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Nàger M, Larsen KB, Bhujabal Z, Kalstad TB, Rössinger J, Myrmel T, Weinberger F, Birgisdottir AB. Mitophagy is induced in human engineered heart tissue after simulated ischemia and reperfusion. J Cell Sci 2025; 138:jcs263408. [PMID: 39912384 PMCID: PMC11959618 DOI: 10.1242/jcs.263408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 01/30/2025] [Indexed: 02/07/2025] Open
Abstract
The paradoxical exacerbation of cellular injury and death during reperfusion remains a problem in the treatment of myocardial infarction. Mitochondrial dysfunction plays a key role in the pathogenesis of myocardial ischemia and reperfusion injury. Dysfunctional mitochondria can be removed by mitophagy, culminating in their degradation within acidic lysosomes. Mitophagy is pivotal in maintaining cardiac homeostasis and emerges as a potential therapeutic target. Here, we employed beating human engineered heart tissue (EHT) to assess mitochondrial dysfunction and mitophagy during ischemia and reperfusion simulation. Our data indicate adverse ultrastructural changes in mitochondrial morphology and impairment of mitochondrial respiration. Furthermore, our pH-sensitive mitophagy reporter EHTs, generated by a CRISPR/Cas9 endogenous knock-in strategy, revealed induced mitophagy flux in EHTs after ischemia and reperfusion simulation. The induced flux required the activity of the protein kinase ULK1, a member of the core autophagy machinery. Our results demonstrate the applicability of the reporter EHTs for mitophagy assessment in a clinically relevant setting. Deciphering mitophagy in the human heart will facilitate development of novel therapeutic strategies.
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Affiliation(s)
- Mireia Nàger
- Division of Cardiothoracic and Respiratory Medicine, University Hospital of North Norway, 9019 Tromsø, Norway
| | - Kenneth B. Larsen
- Department of Clinical Medicine, UiT-The Arctic University of Norway, 9019 Tromsø, Norway
- Department of Medical Biology, UiT-The Arctic University of Norway, 9019 Tromsø, Norway
| | - Zambarlal Bhujabal
- Department of Clinical Medicine, UiT-The Arctic University of Norway, 9019 Tromsø, Norway
| | - Trine B. Kalstad
- Department of Clinical Medicine, UiT-The Arctic University of Norway, 9019 Tromsø, Norway
| | - Judith Rössinger
- Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, 20251 Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 20251 Hamburg, Germany
| | - Truls Myrmel
- Division of Cardiothoracic and Respiratory Medicine, University Hospital of North Norway, 9019 Tromsø, Norway
- Department of Clinical Medicine, UiT-The Arctic University of Norway, 9019 Tromsø, Norway
| | - Florian Weinberger
- Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, 20251 Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 20251 Hamburg, Germany
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
| | - Asa B. Birgisdottir
- Division of Cardiothoracic and Respiratory Medicine, University Hospital of North Norway, 9019 Tromsø, Norway
- Department of Clinical Medicine, UiT-The Arctic University of Norway, 9019 Tromsø, Norway
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Ren ZL, Lan X, Cheng JL, Zheng YX, Chen CA, Liu Y, He YH, Han JH, Wang QG, Cheng FF, Li CX, Wang XQ. Astrocyte-neuron metabolic crosstalk in ischaemic stroke. Neurochem Int 2025; 185:105954. [PMID: 39988284 DOI: 10.1016/j.neuint.2025.105954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 01/20/2025] [Accepted: 02/19/2025] [Indexed: 02/25/2025]
Abstract
Ischemic stroke (IS) is caused by temporary or permanent obstruction of the brain's blood supply. The disruption in glucose and oxygen delivery that results from the drop in blood flow impairs energy metabolism. A significant pathological feature of IS impaired energy metabolism. Astrocytes, as the most prevalent glial cells in the brain, sit in between neurons and the microvasculature. By taking advantage of their special anatomical location, they play a crucial part in regulating cerebral blood flow (CBF) and metabolism. Astrocytes can withstand hypoxic and ischemic conditions better than neurons do. Additionally, astrocytes are essential for maintaining the metabolism and function of neurons. Therefore, the "neurocentric" perspective on neuroenergetics is gradually giving way to a more comprehensive perspective that takes into account metabolic interaction between astrocytes and neurons. Since neurons in the core region of the infarct are unable to undergo oxidative metabolism, the focus of attention in this review is on neurons in the peri-infarct region. We'll go over the metabolic crosstalk of astrocytes and neurons during the acute phase of IS using three different types of metabolites: lactate, fatty acids (FAs), and amino acids, as well as the mitochondria. After IS, astrocytes in the peri-infarct zone can produce lactate, ketone bodies (KBs), glutamine (Gln), and l-serine, shuttling these metabolites, along with mitochondria, to neurons. This process helps maintain the energy requirements of neurons, preserves their redox state, and regulates neurotransmitter receptor activity.
