bims-hypoxi 2021-08-01 papers

bims-hypoxi

Biomed News

on Hypoxia and HIF1-alpha

Issue of 2021‒08‒01
twenty-five papers selected by
Ashish Kaul
University of Tsukuba

Overexpression of HIF-1α enhances the protective effect of mitophagy on steroid-induced osteocytes apoptosis.
The Potential Role of Hypoxia-inducible Factor-1 in the Progression and Therapy of Central Nervous System Diseases.
Analysis of the correlation of the expression level of hypoxia-inducible factor-1α with the glycosylation of oral squamous cell carcinoma.
Expression of Hypoxia-Inducible Factor1-α in Varicocele Disease: a Comprehensive Systematic Review.
Hypoxia stimulates the migration and invasion of osteosarcoma via up-regulating the NUSAP1 expression.
Mitochondrial malic enzyme 2 promotes breast cancer metastasis via stabilizing HIF-1α under hypoxia.
Histone deacetylase inhibitor induced pVHL-independent degradation of HIF-1α and hierarchical quality control of pVHL via chaperone system.
Targeting hypoxia-inducible factor 1 (HIF-1) signaling with natural products toward cancer chemotherapy.
Huperzine A combined with hyperbaric oxygen on the effect on cognitive function and serum hypoxia-inducible factor-1α Level in elderly patients with vascular dementia.
Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair.
Inhibition of the HIF-1α/BNIP3 pathway has a retinal neuroprotective effect.
Melatonin mitigates the adverse effect of hypoxia during myocardial differentiation in mouse embryonic stem cells.
Particle-bound PAHs induced glucose metabolism disorders through HIF-1 pathway.
Acacetin Protects Myocardial Cells against Hypoxia-Reoxygenation Injury through Activation of Autophagy.
Hypoxia and the integrated stress response promote pulmonary hypertension and preeclampsia: Implications in drug development.
Intermittent Hypoxia-Induced Activation of Endothelial Cells Is Mediated via Sympathetic Activation-Dependent Catecholamine Release.
Hypoxia - as a Possible Regulator of the Activity of Epicardial Mesothelial Cells After Myocardial Infarction.
Low oxygen-levels decrease adaptive immune responses and ameliorate experimental asthma in mice.
Intermittent Hypoxia Induces Greater Functional Breathing Motor Recovery as a Fixed Rather Than Varied Duration Treatment after Cervical Spinal Cord Injury in Rats.
Integrated respiratory chemoreflex-mediated regulation of cerebral blood flow in hypoxia: Implications for oxygen delivery and acute mountain sickness.
Intraoperative renal hypoxia and risk of cardiac surgery-associated acute kidney injury.
Therapeutic targeting of the hypoxic tumour microenvironment.
Body Surface Potential Mapping During Heart Ventricular Repolarization in Male Swimmers and Untrained Persons Under Hypoxic and Hypercapnic Hypoxia.
Higher strength gain after hypoxic vs normoxic resistance training despite no changes in muscle thickness and fractional protein synthetic rate.
FOXO1 mediates hypoxia-induced G0/G1 arrest in ovarian somatic granulosa cells by activating the TP53INP1-p53-CDKN1A pathway.

Environ Toxicol. 2021 Jul 26.

Overexpression of HIF-1α enhances the protective effect of mitophagy on steroid-induced osteocytes apoptosis.

Ke Xu, Chao Lu, Xiaoyu Ren, Jing Wang, Peng Xu, Yingang Zhang.

  Glucocorticoid (GC; dexamethasone, DEX) -induced osteonecrosis of the femoral head (GIOFH) is a challenging orthopedic disease, and its underlying mechanism remains not clear. This study exposed murine long bone osteocyte-Y4 (MLO-Y4) cells to DEX below normoxic or hypoxic circumstances and found that cell autophagy have been reduced. At the same time, flow cytometry analysis showed increased apoptosis, which was more pronounced in hypoxic environments. Recent research also claimed that GC induces osteoporosis after osteocyte apoptosis, and subsequent microfractures lead to ischemia and hypoxia of the femoral head, resulted in GIOFH. Presently, we found that both mitophagy-related protein hypoxia-inducible factor-1α (HIF-1α) and BNIP3 were up-regulated in the hypoxic environment, and their expression was down-regulated when exposed to DEX. Besides, we demonstrated that overexpressing HIF-1α resisted DEX-induced apoptosis in a hypoxic environment. Here, we demonstrated that overexpression of HIF-1α, through its downstream marker BNIP3, reduced the suppression of DEX on mitophagy induced by hypoxia and protected bone cells from apoptosis. Also, these findings may provide a direction of the promising application for better GIOFH treatment shortly.

Keywords:  BNIP3; HIF-1α; apoptosis; dexamethasone; glucocorticoid; mitophagy

DOI:  https://doi.org/10.1002/tox.23327
Curr Neuropharmacol. 2021 Jul 29.

The Potential Role of Hypoxia-inducible Factor-1 in the Progression and Therapy of Central Nervous System Diseases.

Hongxiu Chen, Di Ma, Feixue Yue, Yajie Qi, Manman Dou, Liuping Cui, Yingqi Xing.

  Hypoxia-inducible factor-1 (HIF-1) is a heterodimer protein composed of an oxygen-regulated functional subunit, HIF-1α, and a structural subunit, HIF-1β, belonging to the basic helix-loop-helix family. Strict regulation of HIF-1 protein stability and subsequent transcriptional activity involves various molecular interactions and is primarily controlled by post-transcriptional modifications. Hypoxia, owing to impaired cerebral blood flow, has been implicated in a range of central nervous system (CNS) diseases by exerting a deleterious effect on brain function. As a master oxygen-sensitive transcription regulator, HIF-1 is responsible for upregulating a broad spectrum of target genes involved in glucose metabolism, angiogenesis, and erythropoiesis to generate the adaptive response to avoid or minimize hypoxic brain injury. However, prolonged, severe oxygen deprivation may directly contribute to the role-conversion of HIF-1, namely. From neuroprotection to the promotion of cell death. Currently, an increasing number of studies support the fact HIF-1 is involved in a variety of CNS-related diseases, such as intracranial atherosclerosis, stroke, and neurodegenerative diseases. This review article chiefly focuses on the effect of HIF-1 on the pathogenesis and mechanism of progression of numerous CNS-related disorders by mediating the expression of various downstream genes and extensive biological functional events. It presents robust evidence that HIF-1 may represent a potential therapeutic target for CNS-related diseases.

