Adaptation to hypoxia has attracted much public interest because of its clinical significance. However, hypoxic adaptation in the body is complicated and difficult to fully explore. To explore previously unknown conserved mechanisms and key proteins involved in hypoxic adaptation in different species, we first used a yeast model for mechanistic screening. Further multi-omics analyses in multiple species including yeast, zebrafish and mice revealed that glycerophospholipid metabolism was significantly involved in hypoxic adaptation with up-regulation of lysophospholipid acyltransferase (ALE1) in yeast, a key protein for the formation of dipalmitoyl phosphatidylcholine [DPPC (16:0/16:0)], which is a saturated phosphatidylcholine. Importantly, a mammalian homolog of ALE1, lysophosphatidylcholine acyltransferase 1 (LPCAT1), enhanced DPPC levels at the cell membrane and exhibited the same protective effect in mammalian cells under hypoxic conditions. DPPC supplementation effectively attenuated growth restriction, maintained cell membrane integrity and increased the expression of epidermal growth factor receptor under hypoxic conditions, but unsaturated phosphatidylcholine did not. In agreement with these findings, DPPC treatment could also repair hypoxic injury of intestinal mucosa in mice. Taken together, ALE1/LPCAT1-mediated DPPC formation, a key pathway of glycerophospholipid metabolism, is crucial for cell viability under hypoxic conditions. Moreover, we found that ALE1 was also involved in glycolysis to maintain sufficient survival conditions for yeast. The present study offers a novel approach to understanding lipid metabolism under hypoxia and provides new insights into treating hypoxia-related diseases.

Eukaryotic cells utilize oxygen for different functions of cell organelles owing to cellular survival. A balanced oxygen homeostasis is an essential requirement to maintain the regulation of normal cellular systems. Any changes in the oxygen level are stressful and can alter the expression of different homeostasis regulatory genes and proteins. Lack of oxygen or hypoxia results in oxidative stress and formation of hypoxia inducible factors (HIF) and reactive oxygen species (ROS). Substantial cellular damages due to hypoxia have been reported to play a major role in various pathological conditions. There are different studies which demonstrated that the functions of cellular system are disrupted by hypoxia. Currently, study on cellular effects following hypoxia is an important field of research as it not only helps to decipher different signaling pathway modulation, but also helps to explore novel therapeutic strategies. On the basis of the beneficial effect of hypoxia preconditioning of cellular organelles, many therapeutic investigations are ongoing as a promising disease management strategy in near future. Hence, the present review discusses about the effects of hypoxia on different cellular organelles, mechanisms and their involvement in the progression of different diseases.

We studied the role of NO synthase in the infarct-limiting effect of short-term (SNH) and chronic continuous normobaric hypoxia (CNH). In male Wistar rats, SNH (6 sessions of 10-min hypoxia 8% O2 and 10-min reoxygenation) or CNH (12% O2 for 21 days) was modeled. In 30 min after SNH or 24 h after CNH, the rats were subjected to coronary artery occlusion (45 min) and reperfusion (2 h). The following drugs were administered to rats: non-selective NO synthase inhibitor L-NAME (10 mg/kg), inhibitor of inducible NO synthase S-methylthiourea (3 mg/kg), and inhibitor of neuronal NO-synthase 7-nitroindazole (50 mg/kg). NO donor diethylenetriamine was administered intravenously in a dose 2 mg/kg. It was found that L-NAME and S-methylthiourea abolished the infarct-limiting effect of SNH and CNH. Diethylenetriamine increased cardiac tolerance to ischemia/reperfusion. It is believed that inducible NO synthase plays an important role in the cardioprotective effect of normobaric hypoxia.

The plateau pika (Ochotona curzoniae) is native to the Qinghai-Tibet Plateau. In this study, the gene that encodes a heme-binding protein in the pulmonary surfactant (PS) of the pika is identified. The protein is a homotetrameric hemoglobin (δ4) encoded by HBD (δ). HBD is expressed in alveolar epithelial type II (ATII) and type I (ATI) cells, upregulated by hypoxia. δ4 is secreted into alveolar cavities through osmiophilic multilamellar bodies. HBD expression is downregulated by RNAi, which significantly increases hypoxia-inducible factor 1α expression in lung tissue and red blood cells and hemoglobin and blood lactate concentrations but significantly decreases arterial partial pressure of oxygen (PaO2). Our results indicate that plateau pikas physiologically show hypoxemia when HBD expression is downregulated. Therefore, specific HBD expression in the lungs helps plateau pikas to obtain oxygen under hypoxia by maintaining higher PaO2. These findings provide insights into the adaptive mechanisms of plateau pikas to withstand high-altitude environments.