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Affiliation(s)
- Zi-Lin Ren
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xin Lan
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Jia-Lin Cheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yu-Xiao Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Cong-Ai Chen
- Beijing Chinese Medicine Hospital, Capital Medical University, Beijing, 100010, China
| | - Ying Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yan-Hui He
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Jin-Hua Han
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Qing-Guo Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Fa-Feng Cheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Chang-Xiang Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Xue-Qian Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
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Jiang M, Huang J, Guo X, Fu W, Peng L, Wang Y, Liu W, Liu J, Zhou L, Xiao Y. HIF-3α/PPAR-γ Regulates Hypoxia Tolerance by Altering Glycolysis and Lipid Synthesis in Blunt Snout Bream ( Megalobrama amblycephala). Int J Mol Sci 2025; 26:2613. [PMID: 40141255 PMCID: PMC11942064 DOI: 10.3390/ijms26062613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/04/2025] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
Hypoxic stress causes cell damage and serious diseases in organisms, especially in aquatic animals. It is important to elucidate the changes in metabolic function caused by hypoxia and the mechanisms underlying these changes. This study focuses on the low oxygen tolerance feature of a new blunt snout bream strain (GBSBF1). Our data show that GBSBF1 has a different lipid and carbohydrate metabolism pattern than wild-type bream, with altering glycolysis and lipid synthesis. In GBSBF1, the expression levels of phd2 and vhl genes are significantly decreased, while the activation of HIF-3α protein is observed to have risen significantly. The results indicate that enhanced HIF-3α can positively regulate gpd1ab and gpam through PPAR-γ, which increases glucose metabolism and reduces lipolysis of GBSBF1. This research is beneficial for creating new aquaculture strains with low oxygen tolerance traits.
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Affiliation(s)
- Minggui Jiang
- College of Life Sciences, Hunan Normal University, Changsha 410081, China; (M.J.); (J.H.); (X.G.); (W.F.); (L.P.); (W.L.); (J.L.)
- Engineering Research Center of Polyploid Fish Reproduction and Breeding of the State Education Ministry, Changsha 410081, China
| | - Jing Huang
- College of Life Sciences, Hunan Normal University, Changsha 410081, China; (M.J.); (J.H.); (X.G.); (W.F.); (L.P.); (W.L.); (J.L.)
| | - Xing Guo
- College of Life Sciences, Hunan Normal University, Changsha 410081, China; (M.J.); (J.H.); (X.G.); (W.F.); (L.P.); (W.L.); (J.L.)
| | - Wen Fu
- College of Life Sciences, Hunan Normal University, Changsha 410081, China; (M.J.); (J.H.); (X.G.); (W.F.); (L.P.); (W.L.); (J.L.)
- Engineering Research Center of Polyploid Fish Reproduction and Breeding of the State Education Ministry, Changsha 410081, China
| | - Liangyue Peng
- College of Life Sciences, Hunan Normal University, Changsha 410081, China; (M.J.); (J.H.); (X.G.); (W.F.); (L.P.); (W.L.); (J.L.)
- Engineering Research Center of Polyploid Fish Reproduction and Breeding of the State Education Ministry, Changsha 410081, China
| | - Yang Wang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; (Y.W.); (L.Z.)
| | - Wenbin Liu
- College of Life Sciences, Hunan Normal University, Changsha 410081, China; (M.J.); (J.H.); (X.G.); (W.F.); (L.P.); (W.L.); (J.L.)
