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Humans living at high-altitude (HA) have adapted to this environment by increasing pulmonary vascular and alveolar growth. RNA sequencing data from a novel murine model that mimics this phenotypical response to HA suggested estrogen signaling via estrogen receptor alpha (ERα) may be involved in this adaptation. We hypothesized ERα was a key mediator in the cardiopulmonary adaptation to chronic hypoxia and sought to delineate the mechanistic role ERα contributes to this process by exposing novel loss-of-function ERα mutant (ERαMut) rats to simulated HA. ERα mutant or wild-type (wt) rats were exposed to normoxia or hypoxia starting at conception and continued postnatally until 6 wk of age. Both wt and ERαMut animals born and raised in hypoxia exhibited lower body mass and higher hematocrits, total alveolar volumes (Va), diffusion capacities of carbon monoxide (DLCO), pulmonary arteriole (PA) wall thickness, and Fulton indices than normoxia animals. Right ventricle adaptation was maintained in the setting of hypoxia. Although no major physiologic differences were seen between wt and ERαMut animals at either exposure, ERαMut animals exhibited smaller mean linear intercepts (MLI) and increased PA total and lumen areas. Hypoxia exposure or ERα loss-of-function did not affect lung mRNA abundance of vascular endothelial growth factor, angiopoietin 2, or apelin. Sexual dimorphisms were noted in PA wall thickness and PA lumen area in ERαMut rats. In summary, in room air-exposed rats and rats with peri- and postnatal hypoxia exposure, ERα loss-of-function was associated with decreased alveolar size (primarily driven by hypoxic animals) and increased PA remodeling. NEW & NOTEWORTHY By exposing novel loss-of-function estrogen receptor alpha (Erα) mutant rats to a novel model of human high-altitude exposure, we demonstrate that ERα has subtle but inconsistent effects on endpoints relevant to cardiopulmonary adaptation to chronic hypoxia. Given that we observed some histologic, sex, and genotype differences, further research into cell-specific effects of ERα during hypoxia-induced cardiopulmonary adaptation is warranted. [ABSTRACT FROM AUTHOR]

Background. It is known that the protective effect of adaptation and conditioning influence is weakened in animals with metabolic syndrome. Metabolic syndrome may be the basis for the failure of cardioprotection in clinical settings.The aim of the study. To identify the relationship between disorder in carbohydrate and lipid metabolism and a decrease in the effectiveness of the infarct-limiting effect of moderate chronic normobaric hypoxia; to check the possibility of correcting reduced cardioprotection by normalizing carbohydrate and lipid metabolism.Methods. The study included 64 Wistar rats. Metabolic syndrome was induced by feeding animals a high-carbohydrate, high-fat diet for 84 days. Chronic normobaric hypoxia was carried out for 21 days in the following mode: 12 % O2 : 0.3 % CO2. Metformin at a dose of 200 mg/kg/day or PPARα agonist WY14643 at a dose of 1 mg/kg/day were added to the drinking water of rats with metabolic syndrome during adaptation period to hypoxia. A 45-minute coronary occlusion and 120-minute reperfusion were performed, and the infarct size was determined. Indicators of lipid and carbohydrate metabolism, leptin, and adiponectin were studied in the blood serum.Results. The infarct-limiting effect of chronic normobaric hypoxia was weakened in animals with metabolic syndrome. Infarct size showed a direct correlation with decreased glucose tolerance and serum triglyceride levels. Using metformin therapy did not lead to the restoration of the infarct-limiting effect of chronic normobaric hypoxia, while the normalization of lipid metabolism with the use of the PPARα agonist WY14643 corrected the impairment of adaptive cardioprotection in rats with metabolic syndrome.Conclusion. The lack of cardioprotection at chronic normobaric hypoxia in rats with metabolic syndrome is associated with impaired carbohydrate and lipid metabolism. The PPARα agonist restores impaired lipid metabolism and adaptive cardioprotection.

