Effects of simulated high altitude on blood glucose levels during exercise in individuals with Type 1 Diabetes

Context Current exercise guidelines for individuals with type 1 diabetes (T1D) do not consider the impact that high altitude may have on blood glucose levels (BGL) during exercise. Objective To investigate the effect of acute hypoxia (simulated high altitude) on BGL and carbohydrate oxidation rates during moderate intensity exercise in individuals with T1D. Methods Using a counterbalanced, repeated measures study design, 7 individuals with T1D completed two exercise sessions; normoxia and hypoxia (~4,200m simulated altitude). Participants cycled for 60min on an ergometer at 45% of their sea-level V̇O2peak, and then recovered for 60min. Before, during and after exercise, blood samples were taken to measure glucose, lactate and insulin levels. Respiratory gases were collected to measure carbohydrate oxidation rates. Results Early during exercise (<30min), there was no fall in BGL in either condition. After one hour of exercise and during recovery, BGL were significantly lower under the hypoxic condition compared to both pre-exercise levels (p=0.008) and the normoxic condition (p=0.027). Exercise in both conditions resulted in a significant rise in carbohydrate oxidation rates, which returned to baseline levels post-exercise. Before, during and after exercise, carbohydrate oxidation rates were higher under the hypoxic compared with the normoxic condition (p<0.001). Conclusions The greater decline in BGL during and after exercise performed under acute hypoxia suggests that exercise during acute exposure to high altitude may increase the risk of hypoglycemia in individuals with T1D. Future guidelines may have to consider the impact altitude has on exercise-mediated hypoglycemia.

Chest Compression Duration May Be Improved When Rescuers Breathe Supplemental Oxygen

BACKGROUND: At sea level, performing chest compressions is a demanding physical exercise. On a commercial flight at cruise altitude, the barometric pressure in the cabin is approximately equal to an altitude of 2438 m. This results in a Po2 equivalent to breathing an FIo2 of 15% at sea level, a condition under which both the duration and quality of cardiopulmonary resuscitation (CPR) may deteriorate. We hypothesized that rescuers will be able to perform fewer rounds of high-quality CPR at an FIo2 of 15%.METHODS: In this crossover simulation trial, 16 healthy volunteers participated in 2 separate sessions and performed up to 14 2-min rounds of chest compressions at an FIo2 of either 0.15 or 0.21 in randomized order. Subjects were stopped if their Spo2 was below 80%, if chest compression rate or depth was not achieved for 2/3 of compressions, or if they felt fatigued or dyspneic.RESULTS: Fewer rounds of chest compressions were successfully completed in the hypoxic than in the normoxic condition, (median [IQR] 4.5 [3,8.5]) vs. 5 [4,14]). The decline in arterial Spo2 while performing chest compressions was greater in the hypoxic condition than in the normoxic condition [mean (SD), 6.19% (4.1) vs. 2% (1.66)].DISCUSSION: Our findings suggest that the ability of rescuers to perform chest compressions in a commercial airline cabin at cruising altitude may be limited due to hypoxia. One possible solution is supplemental oxygen for rescuers who perform chest compressions for in-flight cardiac arrest.Clebone A, Reis K, Tung A, OConnor M, Ruskin KJ. Chest compression duration may be improved when rescuers breathe supplemental oxygen. Aerosp Med Hum Perform. 2020; 91(12):918922.

Co-Delivery of Chloroquine and Doxorubicin by Hypoxia-Responsive Liposomes for Enhanced Synergistic Antitumor Activity in Treating Solid Tumor

Chloroquine, initially used to treat malaria, has been discovered as a sensitizer to augment antitumor activity of other clinically used chemotherapeutics. In this work, chloroquine and doxorubicin were co-loaded into hypoxia-responsive liposomes to synergistically treat solid tumor. In vitro drug release profiles demonstrated that the liposomes were of not only good stability under normoxic condition but also high sensitivity under hypoxic condition. In vitro cell experiments demonstrated that chloroquine augmented doxorubicin cytotoxicity, and co-loaded liposomes were thus more toxic than single-loaded liposomes, especially under hypoxic condition, as a result of hypoxia-responsive drug release. These findings highlighted the potential for chloroquine and doxorubicin co-loaded hypoxia-responsive liposomes in treating solid tumors.