- Engineering Research Center of Polyploid Fish Reproduction and Breeding of the State Education Ministry, Changsha 410081, China
| | - Jinhui Liu
- College of Life Sciences, Hunan Normal University, Changsha 410081, China; (M.J.); (J.H.); (X.G.); (W.F.); (L.P.); (W.L.); (J.L.)
- Engineering Research Center of Polyploid Fish Reproduction and Breeding of the State Education Ministry, Changsha 410081, China
| | - Li Zhou
- State Key Laboratory of Freshwater Ecology and Biotechnology, Hubei Hongshan Laboratory, The Innovation Academy of Seed Design, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; (Y.W.); (L.Z.)
| | - Yamei Xiao
- College of Life Sciences, Hunan Normal University, Changsha 410081, China; (M.J.); (J.H.); (X.G.); (W.F.); (L.P.); (W.L.); (J.L.)
- Engineering Research Center of Polyploid Fish Reproduction and Breeding of the State Education Ministry, Changsha 410081, China
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McDermott A, Tavassoli A. Hypoxia-inducible transcription factors: architects of tumorigenesis and targets for anticancer drug discovery. Transcription 2025; 16:86-117. [PMID: 39470609 PMCID: PMC11970764 DOI: 10.1080/21541264.2024.2417475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 10/10/2024] [Accepted: 10/12/2024] [Indexed: 10/30/2024] Open
Abstract
Hypoxia-inducible factors (HIFs) play a pivotal role as master regulators of tumor survival and growth, controlling a wide array of cellular processes in response to hypoxic stress. Clinical data correlates upregulated HIF-1 and HIF-2 levels with an aggressive tumor phenotype and poor patient outcome. Despite extensive validation as a target in cancer, pharmaceutical targeting of HIFs, particularly the interaction between α and βsubunits that forms the active transcription factor, has proved challenging. Nonetheless, many indirect inhibitors of HIFs have been identified, targeting diverse parts of this pathway. Significant strides have also been made in the development of direct inhibitors of HIF-2, exemplified by the FDA approval of Belzutifan for the treatment of metastatic clear cell renal carcinoma. While efforts to target HIF-1 using various therapeutic modalities have shown promise, no clinical candidates have yet emerged. This review aims to provide insights into the intricate and extensive role played by HIFs in cancer, and the ongoing efforts to develop therapeutic agents against this target.
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Affiliation(s)
| | - Ali Tavassoli
- School of Chemistry, University of Southampton, Southampton, UK
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Li Y, Chen B, Wu S, Zhong Y, Zhang Y, Wu J. Hypoxia inducible factor-1α promotes non-small cell lung cancer progression by activating leptin receptor transcription. Cancer Biomark 2025; 42:18758592251330479. [PMID: 40179486 DOI: 10.1177/18758592251330479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
BackgroundHypoxia and leptin receptors (also called obesity receptors, OB-R) are evident markers of tumor progression and have been demonstrated to be essential oncogenes in a variety of cancers. However, the specific role of OB-R in lung cancer, especially non-small cell lung cancer (NSCLC) and its correlation with HIF1α remains unclear. Present study aims to explore the potential functions and mechanisms of OB-R in NSCLC.MethodsThe RNA levels of HIF1α and OB-R in NSCLC cells were detected by quantitative real-time PCR (qRT-PCR) and western blotting. The HIF-1α, OB-R, and Ki67 levels in tumor tissues were detected by immunohistochemistry. CCK8 assays for proliferation, transwell assays for migration were performed to determine the role of HIF-1α and OB-R in vitro, while subcutaneous tumors in nude mice were used for in vivo functional studies. Mechanically, chromatin immunoprecipitation and luciferase reporter gene analyses were executed to determine the relationship between HIF-1α and OB-R.ResultsqRT-PCR and western blotting revealed that HIF-1α and OB-R was highly expressed in NSCLC cells. Moreover, hypoxia up-regulated OB-R expression in NSCLC cells via HIF-1α. Hence, down-regulating HIF-1α significantly reduced the mRNA level of OB-R. In addition, HIF-1α silencing reduced cell proliferation and migration in vitro. Xenograft mouse models indicated that decrease of HIF-1α led to tumor growth by decreasing OB-R in vivo. Mechanically, we unveiled that HIF-1α bound to the promoter region (-831 to -824) and positively regulated OB-R expression by activating its transcription. Additionally, by immunohistochemical staining, we observed that high levels of HIF-1α and OB-R were positively associated with tumor size and lymph node metastasis.ConclusionIn conclusion, our present results demonstrated that HIF-1α positively regulates the expression of OB-R, which acts as an oncogene in NSCLC. HIF-1α and OB-R are potential therapeutic targets in NSCLC.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Animals