Keywords:  angiogenesis; apoptosis; central nervous system; erythropoiesis; hypoxia-inducible factor-1; inflammation; neuroprotection

DOI:  https://doi.org/10.2174/1570159X19666210729123137
Am J Transl Res. 2021 ;13(6): 6686-6693

Analysis of the correlation of the expression level of hypoxia-inducible factor-1α with the glycosylation of oral squamous cell carcinoma.

Xiaoliang Xu, Hui Liu, Ran Wu, Weiwen Zuo, Tiantao Wang, Dong Chen.

OBJECTIVE: To investigate the correlation of the expression level of hypoxia-inducible factor-1α (HIF-1α) with the glycosylation of oral squamous cell carcinoma (OSCC).METHODS: We conducted an immunohistochemical SP method to detect the expression levels of HIF-1α and O-glycosylation-related proteins (O-linked N-acetylglucosamine [O-GlcNAc], O-GlcNAcase [OGA], and O-GlcNAc transferase [OGT]) in 30 cases of OSCC tissues that were surgically removed and confirmed by pathology in our hospital from January 2018 to July 2020. Meanwhile, the expression levels of O-GlcNAc, OGA, and OGT under the action of the HIF-1α inhibitor PX-478 were detected by Western blotting in the human OSCC cell line (Tca8113 line).
RESULTS: ① The expression of HIF-1α and O-glycosylation-related proteins in OSCC was reported at an increased level. ② The positive expression of HIF-1α was associated with the age and tumor size of OSCC patients (P < 0.05); the positive expression of O-GlcNAc and OGT was related to the tumor size of OSCC patients (P < 0.05). ③ Expression of HIF-1α, O-GlcNAc and OGT in OSCC tissues was positively correlated (φcorrelation coefficient = 0.550). ④ Under HIF-1α inhibition, a statistically significant decrease occurred in the expression levels of O-GlcNAc and OGT at a dose of 25 μM PX-478 (P < 0.05), but a statistically significant increase occurred in OGA (P < 0.05). ⑤ Under the action of PX-478, there was a statistically significant and gradual decrease in the OGT content over time (P < 0.05).
CONCLUSIONS: The expression of HIF-1α and O-glycosylation-related proteins increases in OSCC, and the expression level increases proportionally with tumor volume. Expression of HIF-1α and O-GlcNAc and OGT was positively correlated. HIF-1α inhibition by PX-478 led to decreased expression levels of O-GlcNAc and OGT but the increased expression level of OGA. PX-478 can affect Tca8113 glycosylation by reducing the expression level of OGT.

Keywords: Hypoxia-inducible factor-1α; O-glycosylation; correlation; expression level; oral squamous cell carcinoma
Reprod Sci. 2021 Jul 27.

Expression of Hypoxia-Inducible Factor1-α in Varicocele Disease: a Comprehensive Systematic Review.

Atefeh Babaei, Sajjad Moradi, Zohreh Hoseinkhani, Davood Rezazadeh, Sadat Dokaneheifard, Reza Asadpour, Gaurav Sharma, Kamran Mansouri.

  Hypoxia has been suggested as an important pathophysiological feature in varicocele disease. On the other hand, the expression of hypoxia-inducible factor 1-alpha (HIF1-α) is associated with the incidence of hypoxia. In this study, we investigated the expression of HIF1-α in varicocele disease through a comprehensive systematic review. We searched PubMed, Scopus, Web of Science, and Embase databases to identify the related studies published up to February 2021. Human studies have demonstrated an increase in the HIF-1α protein expression in the internal spermatic vein (ISV) of the varicocele testicle. HIF-1α mRNA expression in the seminal plasma was significantly higher in infertile varicocele patient compared with fertile ones. Similarly, most animal studies demonstrated a significant increase in HIF-1α gene and protein expression in varicocele testicular tissue compared with control groups. The studies illustrated that hypoxia followed by increased expression of hypoxia-inducible factor 1-alpha (HIF1-α) mRNA and protein occurs in varicocele disease. Expression of HIF-1α regulates the expression of many genes, including VEGF, p53, GLUT, Bax, and Caspase-3, that could be involved in many of the varicocele pathophysiological effects such as DNA fragmentation and apoptosis of sperm cells. Further studies with a large number of patients are necessary and can provide more definitive evidence.

Keywords:  HIF1-α; Hypoxia; Systematic review; Varicocele

DOI:  https://doi.org/10.1007/s43032-021-00696-y
Open Med (Wars). 2021 ;16(1): 1083-1089

Hypoxia stimulates the migration and invasion of osteosarcoma via up-regulating the NUSAP1 expression.

Ling Zhang, Jingtao Song, Xu Xin, Donghong Sun, Huiting Huang, Yang Chen, Tao Zhang, Yiming Zhang.

  Osteosarcoma is a highly aggressive malignant tumor, which most commonly occurs in children and adolescents. This study aims to reveal that hypoxia promotes the invasion of osteosarcoma cells by up-regulating the expression of NUSAP1. The expression of HIF-1α and NUSAP1 was significantly up-regulated in MG63 cells cultured in hypoxia for 6-36 h. Furthermore, hypoxia induced the migration and invasion of MG63 cells and regulated the level of E-cad, N-cad, Vimentin, Snail, Slug, MMP2, and MMP9 proteins. Importantly, knockdown of NUSAP1 inhibited hypoxia-induced cell migration and invasion. In the hypoxia microenvironment, the addition of HIF-1α inhibitor or the transfection of siRNA specifically targeting HIF-1α significantly reduced the expression of HIF-1α and NUSAP1 and markedly inhibited the migration and invasion of MG63 cells under the hypoxia microenvironment. In conclusion, hypoxia induced the expression of NUSAP1 in a HIF-1α-dependent manner, stimulating the migration and invasion of MG63 cells.