Background. It is known that adaptation to chronic continuous hypoxia leads to a pronounced cardioprotective effect. The efficiency of acute adaptation to hypoxia is reduced in metabolic syndrome. However, the effectiveness of the myocardial infarct size-limiting effect of chronic continuous hypoxia in metabolic syndrome remains an understudied fact. The aim. To study the effectiveness of the development of the myocardial infarct size-limiting effect of chronic continuous hypoxia in rats with metabolic syndrome. Materials and methods. The study was carried out on 43 Wistar rats. Adaptation of animals to chronic hypoxia was performed during 21 days in a hypoxic chamber (12 % O2, 0.3 % CO2). Metabolic syndrome was modeled by keeping rats on a high-carbohydrate and high-fat diet (proteins 16 %, fats 21 %, carbohydrates 46 % (including fructose 17 %), cholesterol 0.125 %, cholic acid 0.5 %) for 12 weeks with replacement of drinking water with 20% fructose solution. Coronary occlusion-reperfusion was performed in vivo. The effect of chronic hypoxia and metabolic syndrome on myocardial infarct size was assessed. Results. It was found that myocardial infarct size in rats after chronic continuous hypoxia was 38 % less than in animals of the control group. In rats which were kept on a high-carbohydrate and high-fat diet we observed the obesity, decreased glucose tolerance, increased serum triglycerides level, and hypertension. Adaptation to chronic continuous hypoxia in animals on a high-carbohydrate and high-fat diet improved carbohydrate metabolism, but did not affect the severity of other metabolic disorders. At the same time, the myocardial infarct size-limiting effect of chronic hypoxia was not observed in rats with metabolic syndrome. Conclusion. Metabolic syndrome eliminated myocardial infarct size-limiting effect of chronic continuous hypoxia.

We studied the infarct-limiting effect of adaptation to chronic normobaric hypoxia in rats with induced metabolic syndrome and the relationship between disturbances of adaptive cardioprotection and disorders of carbohydrate and lipid metabolism. Adaptation to chronic normobaric hypoxia was carried out for 21 days at 12% O2 and 0.3% CO2. The metabolic syndrome was modeled with a high-carbohydrate high-fat diet for 84 days with replacement of drinking water with a 20% fructose solution. The infarct size in rats exposed to chronic normobaric hypoxia was 38% smaller than in control animals. In rats with induced metabolic syndrome, hypertension, obesity, decreased glucose tolerance, increased serum triglyceride, and no infarction-limiting effect of chronic normobaric hypoxia were observed. Infarct size showed a direct correlation with impaired glucose tolerance and serum triglyceride levels. The study allows us to conclude that the lack of cardioprotection in chronic normobaric hypoxia in rats with induced metabolic syndrome is associated with impaired carbohydrate and lipid metabolism. [ABSTRACT FROM AUTHOR]

We studied the role of KATP channels in the infarct-limiting effect of short-term normobaric hypoxia. Male Wistar rats were subjected to a 45-min coronary artery occlusion followed by a 120-min reperfusion. Normobaric hypoxia was simulated 30 min before coronary artery occlusion: 6 sessions of hypoxia (8% O2, 10 min) and reoxygenation (21% O2, 10 min). The following drugs were administered to rats: glibenclamide, 5-hydroxydecanoate, and HMR1098. It was found that normobaric hypoxia contributes to a decrease in myocardial infarct size by 36%. Preliminary administration of glibenclamide or 5-hydroxydecanoate eliminated the infarct-reducing effect of normobaric hypoxia. Activator of mitochondrial KATP channel diazoxide limited the infarct size. These findings suggest that mitochondrial KATP channels are involved into the cardioprotective effect of normobaric hypoxia [ABSTRACT FROM AUTHOR]

Abstract Life underground has provided remarkable examples of adaptive evolution in subterranean mammals; however, genome‐wide adaptive evolution to underground stresses still needs further research. There are approximately 250 species of subterranean mammals across three suborders and six families. These species not only inhabit hypoxic and dark burrows but also exhibit evolved adaptation to hypoxia, cancer resistance, and specialized sensory systems, making them an excellent model of evolution. The adaptive evolution of subterranean mammals has attracted great attention and needs further study. In the present study, phylogenetic analysis of 5,853 single‐copy orthologous gene families of five subterranean mammals (Nannospalax galili, Heterocephalus glaber, Fukomys damarensis, Condylura cristata, and Chrysochloris asiatica) showed that they formed fou distinct clusters. This result is consistent with the traditional systematics of these species. Furthermore, comparison of the high‐quality genomes of these five subterranean mammalian species led to the identification of the genomic signatures of adaptive evolution. Our results show that the five subterranean mammalian did not share positively selected genes but had similar functional enrichment categories, including hypoxia tolerance, immunity promotion, and sensory specialization, which adapted to the environment of underground stresses. Moreover, variations in soil hardness, climate, and lifestyles have resulted in different molecular mechanisms of adaptation to the hypoxic environment and different degrees of visual degradation. These results provide insights into the genome‐wide adaptive evolution to underground stresses in subterranean mammals, with special focus on the characteristics of hypoxia adaption, immunity promotion, and sensory specialization response to the life underground.