- Receptors, Leptin/genetics
- Receptors, Leptin/metabolism
- Lung Neoplasms/pathology
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Mice
- Cell Proliferation
- Gene Expression Regulation, Neoplastic
- Disease Progression
- Cell Line, Tumor
- Female
- Male
- Mice, Nude
- Cell Movement
- Middle Aged
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Affiliation(s)
- Yan Li
- Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Bo Chen
- Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuangshuang Wu
- Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yijue Zhong
- Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuxing Zhang
- Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jianqing Wu
- Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Gong X, Yang SY, Wang ZY, Tang M. The role of hypoxic microenvironment in autoimmune diseases. Front Immunol 2024; 15:1435306. [PMID: 39575238 PMCID: PMC11578973 DOI: 10.3389/fimmu.2024.1435306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 10/21/2024] [Indexed: 11/24/2024] Open
Abstract
The hypoxic microenvironment, characterized by significantly reduced oxygen levels within tissues, has emerged as a critical factor in the pathogenesis and progression of various autoimmune diseases (AIDs). Central to this process is the hypoxia-inducible factor-1 (HIF-1), which orchestrates a wide array of cellular responses under low oxygen conditions. This review delves into the multifaceted roles of the hypoxic microenvironment in modulating immune cell function, particularly highlighting its impact on immune activation, metabolic reprogramming, and angiogenesis. Specific focus is given to the mechanisms by which hypoxia contributes to the development and exacerbation of diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and dermatomyositis (DM). In these conditions, the hypoxic microenvironment not only disrupts immune tolerance but also enhances inflammatory responses and promotes tissue damage. The review also discusses emerging therapeutic strategies aimed at targeting the hypoxic pathways, including the application of HIF-1α inhibitors, mTOR inhibitors, and other modulators of the hypoxic response. By providing a comprehensive overview of the interplay between hypoxia and immune dysfunction in AIDs, this review offers new perspectives on the underlying mechanisms of these diseases and highlights potential avenues for therapeutic intervention.
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Affiliation(s)
- Xun Gong
- Department of Rheumatology and Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Su-Yin Yang
- Department of Rheumatology and Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhen-Yu Wang
- Department of Rheumatology and Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Min Tang
- School of Life Sciences, Jiangsu University, Zhenjiang, China
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Schönberger T, Jakobs M, Friedel AL, Hörbelt-Grünheidt T, Tebbe B, Witzke O, Schedlowski M, Fandrey J. Exposure to normobaric hypoxia shapes the acute inflammatory response in human whole blood cells in vivo. Pflugers Arch 2024; 476:1369-1381. [PMID: 38714572 PMCID: PMC11310243 DOI: 10.1007/s00424-024-02969-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/10/2024]
Abstract
Cells of the immune defence, especially leukocytes, often have to perform their function in tissue areas that are characterized by oxygen deficiency, so-called hypoxia. Physiological hypoxia significantly affects leukocyte function and controls the innate and adaptive immune response mainly through transcriptional gene regulation via the hypoxia-inducible factors (HIFs). Multiple pathogens including components of bacteria, such as lipopolysaccharides (LPS) trigger the activation of leukocytes. HIF pathway activation enables immune cells to adapt to both hypoxic environments in physiological and inflammatory settings and modulates immune cell responses through metabolism changes and crosstalk with other immune-relevant signalling pathways. To study the mutual influence of both processes in vivo, we used a human endotoxemia model, challenging participants with an intravenous LPS injection post or prior to a 4-h stay in a hypoxic chamber with normobaric hypoxia of 10.5% oxygen. We analysed changes in gene expression in whole blood cells and determined inflammatory markers to unveil the crosstalk between both processes. Our investigations showed differentially altered gene expression patterns of HIF and target genes upon in vivo treatment with LPS and hypoxia. Further, we found evidence for effects of hypoxic priming upon inflammation in combination with immunomodulatory effects in whole blood cells in vivo. Our work elucidates the complex interplay of hypoxic and inflammatory HIF regulation in human immune cells and offers new perspectives for further clinical research.