Keywords:  HIF-1α; NUSAP1; hypoxia; invasion; migration; osteosarcoma

DOI:  https://doi.org/10.1515/med-2020-0180
Chin J Cancer Res. 2021 Jun 30. 33(3): 308-322

Mitochondrial malic enzyme 2 promotes breast cancer metastasis via stabilizing HIF-1α under hypoxia.

Duo You, Danfeng Du, Xueke Zhao, Xinmin Li, Minfeng Ying, Xun Hu.

  Objective: α-ketoglutarate (α-KG) is the substrate to hydroxylate collagen and hypoxia-inducible factor-1α (HIF-1α), which are important for cancer metastasis. Previous studies have shown that the upregulation of collagen prolyl 4-hydroxylase in breast cancer cells stabilizes the expression of HIF-1α by depleting α-KG levels. We hypothesized that mitochondrial malic enzyme 2 (ME2) might also affect HIF-1α expression via modulating α-KG levels in breast cancer cells.Methods: We evaluated ME2 protein expression in 100 breast cancer patients using immunohistochemistry and correlated with clinicopathological indicators. The effect of ME2 knockout on cancer metastasis was evaluated using an orthotopic breast cancer model. The effect of ME2 knockout or knockdown on the levels of α-KG and HIF-1α proteins in breast cancer cell lines was determined both in vitro and in vivo.
Results: ME2 was found to be upregulated in the human breast cancerous tissues compared with the matched precancerous tissues (P<0.001). The elevated expression of ME2 was associated with a poor prognosis (P=0.019). ME2 upregulation was also related to lymph node metastasis (P=0.016), pathological staging (P=0.033), and vascular cancer embolus (P=0.014). Also, ME2 knockout significantly inhibited lung metastasisin vivo. In the tumors formed by ME2 knockout cells, the levels of α-KG were significantly increased and collagen hydroxylation level did not change significantly but HIF-1α protein expression was significantly decreased, compared to the control samples. In cell culture, cells with ME2 knockout or knockdown demonstrated significantly higher α-KG levels but significantly lower HIF-1α protein expression than control cells under hypoxia. Exogenous malate and α-KG exerted similar effect on HIF-1α in breast cancer cells to ME2 knockout or knockdown. Additionally, treatment with malate significantly decreased 4T1 breast cancer lung metastasis. ME2 expression was associated with HIF-1α levels in human breast cancer samples (P=0.008).
Conclusions: Our results provide evidence that upregulation of ME2 is associated with a poor prognosis of breast cancer patients and propose a mechanistic understanding of a link between ME2 and breast cancer metastasis.

Keywords:  Malic enzyme 2; breast cancer; hypoxia-inducible factor-1α; malate; metastasis; α-ketoglutarate

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2021.03.03
PLoS One. 2021 ;16(7): e0248019

Histone deacetylase inhibitor induced pVHL-independent degradation of HIF-1α and hierarchical quality control of pVHL via chaperone system.

Jieming Ni, Anping Ni.

The mortality rate of ovarian cancer is increasing and the role of hypoxia inducible factor-1α (HIF-1α) in tumor progression has been confirmed. von Hippel-Lindau tumor suppressor protein (pVHL) binds HIF-1α and mediates proteasome degradation of HIF-1α. Besides, histone deacetylase inhibitor (HDACi) mitigates tumor growth via targeting HIF-1α, whereas underlying mechanism still requires investigation. In this research, we exposed ovarian cancer cell lines OV-90 and SKOV-3 to escalating concentrations of HDACi LBH589. As a result, cell viability was significantly suppressed and expression of HIF-1α was remarkably reduced along with decreased levels of signal molecules, including phosphoinositide 3-kinase (PI3K) and glycogen synthase kinase 3β (GSK3β) (P = 0.000). Interestingly, pVHL was expressed in a notably declining tendency (P = 0.000). Chaperone heat shock protein-70 (HSP70) was expressed in an ascending manner, whereas expression of chaperonin TCP-1α was reduced clearly (P = 0.000). Besides, co-inhibition of pVHL plus HDAC did not contribute to a remarkable difference in HIF-1α expression as compared with single HDAC inhibition. Furthermore, both cell lines were transfected with plasmids of VHL plus VHL binding protein-1 (VBP-1). Consequently, the expression of HIF-1α as well as lactate dehydrogenase-A (LDHA) was remarkably decreased (P = 0.000). These findings indicate HDACi may repress expression of HIF-1α via inhibiting PI3K and GSK3β and promote degradation of HIF-1α via HSP70, independent of pVHL. Additionally, a sophisticated network of HDAC and chaperones may involve in pVHL quality control.

DOI: https://doi.org/10.1371/journal.pone.0248019
J Antibiot (Tokyo). 2021 Jul 30.

Targeting hypoxia-inducible factor 1 (HIF-1) signaling with natural products toward cancer chemotherapy.

Hiroaki Ikeda, Hideaki Kakeya.

Tumor cells are often exposed to hypoxia because of the lower oxygen supply deep inside the tumor tissues. However, tumor cells survive in these severe conditions by adapting to hypoxic stress through the induction of hypoxia-inducible factor 1 (HIF-1) signaling. HIF-1 activation is responsible for the expression of numerous HIF-1 target genes, which are related to cell survival, proliferation, angiogenesis, invasion, metastasis, cancer stemness, and metabolic reprogramming. Therefore, HIF-1 is expected to be a potential pharmacological target for cancer therapy. Small molecules derived from natural products (microbial origin, plant-derived, or marine organisms) have been shown to have unique chemical structures and biological activities, including HIF-1 inhibition. Several studies identified HIF-1 inhibitors from natural products. In this review, we summarize the current HIF-1 signaling inhibitors originating from natural products with a variety of modes of action, mainly focusing on microbial metabolites.

DOI: https://doi.org/10.1038/s41429-021-00451-0
Am J Transl Res. 2021 ;13(6): 6897-6904

Huperzine A combined with hyperbaric oxygen on the effect on cognitive function and serum hypoxia-inducible factor-1α Level in elderly patients with vascular dementia.

Jiajun Li, Xiangen Meng, Fang Li, Jiamin Liu, Mingyang Ma, Wangkun Chen.