Current evidence indicates that the toxicity of carbon monoxide (CO) poisoning results from increases in reactive oxygen species (ROS) generation plus tissue hypoxia resulting from decreases in capillary PO2 evoked by effects of increases in blood [carboxyhemoglobin] on the oxyhemoglobin dissociation curve. There has not been consideration of how increases in PCO could influence metabolism-blood flow coupling, a physiological mechanism that regulates the uniformity of tissue PO2, and alveolar ventilation- blood flow coupling, a mechanism that increases the efficiency of pulmonary O2 uptake. Using published data, I consider hypotheses that these coupling mechanisms, triggered by O2 and CO sensors located in arterial and arteriolar vessels in the coronary and cerebral circulations and in lung intralobar arteries, are disrupted during acute CO poisoning. These hypotheses are supported by calculations that show that the PCO in these vessels can reach levels during CO poisoning that would exert effects on signal transduction molecules involved in these coupling mechanisms. [ABSTRACT FROM AUTHOR]

Life underground has provided remarkable examples of adaptive evolution in subterranean mammals; however, genome‐wide adaptive evolution to underground stresses still needs further research. There are approximately 250 species of subterranean mammals across three suborders and six families. These species not only inhabit hypoxic and dark burrows but also exhibit evolved adaptation to hypoxia, cancer resistance, and specialized sensory systems, making them an excellent model of evolution. The adaptive evolution of subterranean mammals has attracted great attention and needs further study. In the present study, phylogenetic analysis of 5,853 single‐copy orthologous gene families of five subterranean mammals (Nannospalax galili, Heterocephalus glaber, Fukomys damarensis, Condylura cristata, and Chrysochloris asiatica) showed that they formed fou distinct clusters. This result is consistent with the traditional systematics of these species. Furthermore, comparison of the high‐quality genomes of these five subterranean mammalian species led to the identification of the genomic signatures of adaptive evolution. Our results show that the five subterranean mammalian did not share positively selected genes but had similar functional enrichment categories, including hypoxia tolerance, immunity promotion, and sensory specialization, which adapted to the environment of underground stresses. Moreover, variations in soil hardness, climate, and lifestyles have resulted in different molecular mechanisms of adaptation to the hypoxic environment and different degrees of visual degradation. These results provide insights into the genome‐wide adaptive evolution to underground stresses in subterranean mammals, with special focus on the characteristics of hypoxia adaption, immunity promotion, and sensory specialization response to the life underground. [ABSTRACT FROM AUTHOR]

The discourse characterizes types, causes and key links of the pathogenesis of different types of hypoxia, their main manifestations and mechanisms of their development, disorders in the body under hypoxic conditions, principles of their elimination. The mechanisms of a body adaptation to acute and chronic hypoxia, as well as the idea of its superoxygenation are described.

Oxygen (O2) is fundamental for cell and wholebody homeostasis. Our understanding of the adaptive processes that take place in response to a lack of O2 (hypoxia) has progressed significantly in recent years. The carotid body (CB) is the main arterial chemoreceptor that mediates the acute cardiorespiratory reflexes (hyperventilation and sympathetic activation) triggered by hypoxia. The CB is composed of clusters of cells (glomeruli) in close contact with blood vessels and nerve fibers. Glomus cells, the O2-sensitive elements in the CB, are neuron-like cells that contain O2-sensitive K+ channels, which are inhibited by hypoxia. This leads to cell depolarization, Ca2+ entry, and the release of transmitters to activate sensory fibers terminating at the respiratory center. The mechanism whereby O2 modulates K+ channels has remained elusive, although several appealing hypotheses have been postulated. Recent data suggest that mitochondria complex I signaling to membrane K+ channels plays a fundamental role in acute O2 sensing. CB activation during exposure to low PO2 is also necessary for acclimatization to chronic hypoxia. CB growth during sustained hypoxia depends on the activation of a resident population of stem cells, which are also activated by transmitters released from the O2-sensitive glomus cells. These advances should foster further studies on the role of CB dysfunction in the pathogenesis of highly prevalent human diseases. [ABSTRACT FROM AUTHOR]

