Chronic Intermittent 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.

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.

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.

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.

Reparative effects of chronic intermittent hypobaric hypoxia pre‑treatment on intervertebral disc degeneration in rats.

Previous studies have indicated that chronic intermittent hypobaric hypoxia (CIHH) preconditioning can inhibit TNF-α and other related inflammatory cytokines and exerts protective effect on intervertebral disc degeneration disease (IDD) in rats; however, the mechanism is still unclear. The present study aimed to explore the repair mechanisms of CIHH on IDD in rats. In the experiment, 48 adult Sprague-Dawley rats were selected and randomly divided into an experimental group (CIHH-IDD), a degenerative group (IDD) and a control group (CON). The CIHH-IDD group of rats (n=16) were treated with CIHH (simulated 3000 m altitude, 5 h per day, 28 days; PO2=108.8 mmHg) before disc degeneration surgery. The IDD group of rats (n=16) underwent tail-vertebral intervertebral disc surgery to establish a model of intervertebral disc degeneration. The CON group of rats (n=16) did not receive any treatments. After surgery, the disc height index was calculated using X-ray analysis of rat tail vertebrae, the degeneration process was observed and repair was evaluated by chemically staining degenerative intervertebral disc tissue slices. The expression levels of basic fibroblast growth factor (bFGF), TGFβ1, Collagen I and Collagen II were measured in the intervertebral disc tissue using western blotting; while the expression levels of bFGF, TGFβ1 and hypoxia-inducible factor 1-α (HIF-1α) were measured in rat serum using ELISA. The results demonstrated that: i) The degree of intervertebral disc height degeneration in CIHH-IDD rats was significantly lower compared with that in IDD rats (P<0.05); ii) the expression levels of bFGF, TGFβ1 and HIF-1α were higher in CIHH-IDD rat serum compared with those in IDD rat serum (P<0.05); iii) optical microscopy revealed that the degree of disc degeneration was relatively mild in CIHH-IDD rats; and iv) the protein expression levels of bFGF, TGFβ1 and collagen II were increased in CIHH-IDD rat intervertebral disc tissues compared with those of IDD rats, while the overexpression of collagen I protein was inhibited. Overall, after CIHH pre-treatment, the expression levels of bFGF and TGFβ1 were up-regulated, which play notable roles in repairing degenerative intervertebral discs in rats.

Dysregulation of the Nitric Oxide/Dimethylarginine Pathway in Hypoxic Pulmonary Vasoconstriction—Molecular Mechanisms and Clinical Significance

The pulmonary circulation responds to hypoxia with vasoconstriction, a mechanism that helps to adapt to short-lived hypoxic episodes. When sustained, hypoxic pulmonary vasoconstriction (HPV) may become deleterious, causing right ventricular hypertrophy and failure, and contributing to morbidity and mortality in the late stages of several chronic pulmonary diseases. Nitric oxide (NO) is an important endothelial vasodilator. Its release is regulated, amongst other mechanisms, by the presence of endogenous inhibitors like asymmetric dimethylarginine (ADMA). Evidence has accumulated in recent years that elevated ADMA may be implicated in the pathogenesis of HPV and in its clinical sequelae, like pulmonary arterial hypertension (PAH). PAH is one phenotypic trait in experimental models with disrupted ADMA metabolism. In high altitude, elevation of ADMA occurs during long-term exposure to chronic or chronic intermittent hypobaric hypoxia; ADMA is significantly associated with high altitude pulmonary hypertension. High ADMA concentration was also reported in patients with chronic obstructive lung disease, obstructive sleep apnoea syndrome, and overlap syndrome, suggesting a pathophysiological role for ADMA-mediated impairment of endothelium-dependent, NO-mediated pulmonary vasodilation in these clinically relevant conditions. Improved understanding of the molecular (dys-)regulation of pathways controlling ADMA concentration may help to dissect the pathophysiology and find novel therapeutic options for these diseases.

The Effect of Chronic Intermittent Hypobaric Hypoxia on Sleep Quality and Melatonin Serum Levels in Chilean Miners.