OBJECTIVE: To explore the clinical effect of huperzine A combined with hyperbaric oxygen on cognitive function and serum hypoxia-inducible factor-1α (HIF-1α) level in elderly patients with vascular dementia (VD).METHODS: 120 elderly VD patients admitted to our hospital from February 2018 to March 2020 were selected and divided into two groups according to the treatment method (n = 60 each). They were administered for huperzine A and huperzine A combined with hyperbaric oxygen, respectively. The comparison of disease control rate (DCR), mini-mental state examination (MMSE) score, revised hasegawa's dementia scale (HDS-R) score and serum index were conducted.
RESULTS: At 2 and 4 weeks after treatment, the HDS-R and MMSE scores were reported to be higher in the observation group than those in the control group (P < 0.05), and the vascular endothelial growth factor (VEGF), anti-apoptotic factor (Livin), and HIF-1α showed a higher level of improvement as compared with the control group (P < 0.05). Moreover, the DCR in the observation group was much higher than that in the control group (P < 0.05).
CONCLUSION: Huperzine A combined with hyperbaric oxygen is remarkably effective in the treatment of elderly VD patients. It can improve the serum HIF-1α level and speed up the recovery of cognitive function.

Keywords: Vascular dementia; cognitive function; huperzine A; hyperbaric oxygen; hypoxia inducible factor-1α
J Exp Med. 2021 Sep 06. pii: e20200667. [Epub ahead of print]218(9):

Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair.

Matthew DeBerge, Connor Lantz, Shirley Dehn, David P Sullivan, Anja M van der Laan, Hans W M Niessen, Margaret E Flanagan, Daniel J Brat, Matthew J Feinstein, Sunjay Kaushal, Lisa D Wilsbacher, Edward B Thorp.

Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.

DOI: https://doi.org/10.1084/jem.20200667
FASEB J. 2021 08;35(8): e21829

Inhibition of the HIF-1α/BNIP3 pathway has a retinal neuroprotective effect.

Hiromitsu Kunimi, Deokho Lee, Mari Ibuki, Yusaku Katada, Kazuno Negishi, Kazuo Tsubota, Toshihide Kurihara.

  Retinal ischemia is a leading cause of irreversible blindness worldwide. Inner retinal dysfunction including loss of retinal ganglion cells is encountered in a number of retinal ischemic disorders. We previously reported administration of two different hypoxia-inducible factor (HIF) inhibitors exerted neuroprotective effects in a murine model of retinal ischemia/reperfusion (I/R) which mimics these disorders, as inner retinal degeneration could be involved in pathological HIF induction. However, this notion needs further investigation. Therefore, in this study, we attempted to use retina-specific Hif-1α conditional knockout (cKO) mice to uncover this notion more clearly under the same condition. Hif-1α cKO mice showed inner retinal neurodegeneration to a lesser extent than control mice. Hif-1α depletion in a murine 661W retinal cell line reduced cell death under pseudohypoxic and hypoxic conditions. Among hypoxia-related genes, the expression of BCL2 19 kDa protein-interacting protein 3 (Bnip3) was substantially upregulated in the inner retinal layer after retinal I/R. In this regard, we further examined Bnip3 depletion in retinal neurons in vitro and in vivo and found the similar neuroprotective effects. Our results support the notion that the HIF-1α/BNIP3 pathway may have a critical role in inner retinal neurodegeneration, which can be linked with the development of new promising therapeutics for inner retinal ischemic disorders.

Keywords:  BNIP3; HIF; inner retinal degeneration; neuroprotection; retinal ischemia

DOI:  https://doi.org/10.1096/fj.202100572R
J Vet Sci. 2021 Jul;22(4): e54

Melatonin mitigates the adverse effect of hypoxia during myocardial differentiation in mouse embryonic stem cells.

Jae Hwan Lee, Yeong Min Yoo, Bonn Lee, SunHwa Jeong, Dinh Nam Tran, Eui Bae Jeung.

  BACKGROUND: Hypoxia causes oxidative stress and affects cardiovascular function and the programming of cardiovascular disease. Melatonin promotes antioxidant enzymes such as superoxide dismutase, glutathione reductase, glutathione peroxidase, and catalase.OBJECTIVES: This study aims to investigate the correlation between melatonin and hypoxia induction in cardiomyocytes differentiation.
METHODS: Mouse embryonic stem cells (mESCs) were induced to myocardial differentiation. To demonstrate the influence of melatonin under hypoxia, mESC was pretreated with melatonin and then cultured in hypoxic condition. The cardiac beating ratio of the mESC-derived cardiomyocytes, mRNA and protein expression levels were investigated.
RESULTS: Under hypoxic condition, the mRNA expression of cardiac-lineage markers (Brachyury, Tbx20, and cTn1) and melatonin receptor (Mtnr1a) was reduced. The mRNA expression of cTn1 and the beating ratio of mESCs increased when melatonin was treated simultaneously with hypoxia, compared to when only exposed to hypoxia. Hypoxia-inducible factor (HIF)-1α protein decreased with melatonin treatment under hypoxia, and Mtnr1a mRNA expression increased. When the cells were exposed to hypoxia with melatonin treatment, the protein expressions of phospho-extracellular signal-related kinase (p-ERK) and Bcl-2-associated X proteins (Bax) decreased, however, the levels of phospho-protein kinase B (p-Akt), phosphatidylinositol 3-kinase (PI3K), B-cell lymphoma 2 (Bcl-2) proteins, and antioxidant enzymes including Cu/Zn-SOD, Mn-SOD, and catalase were increased. Competitive melatonin receptor antagonist luzindole blocked the melatonin-induced effects.
CONCLUSIONS: This study demonstrates that hypoxia inhibits cardiomyocytes differentiation and melatonin partially mitigates the adverse effect of hypoxia in myocardial differentiation by regulating apoptosis and oxidative stress through the p-AKT and PI3K pathway.

Keywords:  Apoptosis; Melatonin; cardiomyocytes; hypoxia; mESCs

DOI:  https://doi.org/10.4142/jvs.2021.22.e54
Sci Total Environ. 2021 Jul 20. pii: S0048-9697(21)04205-4. [Epub ahead of print]797 149132

Particle-bound PAHs induced glucose metabolism disorders through HIF-1 pathway.

Siqi Wu, Zhongli Chen, Li Yang, Yulin Zhang, Xiaohe Luo, Jinsong Guo, Ying Shao.