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Affiliation(s)
- Tina Schönberger
- Institute of Physiology, University Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.
| | - Marie Jakobs
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, 45147, Essen, Germany
| | - Anna-Lena Friedel
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, 45147, Essen, Germany
| | - Tina Hörbelt-Grünheidt
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, 45147, Essen, Germany
| | - Bastian Tebbe
- Institute of Physiology, University Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany
- Department of Nephrology, University Hospital Essen, 45147, Essen, Germany
| | - Oliver Witzke
- Department of Infectious Diseases, West German Centre of Infectious Diseases, University Hospital Essen, 45147, Essen, Germany
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, 45147, Essen, Germany
- Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Joachim Fandrey
- Institute of Physiology, University Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany
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Alanova P, Alan L, Opletalova B, Bohuslavova R, Abaffy P, Matejkova K, Holzerova K, Benak D, Kaludercic N, Menabo R, Di Lisa F, Ostadal B, Kolar F, Pavlinkova G. HIF-1α limits myocardial infarction by promoting mitophagy in mouse hearts adapted to chronic hypoxia. Acta Physiol (Oxf) 2024; 240:e14202. [PMID: 39016532 DOI: 10.1111/apha.14202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 05/24/2024] [Accepted: 07/04/2024] [Indexed: 07/18/2024]
Abstract
AIM The transcriptional factor HIF-1α is recognized for its contribution to cardioprotection against acute ischemia/reperfusion injury. Adaptation to chronic hypoxia (CH) is known to stabilize HIF-1α and increase myocardial ischemic tolerance. However, the precise role of HIF-1α in mediating the protective effect remains incompletely understood. METHODS Male wild-type (WT) mice and mice with partial Hif1a deficiency (hif1a +/-) were exposed to CH for 4 weeks, while their respective controls were kept under normoxic conditions. Subsequently, their isolated perfused hearts were subjected to ischemia/reperfusion to determine infarct size, while RNA-sequencing of isolated cardiomyocytes was performed. Mitochondrial respiration was measured to evaluate mitochondrial function, and western blots were performed to assess mitophagy. RESULTS We demonstrated enhanced ischemic tolerance in WT mice induced by adaptation to CH compared with their normoxic controls and chronically hypoxic hif1a +/- mice. Through cardiomyocyte bulk mRNA sequencing analysis, we unveiled significant reprogramming of cardiomyocytes induced by CH emphasizing mitochondrial processes. CH reduced mitochondrial content and respiration and altered mitochondrial ultrastructure. Notably, the reduced mitochondrial content correlated with enhanced autophagosome formation exclusively in chronically hypoxic WT mice, supported by an increase in the LC3-II/LC3-I ratio, expression of PINK1, and degradation of SQSTM1/p62. Furthermore, pretreatment with the mitochondrial division inhibitor (mdivi-1) abolished the infarct size-limiting effect of CH in WT mice, highlighting the key role of mitophagy in CH-induced cardioprotection. CONCLUSION These findings provide new insights into the contribution of HIF-1α to cardiomyocyte survival during acute ischemia/reperfusion injury by activating the selective autophagy pathway.