High-altitude mining is an important economic resource for Chile. These workers are exposed to chronic intermittent hypobaric hypoxia (CIHH), which reduces their sleep quality and increases the risk of accidents and long-term illnesses. Melatonin, a hormone produced by the pineal gland, is a sleep inducer that regulates the circadian cycle and may be altered in populations subjected to CIHH. This work aimed to assess the relationship between altitude, sleep quality, and plasma melatonin concentrations in miners with CIHH exposure. 288 volunteers were recruited from five altitudes (0, 1,600, 2,500, 3,500, and 4,500 m). All volunteers worked for 7 days at altitude, followed by 7 days of rest at sea level. We performed anthropometric assessments, nocturnal oximetry, sleep quality and sleepiness surveys, and serum melatonin levels upon awakening. Although oxygen saturation progressively decreased and heart rate increased at higher altitudes, subjective perception of sleep quality was not significantly different, and sleepiness increased in all groups compared to population at sea level. Similarly, melatonin levels increased at all assessed altitudes compared to the population at sea level. These data confirm that sleep disturbances associated with CIHH increase morning melatonin levels. Therefore, this hormone and could potentially serve as a biomarker of sleep quality.

Adenosine mono-phosphate-activated protein kinase-mammalian target of rapamycin signaling participates in the protective effect of chronic intermittent hypobaric hypoxia on vascular endothelium of metabolic syndrome rats.

Our previous study demonstrated that chronic intermittent hypobaric hypoxia (CIHH) protects vascular endothelium function through ameliorating autophagy in mesenteric arteries of metabolic syndrome (MS) rats. This study aimed to investigate the role of adenosine mono-phosphate-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling in CIHH effect. Six-week-old male Sprague-Dawley rats were divided into control (CON), MS model, CIHH treatment (CIHH), and MS + CIHH groups. Serum pro-inflammatory cytokines were measured. The endothelium dependent relaxation (EDR), endothelial ultrastructure and autophagosomes were observed in mesenteric arteries. The expression of phosphor (p)-AMPKα, p-mTOR, autophagy-related and endoplasmic reticulum stress-related proteins, p-endothelial nitric oxide synthase, and cathepsin D were assayed. In MS rats, pro-inflammatory cytokines were increased, EDR was attenuated, and endothelial integrity was impaired. In addition, the expression level of p-AMPKα and cathepsin D was down-regulated, but the level of p-mTOR was up-regulated. While in MS + CIHH rats, all aforementioned abnormalities were ameliorated, and the beneficial effect of CIHH was cancelled by AMPKα inhibitor. In conclusion, AMPK-mTOR signaling pathway participates in the protection of CIHH on vascular endothelium of MS rats.

Effect of Chronic Intermittent Hypobaric Hypoxia on Cardiac Function in Female Metabolic Syndrome Rats

Effect of Chronic Intermittent Hypobaric Hypoxia on Cardiac Function in Female Metabolic Syndrome Rats

Chronic intermittent hypobaric hypoxia attenuates ischemic limb injury by promoting angiogenesis in mice.

This study aimed to evaluate the protective effect of chronic intermittent hypobaric hypoxia (CIHH) against limb ischemic injury. C57BL/6 mice were randomly divided into three groups: limb ischemic injury group (Ischemia, induced by ligation and excision of the left femoral artery), limb ischemia following CIHH pretreatment group (CIHH+Ischemia, simulated a 5000 m altitude hypoxia, 6h per day for 28days, before induction of hind-limb ischemia), and sham group (Sham). The blood flow in the mouse models of hind-limb ischemia was examined using laser doppler imaging. The functional and morphological performance of ischemic muscle was evaluated using contraction force and hematoxylin-eosin and Masson's trichrome staining. Angiogenesis was determined by immunohistochemistry staining of the endothelial markers CD31 and CD34. The protein expressions of angiogenesis-related genes were detected using Western blot assay. Chronic ischemia resulted in reduced blood perfusion, decreased contraction tension, and morphological destruction in gastrocnemius muscle. CIHH pretreatment increased the contractile force and muscle fiber diameter and decreased necrosis and fibrosis of the ischemic muscle. Also, CIHH significantly increased the density of CD31+ and CD34+ cells and promoted the expression of angiogenesis-related molecules in ischemic muscle. These data demonstrate that CIHH has a protective effect against chronic limb ischemia by promoting angiogenesis.