  Vehicle exhaust, as one of the most important compositions of air pollution, induced various adverse health effects, especially diabetes, on human beings. Even though monitoring and epidemiological data indicates that particle-bound polycyclic aromatic hydrocarbons (PAHs) is an inducing factor of diabetes, the specific causative mechanisms are still unclear. In the current study, the concentration of particulate matters (PMs, including PM1.0, PM2.5 and PM10.0) and PAHs was investigated at rush hour of weekday in three urban underground parking garages (UPGs). To evaluate the impacts of particle-bound PAHs on human beings, analysis of non-target metabolomics and unmetabolized PAHs were conducted for UPG and non-UPG worker urine samples. The results showed that the highest concentrations of PMs and total PAHs were found at the UPG entrance. The concentrations of unmetabolized 5-6 rings PAHs in the UPG worker urine were significantly higher than that in non-UPG worker urine samples, which induced glucose metabolism disorders through hypoxia-inducible factor 1 (HIF-1) signaling pathway. This could be a reason for particle-bound PAHs induced-diabetes on road workers, drivers and garage staff. These findings can serve as a step towards air pollution management and the pathological mechanism analysis of environmental factor induced-diseases.

Keywords:  Hypoxia-inducible factor 1 signaling pathway; Public health; Unmetabolized 5-6 rings PAHs; Vehicle exhaust

DOI:  https://doi.org/10.1016/j.scitotenv.2021.149132
J Immunol Res. 2021 ;2021 9979843

Acacetin Protects Myocardial Cells against Hypoxia-Reoxygenation Injury through Activation of Autophagy.

Chong Liu, Minmin Zhang, Shenyi Ye, Chenliang Hong, Jiaxi Chen, Ruyue Lu, Bingjie Hu, Weijun Yang, Bo Shen, Zhengyi Gu.

Ischemic heart disease is a leading cause of mortality and morbidity worldwide. We previously demonstrated that acacetin protects against myocardial ischemia reperfusion injury in rats, although the underlying mechanism remains to be elucidated. In the present study, we investigated the effects of acacetin on autophagy during hypoxia/reoxygenation (H/R) injury by exposing H9c2 myocardial cells to H/R with or without acacetin pretreatment during hypoxia. Our results show that acacetin significantly increased cell viability in a dose-dependent manner, enhanced antioxidant capacity, and suppressed protein apoptosis of rat cardiomyocytes H9c2 cells following H/R injury. In addition, lentiviral infection of H9c2 cardiomyocytes revealed that acacetin pretreatment significantly enhanced the fluorescence intensity of autophagy proteins Beclin 1, LC3-II, and p62. These results indicate that acacetin protected H9c2 cardiomyocytes from H/R damage by enhancing autophagy. Moreover, we found that application of acacetin increased activation of the PI3K/Akt signaling pathway, whereas cotreatment with the PI3K inhibitor LY294002 reversed the inhibition of apoptosis and autophagy induced by acacetin. In conclusion, acacetin mitigated H/R injury by promoting autophagy through activating the PI3K/Akt/mTOR signaling pathway.

DOI: https://doi.org/10.1155/2021/9979843
Drug Discov Today. 2021 Jul 22. pii: S1359-6446(21)00319-6. [Epub ahead of print]

Hypoxia and the integrated stress response promote pulmonary hypertension and preeclampsia: Implications in drug development.

Xiang-Qun Hu, Lubo Zhang.

  Chronic hypoxia is a common cause of pulmonary hypertension, preeclampsia, and intrauterine growth restriction (IUGR). The molecular mechanisms underlying these diseases are not completely understood. Chronic hypoxia may induce the generation of reactive oxygen species (ROS) in mitochondria, promote endoplasmic reticulum (ER) stress, and result in the integrated stress response (ISR) in the pulmonary artery and uteroplacental tissues. Numerous studies have implicated hypoxia-inducible factors (HIFs), oxidative stress, and ER stress/unfolded protein response (UPR) in the development of pulmonary hypertension, preeclampsia and IUGR. This review highlights the roles of HIFs, mitochondria-derived ROS and UPR, as well as their interplay, in the pathogenesis of pulmonary hypertension and preeclampsia, and their implications in drug development.

Keywords:  Endoplasmic reticulum; Hypoxia; Integrated stress response; Mitochondria; Preeclampsia; Pulmonary hypertension; Reactive oxygen species; Unfolded protein response; Vascular remodeling

DOI:  https://doi.org/10.1016/j.drudis.2021.07.011
Front Physiol. 2021 ;12 701995

Intermittent Hypoxia-Induced Activation of Endothelial Cells Is Mediated via Sympathetic Activation-Dependent Catecholamine Release.

Rengul Cetin-Atalay, Angelo Y Meliton, David Wu, Parker S Woods, Kaitlyn A Sun, Ying-Jie Peng, Jayasri Nanduri, Xiaoyu Su, Yun Fang, Robert B Hamanaka, Nanduri Prabhakar, Gökhan M Mutlu.

  Obstructive sleep apnea (OSA) is a common breathing disorder affecting a significant percentage of the adult population. OSA is an independent risk factor for cardiovascular disease (CVD); however, the underlying mechanisms are not completely understood. Since the severity of hypoxia correlates with some of the cardiovascular effects, intermittent hypoxia (IH) is thought to be one of the mechanisms by which OSA may cause CVD. Here, we investigated the effect of IH on endothelial cell (EC) activation, characterized by the expression of inflammatory genes, that is known to play an important role in the pathogenesis of CVD. Exposure of C57BL/6 mice to IH led to aortic EC activation, while in vitro exposure of ECs to IH failed to do so, suggesting that IH does not induce EC activation directly, but indirectly. One of the consequences of IH is activation of the sympathetic nervous system and catecholamine release. We found that exposure of mice to IH caused elevation of circulating levels of catecholamines. Inhibition of the IH-induced increase in catecholamines by pharmacologic inhibition or by adrenalectomy or carotid body ablation prevented the IH-induced EC activation in mice. Supporting a key role for catecholamines, epinephrine alone was sufficient to cause EC activation in vivo and in vitro. Together, these results suggested that IH does not directly induce EC activation, but does so indirectly via release of catecholamines. These results suggest that targeting IH-induced sympathetic nerve activity and catecholamine release may be a potential therapeutic target to attenuate the CV effects of OSA.