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Affiliation(s)
- Petra Alanova
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Lukas Alan
- Laboratory of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
- Department of Biology, University of Padova, Padova, Italy
| | - Barbora Opletalova
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
- Faculty of Science, Charles University, Prague, Czech Republic
| | - Romana Bohuslavova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czechia
| | - Pavel Abaffy
- Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czechia
| | - Katerina Matejkova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czechia
| | - Kristyna Holzerova
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Daniel Benak
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Nina Kaludercic
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- Neuroscience Institute, National Research Council of Italy (CNR), Padova, Italy
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza (IRP), Padova, Italy
| | - Roberta Menabo
- Neuroscience Institute, National Research Council of Italy (CNR), Padova, Italy
| | - Fabio Di Lisa
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- Neuroscience Institute, National Research Council of Italy (CNR), Padova, Italy
| | - Bohuslav Ostadal
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Frantisek Kolar
- Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Gabriela Pavlinkova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czechia
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9
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Moreira DC, Hermes-Lima M. Dynamics of Redox Metabolism during Complete Metamorphosis of Insects: Insights from the Sunflower Caterpillar Chlosyne lacinia (Lepidoptera). Antioxidants (Basel) 2024; 13:959. [PMID: 39199204 PMCID: PMC11351957 DOI: 10.3390/antiox13080959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/01/2024] [Accepted: 08/06/2024] [Indexed: 09/01/2024] Open
Abstract
Complete insect metamorphosis requires substantial metabolic and physiological adjustments. Although oxidative stress has been implicated in metamorphosis, details on redox metabolism during larva-to-pupa and pupa-to-adult remain scarce. This study explores redox metabolism during metamorphosis of a lepidopteran (Chlosyne lacinia), focusing on core metabolism, antioxidant systems and oxidative stress. The larva-to-pupa transition was characterized by increased lactate dehydrogenase and glutathione peroxidase (GPX) activities, coupled with depletion of reduced glutathione (GSH), high disulfide-to-total-glutathione ratio (GSSG/tGSH), and increased lipid peroxidation. As metamorphosis progressed, metabolic enzyme activities, citrate synthase and glucose 6-phosphate dehydrogenase increased, indicating heightened oxidative metabolism associated with adult development. Concurrently, GSH and GPX levels returned to larval levels and GSSG/tGSH reached its most reduced state right before adult emergence. Adult emergence was marked by a further increase in oxidative metabolism, accompanied by redox imbalance and enhanced antioxidant mechanisms. These findings highlight a fluctuation in redox balance throughout metamorphosis, with periods of oxidative eustress followed by compensatory antioxidant responses. This study is the first to identify concurrent changes in metabolism, antioxidants, redox balance and oxidative stress throughout metamorphosis. Our findings extend knowledge on redox metabolism adjustments and highlight redox adaptations and oxidative stress as natural components of complete insect metamorphosis.
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Affiliation(s)
- Daniel C. Moreira
- Research Center in Morphology and Applied Immunology, Faculty of Medicine, University of Brasilia, Brasilia 70910-900, Brazil
- Cell Biology Department, Biological Sciences Institute, University of Brasilia, Brasilia 70910-900, Brazil;
| | - Marcelo Hermes-Lima
- Cell Biology Department, Biological Sciences Institute, University of Brasilia, Brasilia 70910-900, Brazil;
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10
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Prange-Barczynska M, Jones HA, Sugimoto Y, Cheng X, Lima JD, Ratnayaka I, Douglas G, Buckler KJ, Ratcliffe PJ, Keeley TP, Bishop T. Hif-2α programs oxygen chemosensitivity in chromaffin cells. J Clin Invest 2024; 134:e174661. [PMID: 39106106 PMCID: PMC11405041 DOI: 10.1172/jci174661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 07/29/2024] [Indexed: 08/09/2024] Open
Abstract
The study of transcription factors that determine specialized neuronal functions has provided invaluable insights into the physiology of the nervous system. Peripheral chemoreceptors are neurone-like electrophysiologically excitable cells that link the oxygen concentration of arterial blood to the neuronal control of breathing. In the adult, this oxygen chemosensitivity is exemplified by type I cells of the carotid body, and recent work has revealed one isoform of the hypoxia-inducible transcription factor (HIF), HIF-2α, as having a nonredundant role in the development and function of that organ. Here, we show that activation of HIF-2α, including isolated overexpression of HIF-2α but not HIF-1α, is sufficient to induce oxygen chemosensitivity in adult adrenal medulla. This phenotypic change in the adrenal medulla was associated with retention of extra-adrenal paraganglioma-like tissues resembling the fetal organ of Zuckerkandl, which also manifests oxygen chemosensitivity. Acquisition of chemosensitivity was associated with changes in the adrenal medullary expression of gene classes that are ordinarily characteristic of the carotid body, including G protein regulators and atypical subunits of mitochondrial cytochrome oxidase. Overall, the findings suggest that, at least in certain tissues, HIF-2α acts as a phenotypic driver for cells that display oxygen chemosensitivity, thus linking 2 major oxygen-sensing systems.