The plateau zokor (Myospalax baileyi) is a native species to the Qinghai-Tibetan Plateau, inhabiting hypoxia and hypercapnia sealed subterranean burrows that pose several unique physiological challenges. In this study, we observed a novel heme-containing protein in the pulmonary surfactant (PS) of plateau zokor, identified the encoding gene of the protein, predicted its origination and structure, verified its expression in alveolar epithelial cells, and determined the protein\'s affinity to oxygen and its effect on the oxygen-dissolving capability in the PS of plateau zokors. The protein is an unusual homotetramer hemoglobin consisting of four γ-like subunits, and the subunit is encoded by a paralog gene of γ, that is γ-like. The divergence time of γ-like from γ is estimated by the molecular clock to be about 2.45 Mya. The generation of γ-like in plateau zokors might well relate to long-time stress of the high land hypoxia. Unlike γ, the γ-like has a hypoxia response element (HRE) and a lung tissue-specific enhancer in its upstream region, and it is expressed specifically in lung tissues and up-regulated by hypoxia. The protein is named as γ4-like which is expressed specifically in Alveolar epithelial type II (ATII) cells and secreted into the alveolar cavities through the osmiophilic multilamellar body (LBs). The γ4-like has a higher affinity to oxygen, and that increases significantly oxygen-dissolving capability in the PS of plateau zokors by its oxygenation function, which might be beneficial for the plateau zokors to obtain oxygen from the severe hypoxia environments by facilitating oxygen diffusion from alveoli to blood.

Tibetan sheep have lived on the Qinghai-Tibet Plateau for a long time, and after long-term natural selection, they have shown stable genetic adaptability to high-altitude environments. However, little is known about the molecular mechanisms of the long non-coding (lnc)RNAs involved in the adaptation of Tibetan sheep to hypoxia. Here, we collected lung tissues from high-altitude Tibetan sheep and low-altitude Hu sheep for RNA sequencing to study the regulatory mechanisms of the lncRNAs and mRNAs in the adaptation of Tibetan sheep to hypoxia. We identified 254 differentially expressed lncRNAs and 1,502 differentially expressed mRNAs. We found 20 pairs of cis-regulatory relationships between 15 differentially expressed lncRNAs and 14 protein-coding genes and two pairs of trans-regulatory relationships between two differentially expressed lncRNAs and two protein-coding genes. These differentially expressed mRNAs and lncRNA target genes were mainly enriched in pathways related to lipid metabolism and immune function. Interaction network analysis showed that 17 differentially expressed lncRNAs and 15 differentially expressed mRNAs had an interactive relationship. Additionally, we used six differentially expressed lncRNAs and mRNAs to verify the accuracy of the sequencing data via qRT-PCR. Our results provide a comprehensive overview of the expression patterns of the lncRNAs and mRNAs involved in the adaptation of Tibetan sheep to hypoxia, laying a foundation for further analysis of the adaptations of plateau animals.

BACKGROUND: The yak (Bos grunniens) is an important livestock species that can survive the extremely cold, harsh, and oxygen-poor conditions of the Qinghai-Tibetan Plateau and provide meat, milk, and transportation for the Tibetans living there. However, the regulatory network that drive this hypoxic adaptation remain elusive.
RESULTS: The heart tissues from LeiRoqi (LWQY) yak and their related cattle (Bos Taurus) breeds, which are two native cattle breeds located in high altitude (HAC) and low altitude (LAC) regions, respectively, were collected for RNA sequencing. A total of 178 co-differentially expressed protein-coding transcripts (co-DETs) were discovered in each of the LAC-vs-LWQY and LAC-vs-HAC comparison groups, including NFATC2, NFATC1, ENPP2, ACSL4, BAD, and many other genes whose functions were reported to be associated with the immune-system, endocrine-system, and lipid metabolism. Two and 230 lncRNA transcripts were differentially expressed in the LAC-vs-LWQY and LAC-vs-HAC comparisons\' respectively, but no lncRNA transcripts that were co-differentially expressed. Among the 58 miRNAs that were co-differentially expressed, 18 were up-regulated and 40 were down-regulated. In addition, 640 (501 up-regulated and 139 down-regulated) and 152 (152 up-regulated and one down-regulated) circRNAs showed differential expression in LAC-vs-LWQY and LAC-vs-HAC comparison groups, respectively, and 53 up-regulated co-differentially expressed circRNAs were shared. Multiple co-DETs, which are the targets of miRNAs/lncRNAs, are significantly enriched in high-altitude adaptation related processes, such as, T cell receptor signaling, VEGF signaling, and cAMP signaling. A competing endogenous RNA (ceRNA) network was constructed by integrating the competing relationships among co-differentially expressed mRNAs, miRNAs, lncRNAs and circRNAs. Furthermore, the hypoxic adaptation related ceRNA network was constructed, and the six mRNAs (MAPKAPK3, PXN, NFATC2, ATP7A, DIAPH1, and F2R), the eight miRNAs (including miR-195), and 15 circRNAs (including novel-circ-017096 and novel-circ-018073) are proposed as novel and promising candidates for regulation of hypoxic adaptation in the heart.
CONCLUSIONS: In conclusion, the data recorded in the present study provides new insights into the molecular network of high-altitude adaptation along with more detailed information of protein-coding transcripts and non-coding transcripts involved in this physiological process, the detailed mechanisms behind how these transcripts \"crosstalk\" with each other during the plateau adaptation are worthy of future research efforts.