Keywords:  endothelial cell; epinephrine (adrenaline); inflammation; intermittent hypoxia; obstructive sleep apnea

DOI:  https://doi.org/10.3389/fphys.2021.701995
Kardiologiia. 2021 Jul 01. 61(6): 59-68

Hypoxia - as a Possible Regulator of the Activity of Epicardial Mesothelial Cells After Myocardial Infarction.

K V Dergilev, Z I Tsokolaeva, Yu D Vasilets, I B Beloglazova, B N Kulbitsky, Ye V Parfyonova.

Aim To study the effect of hypoxia on the activity of epithelial-mesenchymal transition (EMT) in epicardial cells, which provides formation of a specialized microenvironment.Material and methods This study used a model of experimental myocardial infarction created by ligation of the anterior descendent coronary artery. The activity of epicardial cells after a hypoxic exposure was studied with the hypoxia marker, pimonidazole, bromodeoxyuridine, immunofluorescent staining of heart cryosections, and in vitro mesothelial cell culture.Results The undamaged heart maintained the quiescent condition of mesothelial cells and low levels of their proliferation, extracellular matrix protein production, and of the EMT activity. Acute ischemic injury induced moderate hypoxia in the epicardial/subepicardial region. This caused a global rearrangement of this region due to the initiation of EMT in cells, changes in the cell composition, and accumulation of extracellular matrix proteins. We found that the initiation of EMT in mesothelial cells may result in the formation of smooth muscle cell precursors, fibroblasts, and a population of Sca-1+ cardiac progenitor cells, which may both participate in construction of new blood vessels and serve as a mesenchymal link for the paracrine support of microenvironmental cells. In in vitro experiments, we showed that 72‑h hypoxia facilitated activation of EMT regulatory genes, induced dissembling of intercellular contacts, cell uncoupling, and increased cell plasticity.Conclusion The epicardium of an adult heart serves as a "reparative reserve" that can be reactivated by a hypoxic exposure. This creates a basis for an approach to influence the epicardium to modulate its activity for regulating reparative processes.

DOI: https://doi.org/10.18087/cardio.2021.6.n1476
Allergy. 2021 Jul 26.

Low oxygen-levels decrease adaptive immune responses and ameliorate experimental asthma in mice.

Mathias Hochgerner, Eva M Sturm, Diana Schnoegl, Grazyna Kwapiszewska, Horst Olschewski, Leigh M Marsh.

  BACKGROUND: High altitude therapy has been used as add-on treatment for allergic asthma with considerable success. However, the underlying mechanisms remain unclear. In order to investigate the possible therapeutic effects of high altitude therapy on allergic asthma, we utilised a new in vivo mouse model.METHODS: Mice were treated with House Dust Mite (HDM) extract over four weeks and co-exposed to 10% oxygen (Hyp) or room air for the final two weeks. Experimental asthma was assessed by airway hyper-responsiveness, mucus hypersecretion and inflammatory cell recruitment. Isolated immune cells from mouse and allergic patients were stimulated in vitro with HDM under Hyp and normoxia in different co-culture systems to analyse the adaptive immune response.
RESULTS: Compared to HDM-treated mice in room air, HDM-treated Hyp-mice displayed ameliorated mucosal hypersecretion and airway hyper-responsiveness. The attenuated asthma phenotype was associated with strongly reduced activation of antigen presenting cells (APCs), effector cell infiltration and cytokine secretion. In vitro, hypoxia almost completely suppressed the HDM-induced adaptive immune response in both mouse and human immune cells. While hypoxia did not affect effector T-cell responses per-se, it interfered with antigen presenting cell (APC) differentiation and APC / effector cell cross-talk.
CONCLUSIONS: Hypoxia-induced reduction of the Th2-response to HDM ameliorates allergic asthma in vivo. Hypoxia interferes with APC / T-cell cross-talk and confers an unresponsive phenotype to APCs.

Keywords:  Allergy; Asthma; Dendritic Cells; Hypoxia; MHC-II

DOI:  https://doi.org/10.1111/all.15020
Neurotrauma Rep. 2021 ;2(1): 343-353

Intermittent Hypoxia Induces Greater Functional Breathing Motor Recovery as a Fixed Rather Than Varied Duration Treatment after Cervical Spinal Cord Injury in Rats.

Aaron L Silverstein, Warren J Alilain.

  Intermittent hypoxia treatment (IH) has been shown to improve respiratory function in both pre-clinical animal models and human subjects following spinal cord injury (SCI), historically consisting of alternating and equal intervals of hypoxic and normoxic exposure. We describe such a procedure as fixed duration IH (FD-IH) and modulation of its severity, intermittency, and post-injury time-point of application differentially affects expression of breathing motor plasticity. As such, the established IH protocol exhibits similarity to instrumental conditioning and can be described as behavioral training through reinforcement. Findings from the field of operant conditioning, a form of more advanced learning, inspire the consideration that FD-IH protocols may be improved through exchanging fixed for varied durations of hypoxia between reinforcement. Thus, we hypothesized that varied duration intermittent hypoxia treatment (VD-IH) would induce greater breathing motor recovery ipsilateral to injury than FD-IH after cervical SCI in rats. To test this hypothesis, we treated animals with VD-IH or FD-IH for 5 days at 1 week and at 8 weeks following cervical SCI, then assessed breathing motor output by diaphragm electromyography (EMG) recording, and compared between groups. At 1 week post-injury, VD-IH-exposed animals trended slightly toward exhibiting greater levels of respiratory recovery in the hemidiaphragm ipsilateral to lesion than did FD-IH-treated animals, but at 8 weeks FD-IH produced significantly greater respiratory motor output than did VD-IH. Thus, these results identify a novel sensitivity of respiratory motor function to variations in the IH protocol that may lead to development of more effective treatments following SCI.

Keywords:  breathing motor plasticity; functional recovery; intermittent hypoxia; neuroplasticity; spinal cord injury

DOI:  https://doi.org/10.1089/neur.2021.0004
Exp Physiol. 2021 Jul 27.

Integrated respiratory chemoreflex-mediated regulation of cerebral blood flow in hypoxia: Implications for oxygen delivery and acute mountain sickness.