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Affiliation(s)
- Maria Prange-Barczynska
- Target Discovery Institute and
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom
| | - Holly A. Jones
- Target Discovery Institute and
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom
| | - Yoichiro Sugimoto
- The Francis Crick Institute, London, United Kingdom
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Xiaotong Cheng
- Target Discovery Institute and
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom
| | - Joanna D.C.C. Lima
- Target Discovery Institute and
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom
| | - Indrika Ratnayaka
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom
| | - Gillian Douglas
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Keith J. Buckler
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom
| | - Peter J. Ratcliffe
- Target Discovery Institute and
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom
- The Francis Crick Institute, London, United Kingdom
| | - Thomas P. Keeley
- Target Discovery Institute and
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom
| | - Tammie Bishop
- Target Discovery Institute and
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom
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11
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Xie T, Yao L, Li X. Advance in Iron Metabolism, Oxidative Stress and Cellular Dysfunction in Experimental and Human Kidney Diseases. Antioxidants (Basel) 2024; 13:659. [PMID: 38929098 PMCID: PMC11200795 DOI: 10.3390/antiox13060659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 05/22/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
Kidney diseases pose a significant global health issue, frequently resulting in the gradual decline of renal function and eventually leading to end-stage renal failure. Abnormal iron metabolism and oxidative stress-mediated cellular dysfunction facilitates the advancement of kidney diseases. Iron homeostasis is strictly regulated in the body, and disturbance in this regulatory system results in abnormal iron accumulation or deficiency, both of which are associated with the pathogenesis of kidney diseases. Iron overload promotes the production of reactive oxygen species (ROS) through the Fenton reaction, resulting in oxidative damage to cellular molecules and impaired cellular function. Increased oxidative stress can also influence iron metabolism through upregulation of iron regulatory proteins and altering the expression and activity of key iron transport and storage proteins. This creates a harmful cycle in which abnormal iron metabolism and oxidative stress perpetuate each other, ultimately contributing to the advancement of kidney diseases. The crosstalk of iron metabolism and oxidative stress involves multiple signaling pathways, such as hypoxia-inducible factor (HIF) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. This review delves into the functions and mechanisms of iron metabolism and oxidative stress, along with the intricate relationship between these two factors in the context of kidney diseases. Understanding the underlying mechanisms should help to identify potential therapeutic targets and develop novel and effective therapeutic strategies to combat the burden of kidney diseases.
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Affiliation(s)
- Tiancheng Xie
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Li Yao
- Department of Nephrology, The First Hospital of China Medical University, Shenyang 110001, China;
| | - Xiaogang Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
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12
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Ubaid S, Kashif M, Laiq Y, Nayak AK, Kumar V, Singh V. Targeting HIF-1α in sickle cell disease and cancer: unraveling therapeutic opportunities and risks. Expert Opin Ther Targets 2024; 28:357-373. [PMID: 38861226 DOI: 10.1080/14728222.2024.2367640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 06/10/2024] [Indexed: 06/12/2024]
Abstract
INTRODUCTION HIF-1α, a key player in medical science, holds immense significance in therapeutic approaches. This review delves into its complex dynamics, emphasizing the delicate balance required for its modulation. HIF-1α stands as a cornerstone in medical research, its role extending to therapeutic strategies. This review explores the intricate interplay surrounding HIF-1α, highlighting its critical involvement and the necessity for cautious modulation. AREAS COVERED In sickle cell disease (SCD), HIF-1α's potential to augment fetal hemoglobin (HbF) production and mitigate symptoms is underscored. Furthermore, its role in cancer is examined, particularly its influence on survival in hypoxic tumor microenvironments, angiogenesis, and metastasis. The discussion extends to the intricate relationship between HIF-1α modulation and cancer risks in SCD patients, emphasizing the importance of balancing therapeutic benefits and potential hazards. EXPERT OPINION Managing HIF-1α modulation in SCD patients requires a nuanced approach, considering therapeutic potential alongside associated risks, especially in exacerbating cancer risks. An evolutionary perspective adds depth, highlighting adaptations in populations adapted to low-oxygen environments and aligning cancer cell metabolism with primitive cells. The role of HIF-1α as a therapeutic target is discussed within the context of complex cancer biology and metabolism, acknowledging varied responses across diverse cancers influenced by intricate evolutionary adaptations.