We studied the mechanisms of adaptation of human breast cancer cells MCF-7 to hypoxia and analyzed the role of AMPK/mTOR signaling pathway in the maintenance of cell proliferation under hypoxic conditions. It was found that long-term culturing (30 days or more) of MCF-7 cells under hypoxic conditions induced their partial adaptation to hypoxia. Cell adaptation to hypoxia was associated with attenuation of hypoxia-dependent AMPK induction with simultaneous constitutive activation of mTOR and Akt. These findings suggest that these proteins can be promising targets for targeted therapy of tumors developing under hypoxic conditions. [ABSTRACT FROM AUTHOR]

It has been documented that adaptation to hypoxia increases myocardial tolerance to ischemia-reperfusion (I/R) injury depending on the regimen of adaptation. Reactive oxygen species (ROS) formed during hypoxia play an important role in the induction of protective cardiac phenotype. On the other hand, the excess of ROS can contribute to tissue damage caused by I/R. Here we investigated the relationship between myocardial tolerance to I/R injury and transcription activity of major antioxidant genes, transcription factors, and oxidative stress in three different regimens of chronic hypoxia. Adult male Wistar rats were exposed to continuous normobaric hypoxia (FIO2 0.1) either continuously (CNH) or intermittently for 8 h/day (INH8) or 23 h/day (INH23) for 3 wk period. A control group was kept in room air. Myocardial infarct size was assessed in anesthetized open-chest animals subjected to 20 min coronary artery occlusion and 3 h reperfusion. Levels of mRNA transcripts and the ratio of reduced and oxidized glutathione (GSH/GSSG) were analyzed by real-time RTPCR and by liquid chromatography, respectively. Whereas CNH as well as INH8 decreased infarct size, 1 h daily reoxygenation (INH23) abolished the cardioprotective effect and decreased GSH/GSSG ratio. The majority of mRNAs of antioxidant genes related to mitochondrial antioxidant defense (manganese superoxide dismutase, glutathione reductase, thioredoxin/thioredoxin reductase, and peroxiredoxin 2) were upregulated in both cardioprotective regimens (CNH, INH8). In contrast, INH23 increased only PRX5, which was not sufficient to induce the cardioprotective phenotype. Our results suggest that the increased mitochondrial antioxidant defense plays an important role in cardioprotection afforded by chronic hypoxia. [ABSTRACT FROM AUTHOR]

Parameters of respiration, transmembrane potential, and Ca-binding capacity of mitochondria isolated from Langendorff-perfused hearts of rats adapted to normobaric hypoxia were analyzed. Ischemia and reperfusion modeling in intact and adapted animals reduced Ca-binding capacity of mitochondria, which indicated increased sensitivity of mitochondrial permeability transition pores (MPTP) to calcium ions. These changes were accompanied by a decrease in transmembrane potential, ADP/O coeffi cient (ratio of added ADP to oxygen consumption in State 3), and inhibition of State 3 respiration. At the same time, adaptation attenuated the negative effect of ischemia and reperfusion on the functional state of mitochondria. [ABSTRACT FROM AUTHOR]

We report here studies addressing the possibility of preventing neurodegenerative changes in the brain using adaptation to periodic hypoxia in rats with experimental Alzheimer’s disease induced by administration of the neurotoxic peptide fragment of β-amyloid (Ab) into the basal magnocellular nucleus. Adaptation to periodic hypoxia was performed in a barochamber (4000 m, 4 h per day, 14 days). The following results were obtained 15 days after administration of Ab. 1. Adaptation to periodic hypoxia significantly blocked Ab-induced memory degradation in rats, as assessed by testing a conditioned passive avoidance reflex. 2. Adaptation to periodic hypoxia significantly restricted increases in oxidative stress, measured spectrophotometrically in the hippocampus in terms of the content of thiobarbituric acid-reactive secondary lipid peroxidation products. 3. Adaptation to periodic hypoxia completely prevented the overproduction of NO in the brains of rats with experimental Alzheimer’s disease, as measured in terms of increases in tissue levels of stable NO metabolites, i.e., nitrites and nitrates. 4. The cerebral cortex of rats given Ab injections after adaptation to periodic hypoxia did not contain neurons with pathomorphological changes or dead neurons (Nissl staining), which were typical in animals with experimental Alzheimer’s disease. Thus, adaptation to periodic hypoxia effectively prevented oxidative and nitrosative stress, protecting against neurodegenerative changes and protecting cognitive functions in experimental Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