Effects of chronic intermittent hypobaric hypoxia on prostate-specific antigen (PSA) in Chilean miners

ObjectiveThe aim was to determine the effects of chronic intermittent hypobaric hypoxia (CIHH) on prostate-specific antigen (PSA) levels in Chilean miners who work at different altitudes.MethodsA cross-sectional study was conducted...

CIHH protects the heart against left ventricular remodelling and myocardial fibrosis by balancing the renin-angiotensin system in SHR

AimThe aim of our study was to clarify the cardioprotection of chronic intermittent hypobaric hypoxia (CIHH) and the underlying mechanism in spontaneously hypertensive rats (SHR). Main methodsAdult male rats were divided into normal blood pressure Wistar-Kyoto rats (WKY) control (WKY-CON), WKY rats with CIHH treatment (WKY-CIHH), SHR control (SHR-CON) and SHR with CIHH treatment (SHR-CIHH) groups. SHR-CIHH and WKY-CIHH rats were subjected to hypobaric hypoxia simulating 4000-m altitude for 35 days, 5 h per day. Arterial blood pressure and cardiac function parameters, including ejection fraction, fractional shortening and left ventricular (LV) wall thickness, were evaluated. Cardiac pathomorphology and myocardial fibrosis were determined. The expression of angiotensin-converting enzyme (ACE), ACE2, Ang II, Ang1-7, AT1 receptor, Mas receptor, IL-6, TNF-α，IL-10, SOD and MDA were assayed in myocardium. Key findingsCIHH significantly decreased arterial blood pressure, alleviated LV hypertrophy, and improved cardiovascular function in SHR (P < 0.05–0.01). Also, CIHH protected SHR heart against morphological changes and fibrosis. In addition, CIHH significantly down-regulated the ACE/Ang II/AT1 receptor axis and up-regulated the ACE2/Ang1–7/Mas axis of renin-angiotensin system (RAS) in SHR (P < 0.05–0.01). CIHH significantly reduced IL-6, TNF-α, and MDA levels, but increased IL-10 and SOD in SHR myocardium (P < 0.05–0.01). SignificanceThe CIHH treatment protected the heart of SHR against LV remodelling and myocardial fibrosis, which might be carried out through a balance in the ACE/Ang II/AT1 axis and the ACE2/Ang1–7/Mas axis of the RAS to reduce inflammation, and inhibit oxidative stress.

Cardiovascular Risk Is Increased in Miner's Chronic Intermittent Hypobaric Hypoxia Exposure From 0 to 2,500 m?

Over the past 40 years, mining activities in Chile have relocated miners who normally live at sea level to work at high altitudes. This results in a form of chronic intermittent hypobaric hypoxia (CIHH) characterized by alternating periods of work at high altitude and rest periods at sea level. Previous studies performed in our laboratory showed that aerobic capacity is reduced at 3,800 m, even when oxygen content is maintained. Our study aimed to determine the corporal composition, food intake, maximum oxygen uptake, and concentration of high sensitivity C reactive protein (hsCRP) in an acclimatized miner population that work from 0 to 2,500 m with CIHH exposure over 4 years. All miners recruited for our study were operators of heavy trucks with CIHH for over 4 years (shiftwork 7*7 days), and our experimental population was composed of 54 miners at sea level, 61 at 1,600 m, and 38 at 2,500 m. All evaluations were performed on the 3rd or 4th day of diurnal shiftwork. To determine corporal composition, we measured weight and height (to calculate body mass index, BMI), skinfolds (to calculate body fatty, BF), and waist circumference (WC); maximal aerobic capacity was evaluated using a ramp-incremental cycling to exhaustion protocol and a venous blood sample before the exercise test to measure (hsCRP) via an ELISA test. We found higher values of BMI, BF, and WC, in the miners’ population but observed no significant difference between populations. We found a decrease in VO2 of 11.6% at 1,600 m and 25.9% at 2,500 m compared to miners at sea level. An increase in (hsCRP) at 1,600 and 2,500 m regards sea level. We observed a high prevalence of overweight and obese subjects, which was related to the ad libitum availability of food and low physical activity (sedentarism). We found that work capacity was maintained despite a decreased VO2 max at moderate altitude. However, overweight and obesity support an increased risk of cardiometabolic disease in miner’s which is unrelated to altitude. In contrast, an increased hsCRP level could be associated with increased inflammatory mechanisms at 1,600 and 2,500 m.

