis. In our previous study, chronic intermittent hypobaric hypoxia (CIHH) could promote bone fracture healing. We speculated that it may act a role in the progression of osteoporosis. The current study purposed to explore the role of CIHH in the osteoporosis triggered by SCI in rats. A SCI-induced SCI model was established by completed transection at T9-T10 spinal cord of Wistar rats. One week after SCI, the rats were conducted toCIHH treatment (PB = 404 mmHg, Po2 = 84 mmHg) 6 hours a day for continuously 7 weeks. The results of X-radiography and Micro-CT assessment demonstrated that compared with sham rats, the areal bone mineral density (BMD), bone volume to tissue volume, volumetric BMD, trabecular thickness, trabecular number, and trabecular connectivity were decreased. Trabecular bone pattern factor, trabecular separation, as well as structure model index were increased at the distal femur and proximal tibia of SCI rats, which were effectively reversed by CIHH treatment. Histomorphometry showed that CIHH treatment increased bone formation of SCI rats, as evidenced by the increased osteoid formation, the decreased number and surface of TRAP-positive osteoclasts. Furthermore, ELISA and real time PCR results showed that the osteoblastogenesis-related biomarkers, such as procollagen type 1 N-terminal propeptide, osteocalcin in serum, as well as ALP and OPG mRNAs in bone tissue were decreased, while the osteoclastogenesis-related biomarkers, including scleorostin in serum and RANKL and TRAP mRNAs in bone tissue were increased in SCI rats. Importantly, the deviations of aforementioned biomarkers were improved by CIHH treatment. Mechanically, the protective effects of CIHH might be at least partly mediated by hypoxia-inducible factor-1 alpha (HIF-1α) signaling pathway. The present study testified that CIHH treatment ameliorates osteoporosis after SCI by balancing osteoblast and osteoclast activities in rats.

Chronic intermittent hypobaric hypoxia ameliorates vascular reactivity through upregulating adiponectin expression of PVAT in metabolic syndrome rats

Cumulating evidence demonstrated that chronic intermittent hypobaric hypoxia (CIHH) had beneficial effects on the body. This study investigated the role of perivascular adipose tissue (PVAT) in ameliorating effect of CIHH on vascular reactivity by adiponectin in mesenteric artery of metabolic syndrome (MS) rats. Main methods: 6-week-old male Sprague-Dawley rats were randomly divided into four groups: control (CON), MS model, CIHH treatment, and MS+CIHH treatment group. The size of adipocytes in PVAT was measured by scanning electron microscopy. Serum adiponectin was measured. The microvessel recording technique was used to observe the effect of CIHH on contraction and relaxation in mesenteric artery rings. Also, the expressions of interleukin-1β, tumor necrosis factor-α, adiponectin, AdipoR1, AdipoR2, APPL1, and endothelial nitric oxide synthase (eNOS) were assayed by Western blotting. Key findings: in MS rats, adipocyte size increased, serum adiponectin decreased, contraction reaction increased while relaxation reaction decreased, the expression of pro-inflammatory cytokines was upregulated, while adiponectin was downregulated in PVAT, and the expressions of AdipoR1, AdipoR2, APPL, and phosphorylated-eNOS were downregulated in mesenteric artery. All aforementioned abnormalities of MS were ameliorated in MS+CIHH rats. We concluded that CIHH treatment improves vascular reactivity through upregulating adiponectin expression and downregulating pro-inflammatory cytokine expression of PVAT in MS rats.

The role of NMDA glutamate receptors in lung injury caused by chronic long-term intermittent hypobaric hypoxia

Chronic intermittent hypoxia (CIH), a component of sleep apnea-hypopnea syndrome, is suggested to cause damage to lung tissue, and the role of glutamate is not well studied. We used a chronic long-term intermittent hypobaric hypoxia (CLTIHH) model of rats to find out if such procedure causes lung injury and the potential effect of N-methyl-D-aspartate receptors (NMDARs) by using receptor antagonist MK-801 (dizocilpine). Thirty-two rats were placed into four groups; a control and three CLTIHH groups where rats were placed into a low-pressure chamber set to 430 mmHg for 5 h/day, 5 days/week, for 5 weeks. Only one group received MK-801 (0.3 mg/kg, ip) daily. We evaluated tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and nuclear factor (NF)-kB for the inflammatory process, superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPX), total antioxidant status (TAS), and total oxidant status (TOS) for oxidative stress, and caspase-9 levels. Blood plasma, bronchoalveolar fluid (BALF), and lung tissue extracts were evaluated. Both oxidant and inflammatory parameters were significantly increased in all the mediums of the CLTIHH groups except the group that received MK-801. Significant evidence was collected on MK-801 alleviating the effect of CLTIHH. Histological evaluations revealed lung damage and fibrotic changes in the CLTIHH groups. It was first shown that the CLTIHH procedure caused chronic lung injury, and that inflammation and oxidant stress were influential in the formation of lung injury. Secondly, NMDAR antagonist MK-801 effectively inhibited the development of lung injury and fibrosis.