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The phenomenon of adaptive stabilization of structures (PhASS) develops during adaptation of the organism to intermittent restraint stress. The PhASS manifests itself in a considerably increased resistance of the heart to a broad spectrum of harmful factors. In the present work, the content of hsp70 and their role in the development of PhASS during adaptation to intermittent restraint stress and to intermittent hypoxia were studied. In adaptation to restraint stress, five hsp70 isoforms with pI ranging from 5.7 to 6.3 were accumulated in the myocardium. The heart simultaneously became strikingly resistant to reperfusion paradox and heat shock. In adaptation to hypoxia, only two hsp70 isoforms with pI about 5.8 were accumulated. The resistance to reperfusion paradox was not increased and the resistance to heat shock was increased only moderately. These data suggest a role of different hsp70 isoforms in the mechanism of PhASS as well as adaptive protection of the heart. [ABSTRACT FROM AUTHOR]

Studies of O supply in freshly isolated adult mammalian cells provide new insight into the factors that limit mitochondrial oxygenation in vivo. Of particular importance, mitochondria are present at high densities and often in apparent clusters, both of which contribute to local O gradients under hypoxic conditions. Current evidence indicates that the mitochondrial distribution is a component of the differentiated phenotype of adult mammalian cells and that specific motors and anchoring mechanisms are present to allow redistribution in response to developmental, physiological and pathological challenges. To compare the importance of resistance to O transfer under different conditions and at different sites along the supply path in vivo, a simple mathematical expression of relative resistance to O supply is introduced. Under various pathophysiological conditions, this resistance increases in specific regions of the pulmonary, circulatory of cellular supply path and results in O deficiency in the mitochondria. Regardless of cause, the relative resistance increases dramatically in the vicinity of mitochondrial clusters during hypoxia. [ABSTRACT FROM AUTHOR]

This study was the first comprehensive investigation of the dependence of mitochondrial enzyme response (catalytic subunits of mitochondrial complexes (MC) I-V, including NDUFV2, SDHA, Cyt b, COX1 and ATP5A) and mitochondrial ultrastructure in the rat cerebral cortex (CC) on the severity and duration of in vivo hypoxic exposures. The role of individual animal's resistance to hypoxia was also studied. The respiratory chain (RC) was shown to respond to changes in environmental [O2] as follows: (a) differential reaction of mitochondrial enzymes, which depends on the severity of the hypoxic exposure and which indicates changes in the content and catalytic properties of mitochondrial enzymes, both during acute and multiple exposures; and (b) ultrastructural changes in mitochondria, which reflect various degrees of mitochondrial energization. Within a specific range of reduced O2 concentrations, activation of the MC II is a compensatory response supporting the RC electron transport function. In this process, MC I develops new kinetic properties, and its function recovers in hypoxia by reprograming the RC substrate site. Therefore, the mitochondrial RC performs as an in vivo molecular oxygen sensor. Substantial differences between responses of rats with high and low resistance to hypoxia were determined. [ABSTRACT FROM AUTHOR]

Oligodendrocyte fusion with neurons in the brain cortex is a part of normal ontogenesis and is a possible means of neuroregeneration. Following such fusion, the oligodendrocyte nucleus undergoes neuron-specific reprogramming, resulting in the formation of binuclear neurons, which doubles the functional capability of the neuron. In this study, we tested the hypothesis that the formation of binuclear neurons is involved in long-term adaptation of the brain to intermittent hypobaric hypoxia, which is known to be neuroprotective. Rats were adapted to hypoxia in an altitude chamber at a simulated altitude of 4000 m above sea level for 14 days (30 min increasing to 4 h, daily). One micrometer sections of the left motor cortex were analyzed by light microscopy. Phases of the fusion and reprogramming process were recorded, and the number of binuclear neurons was counted for all section areas containing pyramidal neurons of layers III-V. For the control group subjected to sham hypoxia, the density of binuclear neurons was 4.49 ± 0.32 mm(2). In the hypoxia-adapted group, this density increased to 5.71 ± 0.39 mm(2) (P < 0.04). In a subgroup of rats exposed to only one hypoxia session, the number of binuclear neurons did not differ from the number observed in the control group. We suggest that the increased content of binuclear neurons may serve as a structural basis for the neuroprotective effects of the adaptation to hypoxia.