Shigehiko Ogoh, Takuro Washio, Benjamin S Stacey, Hayato Tsukamoto, Angelo Iannetelli, Thomas S Owens, Thomas A Calverley, Lewis Fall, Shotaro Saito, Hironori Watanabe, Takeshi Hashimoto, Soichi Ando, Tadayoshi Miyamoto, Damian M Bailey.

  NEW FINDINGS: What is the central question of this study? To what extent does hypoxia-induced changes in the peripheral and central respiratory chemoreflex modulate anterior and posterior cerebral oxygen delivery and corresponding implications for acute mountain sickness susceptibility? What is the main finding and its importance? Evidence for site-specific regulation of cerebral blood flow in hypoxia that preserves oxygen delivery in the posterior but not anterior cerebral circulation, with minimal contribution from the central respiratory chemoreflex. External carotid artery vasodilation may prove an alternative hemodynamic risk factor that predisposes to acute mountain sickness.ABSTRACT: The aim of the present study was to determine to what extent hypoxia-induced changes in the peripheral and central respiratory chemoreflex modulate anterior and posterior cerebral blood flow (CBF), oxygen delivery (CDO2 ) and corresponding implications for the pathophysiology of the neurological syndrome, acute mountain sickness (AMS). Eight healthy males were randomly assigned single-blind to 7 h passive exposure to both normoxia (21% O2 ) and hypoxia (12% O2 ). The peripheral and central respiratory chemoreflex, internal carotid (ICA), external carotid (ECA), and vertebral (VA) artery blood flow (duplex ultrasound) and AMS scores (questionnaires) were measured throughout. A reduction in ICA CDO2 was observed during hypoxia despite a compensatory elevation in perfusion. In contrast, VA and ECA CDO2 were preserved that in the former was due to a more marked increase in perfusion. Hypoxia was associated with progressive activation of the peripheral respiratory chemoreflex (P <0.001) whereas the central respiratory chemoreflex remained unchanged (P >0.05). Symptom severity in participants who developed clinical AMS was positively related to ECA blood flow (LLS, r = 0.546∼0.709, P = 0.004∼0.043; ESQ-C, r = 0.587∼0.771, P = 0.001∼0.027, n = 4). Collectively, these findings highlight the site-specific regulation of CBF in hypoxia that selectively maintains CDO2 in the posterior but not anterior cerebral circulation, with minimal contribution from the central respiratory chemoreflex. Furthermore, ECA vasodilation may represent a hitherto unexplored hemodynamic risk factor implicated in the pathophysiology of AMS. This article is protected by copyright. All rights reserved.

Keywords:  acute mountain sickness; cerebral blood flow; hypoxia; oxygen delivery; respiratory chemoreflex

DOI:  https://doi.org/10.1113/EP089660
J Card Surg. 2021 Jul 29.

Intraoperative renal hypoxia and risk of cardiac surgery-associated acute kidney injury.

Jennifer P Ngo, Khin M Noe, Michael Z L Zhu, Andrew Martin, Meg Ollason, Andrew D Cochrane, Julian A Smith, Amanda G Thrift, Roger G Evans.

  BACKGROUND: Acute kidney injury (AKI) is common after cardiac surgery requiring cardiopulmonary bypass. Renal hypoxia may precede clinically detectable AKI. We compared the efficacy of two indices of renal hypoxia, (i) intraoperative urinary oxygen tension (UPO2 ) and (ii) the change in plasma erythropoietin (pEPO) during surgery, in predicting AKI. We also investigated whether the performance of these prognostic markers varies with preoperative patient characteristics.METHODS: In 82 patients undergoing on-pump cardiac surgery, blood samples were taken upon induction of anesthesia and upon entry into the intensive care unit. UPO2 was continuously measured throughout surgery.
RESULTS: Thirty-two (39%) patients developed postoperative AKI. pEPO increased during surgery, but this increase did not predict AKI, regardless of risk of postoperative mortality assessed by EuroSCORE-II. For patients categorized at higher risk by EuroSCORE-II >1.98 (median score for the cohort), UPO2 ≤10 mmHg at any time during surgery predicted a 4.04-fold excess risk of AKI (p = .04). However, UPO2 did not significantly predict AKI in lower-risk patients. UPO2 significantly predicted AKI in patients who were older, had previous myocardial infarction, diabetes, lower preoperative serum creatinine, or shorter bypass times. pEPO and UPO2 were only weakly correlated.
CONCLUSIONS: Intraoperative change in pEPO does not predict AKI. However, UPO2 shows promise, particularly in patients with higher risk of operative mortality. The disparity between these two markers of renal hypoxia may indicate that UPO2 reflects medullary oxygenation whereas pEPO reflects cortical oxygenation.

Keywords:  acute kidney injury; cardiac surgery; cardiopulmonary bypass; erythropoietin; hypoxia; urinary oxygen tension

DOI:  https://doi.org/10.1111/jocs.15859
Nat Rev Clin Oncol. 2021 Jul 29.

Therapeutic targeting of the hypoxic tumour microenvironment.

Dean C Singleton, Andrew Macann, William R Wilson.

Hypoxia is prevalent in human tumours and contributes to microenvironments that shape cancer evolution and adversely affect therapeutic outcomes. Historically, two different tumour microenvironment (TME) research communities have been discernible. One has focused on physicochemical gradients of oxygen, pH and nutrients in the tumour interstitium, motivated in part by the barrier that hypoxia poses to effective radiotherapy. The other has focused on cellular interactions involving tumour and non-tumour cells within the TME. Over the past decade, strong links have been established between these two themes, providing new insights into fundamental aspects of tumour biology and presenting new strategies for addressing the effects of hypoxia and other microenvironmental features that arise from the inefficient microvascular system in solid tumours. This Review provides a perspective on advances at the interface between these two aspects of the TME, with a focus on translational therapeutic opportunities relating to the elimination and/or exploitation of tumour hypoxia.

DOI: https://doi.org/10.1038/s41571-021-00539-4
High Alt Med Biol. 2021 Jul 26.

Body Surface Potential Mapping During Heart Ventricular Repolarization in Male Swimmers and Untrained Persons Under Hypoxic and Hypercapnic Hypoxia.