Endometrial Cancer Cells Promote M2-Like Macrophage Polarization by Delivering Exosomal miRNA-21 under Hypoxia Condition

Increasing evidence has demonstrated that hypoxia was an aggressive feature in endometrial cancer (EC), which is significantly associated with the tumor grade, lymph node metastasis, and tumor resistance to chemotherapy. However, the relationship between hypoxia and the immune microenvironment in EC is not very clear. Exosomes are small membrane vesicles secreted from a variety of cell types which mediate cell-to-cell communication through transported biomolecules. Here, we investigated whether exosomes can play an immunomodulatory role in intercellular communication between EC cells and macrophages. EC KEL cells were cultured under hypoxia or normoxic condition to collect exosomes. After identification, the exosomes derived from hypoxic or normoxic KEL cells were cultured with the monocyte cell line THP-1 to study the immunoregulation function of KEL cells. The results showed that the total number of exosomes produced by hypoxic KEL cells was significantly higher than that in normoxic condition. In addition, hypoxia markedly stimulated the increase in miRNA-21 expression in the exosomes. After coculture, we found that exosomal miRNA-21 could be horizontally transferred into THP-1 cells. And then, the notably enhanced mRNA expression levels of IL-10 and CD206 in THP-1 cells were observed, suggestive of M2 polarization. To further study the effect of miRNA-21-containing exosomes, we transfected miRNA-21 mimics or inhibitor into THP-1 cells. The results showed that miRNA-21 mimics promoted IL-10 and CD206 mRNA expression levels, and the miRNA-21 inhibitor significantly prevented the alteration induced by intake of hypoxic KEL cell-derived exosomes. In summary, we found that endometrial cancer KEL cells in hypoxic condition promoted monocyte THP-1 cell transformation to M2-like polarization macrophages through delivering exosomal miRNA-21, which may be a potential mechanism of the formation of the immune microenvironment in EC progression.

MO057HYPOXIA AS INDUCER OF FIBROBLAST GROWTH FACTOR 23 IN OSTEOCYTES

Background and Aims Cardiovascular disease accounts for a major proportion of deaths among chronic kidney disease (CKD) patients. Fibroblast Growth Factor 23 (FGF23), a key regulator in phosphate homeostasis and mainly produced by osteocytes, is associated with CKD progression and cardiovascular mortality. FGF23 is involved in the development of left ventricular hypertrophy that can lead to congestive heart failure. Dysfunction of the heart causes tissue malperfusion, for instance in bones, inducing the hypoxia-inducible signaling pathway. Recently, the hypoxia-inducible factor-1α (HIF-1α) has been suggested as inducer of FGF23. Therefore, we investigated whether hypoxia in osteocytes induces FGF23 production mediated by the stabilization of HIFs. Method Human sarcoma osteogenic cells (SaOS2 cell line) and primary human osteocytes were cultured and exposed to hypoxic conditions (1% and 5% O2) and normoxic condition (20% O2) for 24 hours. qPCR was performed to investigate the expression of HIFs and FGF23 mRNA in these cells. HIFs protein expression was also evaluated by Western Blot analysis. Results Our data show that HIF-1α, and not HIF-2α, protein increases in SaOS2 cells and primary osteocytes under hypoxic conditions as compared to normoxic condition. In addition, we found that FGF23 mRNA expression is elevated in SaOS2 cells in these hypoxic conditions compared to normoxic condition (Fig.1). This increase was significant in SaOS2 cells exposed to 1% O2 (p <0.05). Preliminary data of primary osteocytes show that FGF23 mRNA is not expressed in hypoxic conditions compared with normoxic conditions (Fig.1). Conclusion HIF-1α protein was increased in both SaOS2 cells and primary osteocytes exposed to 1% O2. Hypoxic conditions upregulated FGF23 mRNA in SaOS2 cells. Taken together, these findings suggest that bone malperfusion upregulates FGF23 by stabilizing HIF-1α. This could then close a vicious circle where FGF23 induces cardiovascular disease, and circulatory failure upregulates FGF23.