The mammalian brain modulates its microvascular network to accommodate tissue energy demand in a process referred to as angioplasticity. There is an aging effect on cognitive function and adaptive responses to hypoxia. Hypoxia-induced angiogenesis is delayed in the aging mouse brain. Additionally, it has been shown that environmental enrichment provides an environment that fosters increased physical activity and sensory stimulation for mice as compared to standard housing; this stimulation increases neuronal activity and consequently brain oxygen demand. In this study, we investigated the effect of environmental enrichment and chronic hypoxia on cognitive performance in the young (2-4 months old) and the aged mice (17-21 months old). Mice were placed in a non-enriched or an enriched environment for 4 weeks under normoxia followed by 3 weeks of hypobaric hypoxia (~0.4 atm, equivalent to 8% normobaric oxygen at sea level). Cognitive function was evaluated using the Y-maze and the novel object recognition tests in the enriched or non-enriched mice under normoxic or hypoxic conditions. In Y-maze, a high alternation rate is indicative of sustained cognition as the animals must remember which arm was entered last, so as not to re-enter it. Novel object recognition is based on the natural tendency of rodents to investigate a novel object instead of a familiar one; a higher novel object exploration rate is indicative of better cognitive function. The young mice showed a significantly higher alternation rate (%, 63 ± 7 vs. 48 ± 10, n = 8 and 10, respectively) in the Y-Maze test as compared to the aged mice. Under normoxia, the enriched mice showed an improved alternation rate (%, 63 ± 10, n = 10) in Y-Maze test and a higher novel object exploration rate (%, 68 ± 10 vs. 52 ± 10) compared to the non-enriched controls. Similar results were observed for both young and aged mice following hypoxic exposure. Our data suggests that environmental enrichment improved the cognitive performance in the young and aged mice under normoxic and hypoxic conditions.

Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate in mice for HIF-1 and HIF-2. The objective of this study was to investigate the effect of neuronal deletion of HIF-1 and HIF-2 in hypoxic adaptation by using the neuron-specific knockout (KO) mice. The floxed control and KO mice were used. Hypoxic mice were kept in a hypobaric chamber at a pressure of 300 torr (0.4 ATM, which was equivalent to 8% oxygen under normobaric condition) for 3 weeks. The littermate, normoxic control mice were housed in the same room next to the chamber to match ambient conditions. Body weights were monitored throughout the 3-week course. Cognitive function was measured using a Y-maze test; motor functions were measured using the rotarod test and the grip strength test. The hematocrit increased significantly at the end of 3-week hypoxic exposure in both control and KO mice. In the Y-maze test, the alternation rate (indicative of sustained cognition) trended lower in the KO mice compared to the controls following hypoxia (%, 51.3 ± 13.1, n = 6 vs. 63.2 ± 12.0, n = 8). In the rotarod test, the latency (seconds) in the KO mice was significantly lower compared to the controls (50.4 ± 5.7 vs. 77.1 ± 5.0, n = 3 each before hypoxia and 66.4 ± 3.4, n = 6 vs. 98.1 ± 15.4 after hypoxia, n = 3). The grip strength in the KO mice was similar compared to the control mice before hypoxia, but the strength of KO mice trended higher after hypoxic exposure. Our data suggest that deficiency of neuronal HIF-1 and HIF-2 may result in changes in behavioral performance and other adaptative responses to hypoxia.

BACKGROUND: Tibetan chickens, a unique native breed in the Qinghai-Tibet Plateau of China, possess a suite of adaptive features that enable them to tolerate the high-altitude hypoxic environment. Increasing evidence suggests that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play roles in the hypoxic adaptation of high-altitude animals, although their exact involvement remains unclear.
RESULTS: This study aimed to elucidate the global landscape of mRNAs, lncRNAs, and miRNAs using transcriptome sequencing to construct a regulatory network of competing endogenous RNAs (ceRNAs) and thus provide insights into the hypoxic adaptation of Tibetan chicken embryos. In total, 354 differentially expressed genes (DE genes), 389 differentially expressed lncRNAs (DE lncRNAs), and 73 differentially expressed miRNAs (DE miRNAs) were identified between Tibetan chickens (TC) and control Chahua chickens (CH). GO and KEGG enrichment analysis revealed that several important DE miRNAs and their target DE lncRNAs and DE genes are involved in angiogenesis (including blood vessel development and blood circulation) and energy metabolism (including glucose, carbohydrate, and lipid metabolism). The ceRNA network was then constructed with the predicted DE gene-DE miRNA-DE lncRNA interactions, which further revealed the regulatory roles of these differentially expressed RNAs during hypoxic adaptation of Tibetan chickens.
CONCLUSIONS: Analysis of transcriptomic data revealed several key candidate ceRNAs that may play high-priority roles in the hypoxic adaptation of Tibetan chickens by regulating angiogenesis and energy metabolism. These results provide insights into the molecular mechanisms of hypoxic adaptation regulatory networks from the perspective of coding and non-coding RNAs.