Natalya I Ivonina, Andrey A Fokin, Irina M Roshchevskaya.

  Ivonina, Natalya I., Andrey A. Fokin, and Irina M. Roshchevskaya. Body surface potential mapping during heart ventricular repolarization in male swimmers and untrained persons under hypoxic and hypercapnic hypoxia. High Alt Med Biol. 00:000-000, 2021. Background: In swimmers, as a result of prolonged breath-holding during swimming, first hypoxic hypoxia (HH) and then hypercapnic hypoxia (HCH) occurs, which may influence the electrical activity of the heart (EAH). What type of normobaric hypoxia more strongly affects the EAH-normocapnic HH or HCH? Methods: The electrical activity of swimmers' hearts (n = 7) and untrained persons (n = 10) was studied by using electrocardiography (ECG) and body surface potential mapping (BSPM) during the period of ventricular repolarization at baseline, at normocapnic HH, at HCH, and in the recovery period. Results: HH led to more significant changes in the EAH in all participants in comparison with HCH. There was no change in the amplitude of T waveECG at hypoxic and HCH, but a change in the amplitude of the minimum was noted in BSPM. The minimum in athletes changed by the end of the exposure (from -0.40 ± 0.12 mV to -0.26 ± 0.11 mV, p = 0.001); in the control, it decreased earlier (after 8 minutes of exposure to HH, the amplitude of the minimum was -0.24 ± 0.08 mV, p = 0.026). With HH, the duration of the QT interval in athletes was shortened due to the shortening of the J-Tpeak (from 250 to 188 ms, p = 0.001) and the Tpeak-Tend (from 98 to 86 ms) intervals. In controls, the decrease in the QT interval was due to the J-Tpeak shortening only (from 280 to 200 ms, p = 0.026). Conclusions: In the study of the effect of hypoxia on the EAH during ventricular repolarization, the use of the BSPM has proven to be more informative than the use of traditional ECG. When using potential mapping, more significant changes in ventricular repolarization at HH than at HCH were revealed, whereas the parameters changed less in swimmers compared with the baseline than in controls during both exposures.

Keywords:  electrocardiography; hypercapnia; hypoxia; swimmers; ventricular repolarization

DOI:  https://doi.org/10.1089/ham.2020.0103
FASEB J. 2021 Aug;35(8): e21773

Higher strength gain after hypoxic vs normoxic resistance training despite no changes in muscle thickness and fractional protein synthetic rate.

Sophie van Doorslaer de Ten Ryen, Geoffrey Warnier, Olouyomi Gnimassou, Mehdi R Belhaj, Nicolas Benoit, Damien Naslain, Matthew S Brook, Kenneth Smith, Daniel J Wilkinson, Henri Nielens, Philip J Atherton, Marc Francaux, Louise Deldicque.

  Acute hypoxia has previously been suggested to potentiate resistance training-induced hypertrophy by activating satellite cell-dependent myogenesis rather than an improvement in protein balance in human. Here, we tested this hypothesis after a 4-week hypoxic vs normoxic resistance training protocol. For that purpose, 19 physically active male subjects were recruited to perform 6 sets of 10 repetitions of a one-leg knee extension exercise at 80% 1-RM 3 times/week for 4 weeks in normoxia (FiO2 : 0.21; n = 9) or in hypoxia (FiO2 : 0.135, n = 10). Blood and skeletal muscle samples were taken before and after the training period. Muscle fractional protein synthetic rate was measured over the whole period by deuterium incorporation into the protein pool and muscle thickness by ultrasound. At the end of the training protocol, the strength gain was higher in the hypoxic vs the normoxic group despite no changes in muscle thickness and in the fractional protein synthetic rate. Only early myogenesis, as assessed by higher MyoD and Myf5 mRNA levels, appeared to be enhanced by hypoxia compared to normoxia. No effects were found on myosin heavy chain expression, markers of oxidative metabolism and lactate transport in the skeletal muscle. Though the present study failed to unravel clearly the mechanisms by which hypoxic resistance training is particularly potent to increase muscle strength, it is important message to keep in mind that this training strategy could be effective for all athletes looking at developing and optimizing their maximal muscle strength.

Keywords:  deuterium; hypoxia; muscle thickness; myogenesis; protein synthesis

DOI:  https://doi.org/10.1096/fj.202100654RR
Development. 2021 Jul 15. pii: dev199453. [Epub ahead of print]148(14):

FOXO1 mediates hypoxia-induced G0/G1 arrest in ovarian somatic granulosa cells by activating the TP53INP1-p53-CDKN1A pathway.

Chengyu Li, Zhaojun Liu, Gang Wu, Ziyu Zang, Jia-Qing Zhang, Xiaoxuan Li, Jingli Tao, Ming Shen, Honglin Liu.

  The development of ovarian follicles constitutes the foundation of female reproduction. The proliferation of granulosa cells (GCs) is a basic process required to ensure normal follicular development. However, the mechanisms involved in controlling GC cell cycle are not fully understood. Here, by performing gene expression profiling in the domestic pig (Sus scrofa), we showed that cell cycle arrest at G0/G1 phase is highly correlated with pathways associated with hypoxic stress and FOXO signalling. Specifically, the elevated proportion of GCs at the arrested G0/G1 phase was accompanied by increased nuclear translocation of FOXO1 under conditions of hypoxia both in vivo and in vitro. Furthermore, phosphorylation of 14-3-3 by the JNK kinase is required for hypoxia-mediated FOXO1 activation and the resultant G0/G1 arrest. Notably, a FOXO1 mutant without DNA-binding activity failed to induce G0/G1 arrest of GCs during hypoxia. Importantly, we identified a new target gene of FOXO1, namely TP53INP1, which contributes to suppression of the G1-S cell cycle transition in response to hypoxia. Furthermore, we demonstrated that the inhibitory effect of the FOXO1-TP53INP1 axis on the GC cell cycle is mediated through a p53-CDKN1A-dependent mechanism. These findings could provide avenues for the clinical treatment of human infertility caused by impaired follicular development.

Keywords:  Cell cycle; FOXO1-TP53INP1 signalling; G0/G1 arrest; Hypoxia; Porcine granulosa cells

DOI:  https://doi.org/10.1242/dev.199453