Chronic Intermittent Hypobaric Hypoxia Decreases High Blood Pressure by Stabilizing the Vascular Renin-Angiotensin System in Spontaneously Hypertensive Rats.

Background and AimsPrevious studies have demonstrated the anti-hypertensive effect of chronic intermittent hypobaric hypoxia (CIHH) in hypertensive rats. The present study investigated the anti-hypertensive effect of CIHH in spontaneously hypertensive rats (SHR) and the role of the renin-angiotensin system (RAS) in anti-hypertensive effect of CIHH.MethodsFifteen-week-old male SHR and WKY rats were divided into four groups: the SHR without CIHH treatment (SHR-CON), the SHR with CIHH treatment (SHR-CIHH), the WKY without CIHH treatment (WKY-CON), and the WKY with CIHH treatment (WKY-CIHH) groups. The SHR-CIHH and WKY-CIHH rats underwent 35-days of hypobaric hypoxia simulating an altitude of 4,000 m, 5 h per day. Arterial blood pressure and heart rate were recorded by biotelemetry, and angiotensin (Ang) II, Ang1–7, interleukin (IL)-6, tumor necrosis factor-alpha (TNF)-α, and IL-10 in serum and the mesenteric arteries were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The microvessel tension recording technique was used to determine the contraction and relaxation of the mesenteric arteries. Hematoxylin and eosin and Masson’s staining were used to observe vascular morphology and fibrosis. Western blot was employed to detect the expression of the angiotensin-converting enzyme (ACE), ACE2, AT1, and Mas proteins in the mesenteric artery.ResultsThe biotelemetry result showed that CIHH decreased arterial blood pressure in SHR for 3–4 weeks (P < 0.01). The ELISA and immunohistochemistry results showed that CIHH decreased Ang II, but increased Ang1–7 in serum and the mesenteric arteries of SHR. In the CIHH-treated SHR, IL-6 and TNF-α decreased in serum and the mesenteric arteries, and IL-10 increased in serum (P < 0.05–0.01). The microvessel tension results revealed that CIHH inhibited vascular contraction with decreased Ang1–7 in the mesenteric arteries of SHR (P < 0.05–0.01). The staining results revealed that CIHH significantly improved vascular remodeling and fibrosis in SHR. The western blot results demonstrated that CIHH upregulated expression of the ACE2 and Mas proteins, and downregulated expression of the ACE and AT1 proteins (P < 0.05–0.01).ConclusionCIHH decreased high blood pressure in SHR, possibly by inhibiting RAS activity, downregulating the ACE-Ang II-AT1 axis and upregulating the ACE2-(Ang1-7)-Mas axis, which resulted in antagonized vascular remodeling and fibrosis, reduced inflammation, and enhanced vascular relaxation.

Chronic Intermittent Hypobaric Hypoxia Enhances Bone Fracture Healing.

The effect of chronic intermittent hypobaric hypoxia (CIHH) on bone fracture healing is not elucidated. The present study aimed to investigate the role of CIHH on bone fracture healing and the mechanism. The Sprague-Dawley rats were randomly divided into the CIHH group and control group and monitored for 2, 4, or 8 weeks after femoral fracture surgery. Bone healing efficiency was significantly increased in the CIHH group as evidenced by higher high-density bone volume fractions, higher bone mineral density, higher maximum force, and higher stiffness. Histologically, the CIHH group exhibited superior bone formation, endochondral ossification, and angiogenic ability compared with the control group. The expression of HIF-1α and its downstream signaling proteins VEGF, SDF-1/CXCR4 axis were increased by the CIHH treatment. Moreover, the expression of RUNX2, osterix, and type I collagen in the callus tissues were also up-regulated in the CIHH group. In conclusion, our study demonstrated that CIHH treatment improves fracture healing, increases bone mineral density, and increases bone strength via the activation of HIF-1α and bone production-related genes.