Dehydroeffusol inhibits hypoxia-induced epithelial–mesenchymal transition in non-small cell lung cancer cells through the inactivation of Wnt/β-catenin pathway

Dehydroeffusol (DHE) is a phenanthrene compound that possesses anti-tumor activity. However, the effect of DHE on non-small cell lung cancer (NSCLC) has not been investigated previously. Therefore, the objective of our study was to explore the role of DHE in NSCLC and the underlying mechanism. Our results showed that DHE significantly inhibited the cell viability of A549 cells in a dose- and time-dependent manner under normoxic condition. Moreover, A549 cells were more sensitive to DHE under hypoxic condition compared with the A549 cells cultured in normoxic condition. Hypoxia-induced increased migration and invasion abilities were mitigated by DHE in A549 cells. Treatment of DHE caused increased E-cadherin expression and decreased N-cadherin expression in hypoxia-induced A549 cells. DHE also suppressed hypoxia-induced increase in both protein and mRNA levels of hypoxia inducible factor-1α (HIF-1α) expression in A549 cells. Furthermore, DHE inhibited hypoxia-induced activation of Wnt/β-catenin pathway in A549 cells. The inhibitory effect of DHE on hypoxia-induced EMT was reversed by LiCl, which is an activator of Wnt/β-catenin signaling pathway. In conclusion, these findings demonstrated that DHE prevented hypoxia-induced EMT in NSCLC cells by inhibiting the activation of Wnt/β-catenin pathway, suggesting that DHE might serve as a therapeutic target for the NSCLC metastasis.

Effect of hypoxia on the pharmacokinetics and metabolism of zaleplon as a probe of CYP3A1/2 activity

The objective of this study was to compare the pharmacokinetics and metabolism of zaleplon (ZAL) in rats under hypoxic and normoxic condition and the effect of hypoxia on the protein expression and activities of the main metabolic enzyme CYP3A1/2.

Abstract 19126: Endothelial-specific Deletion of Prolyl Hydroxylase Domain Protein 2 (PHD2) Results in Severe Pulmonary Hypertension in Mice by Enhancing the HIF2alpha Signaling Pathway

Rationale: Sustained pulmonary vasoconstriction and excessive vascular remodeling are major causes of elevated pulmonary vascular resistance which leads to increased pulmonary arterial pressure in patients with pulmonary hypertension. Hypoxic-inducible factor (HIF) and its upstream regulators have been linked to the hypoxia response in vascular remodeling and the development of pulmonary hypertension. In this study, we aimed at defining whether increased HIF1α and/or HIF2α, due to endothelial cell specific deletion of prolyl hydroxylase domain protein 2 (PHD2) under normoxic condition are involved in or required for the initiation and progression of pulmonary hypertension. Methods: PHD2, HIF1α and HIF2α conditional knockout mice were created. Right ventricle systolic pressures (RVSP), right ventricular hypertrophy by RV/(LV+S) ratios, and small pulmonary artery smooth muscle layer thickness were measured. Pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs) were isolated from wild type (WT) or knockout (KO) mice, followed with cell-based assays. Results: We report here that mice with targeted deletion of PHD2 developed severe pulmonary hypertension under normoxic condition. Conditional and inducible deletion of HIF2α in endothelial cells, but not smooth muscle cells, dramatically protected mice from hypoxia-induced pulmonary hypertension. HIF2α KO mice had significantly lower RVSP, RV/(LV+S) ratios, and displayed less pulmonary vascular remodeling when exposed to hypoxia compared to their WT mice. Conclusion: This work shows that the endothelium is responsible for the development of pulmonary hypertension and it demonstrates a crucial role of PHD2/HIF signaling for hypoxic response in pulmonary hypertension. These findings unveil temporally and spatially distinct functions for HIFs in the development of pulmonary hypertension.