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Affiliation(s)
- Saba Ubaid
- Department of Biochemistry, King George's Medical University, Lucknow, India
| | - Mohammad Kashif
- Infectious Diseases Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India
| | - Yusra Laiq
- Department of Biotechnology, Era University, Lucknow, India
| | | | - Vipin Kumar
- Infectious Diseases Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India
| | - Vivek Singh
- Department of Biochemistry, King George's Medical University, Lucknow, India
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13
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Ma S, Ming Y, Wu J, Cui G. Cellular metabolism regulates the differentiation and function of T-cell subsets. Cell Mol Immunol 2024; 21:419-435. [PMID: 38565887 PMCID: PMC11061161 DOI: 10.1038/s41423-024-01148-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 02/23/2024] [Indexed: 04/04/2024] Open
Abstract
T cells are an important component of adaptive immunity and protect the host from infectious diseases and cancers. However, uncontrolled T cell immunity may cause autoimmune disorders. In both situations, antigen-specific T cells undergo clonal expansion upon the engagement and activation of antigens. Cellular metabolism is reprogrammed to meet the increase in bioenergetic and biosynthetic demands associated with effector T cell expansion. Metabolites not only serve as building blocks or energy sources to fuel cell growth and expansion but also regulate a broad spectrum of cellular signals that instruct the differentiation of multiple T cell subsets. The realm of immunometabolism research is undergoing swift advancements. Encapsulating all the recent progress within this concise review in not possible. Instead, our objective is to provide a succinct introduction to this swiftly progressing research, concentrating on the metabolic intricacies of three pivotal nutrient classes-lipids, glucose, and amino acids-in T cells. We shed light on recent investigations elucidating the roles of these three groups of metabolites in mediating the metabolic and immune functions of T cells. Moreover, we delve into the prospect of "editing" metabolic pathways within T cells using pharmacological or genetic approaches, with the aim of synergizing this approach with existing immunotherapies and enhancing the efficacy of antitumor and antiinfection immune responses.
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Affiliation(s)
- Sicong Ma
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230601, China
| | - Yanan Ming
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230601, China
| | - Jingxia Wu
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230601, China.
| | - Guoliang Cui
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230601, China.
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14
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Warnhoff K, Bhattacharya S, Snoozy J, Breen PC, Ruvkun G. Hypoxia-inducible factor induces cysteine dioxygenase and promotes cysteine homeostasis in Caenorhabditis elegans. eLife 2024; 12:RP89173. [PMID: 38349720 PMCID: PMC10942545 DOI: 10.7554/elife.89173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2024] Open
Abstract
Dedicated genetic pathways regulate cysteine homeostasis. For example, high levels of cysteine activate cysteine dioxygenase, a key enzyme in cysteine catabolism in most animal and many fungal species. The mechanism by which cysteine dioxygenase is regulated is largely unknown. In an unbiased genetic screen for mutations that activate cysteine dioxygenase (cdo-1) in the nematode Caenorhabditis elegans, we isolated loss-of-function mutations in rhy-1 and egl-9, which encode proteins that negatively regulate the stability or activity of the oxygen-sensing hypoxia inducible transcription factor (hif-1). EGL-9 and HIF-1 are core members of the conserved eukaryotic hypoxia response. However, we demonstrate that the mechanism of HIF-1-mediated induction of cdo-1 is largely independent of EGL-9 prolyl hydroxylase activity and the von Hippel-Lindau E3 ubiquitin ligase, the classical hypoxia signaling pathway components. We demonstrate that C. elegans cdo-1 is transcriptionally activated by high levels of cysteine and hif-1. hif-1-dependent activation of cdo-1 occurs downstream of an H2S-sensing pathway that includes rhy-1, cysl-1, and egl-9. cdo-1 transcription is primarily activated in the hypodermis where it is also sufficient to drive sulfur amino acid metabolism. Thus, the regulation of cdo-1 by hif-1 reveals a negative feedback loop that maintains cysteine homeostasis. High levels of cysteine stimulate the production of an H2S signal. H2S then acts through the rhy-1/cysl-1/egl-9 signaling pathway to increase HIF-1-mediated transcription of cdo-1, promoting degradation of cysteine via CDO-1.
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Affiliation(s)
- Kurt Warnhoff
- Pediatrics and Rare Diseases Group, Sanford ResearchSioux FallsUnited States
- Department of Pediatrics, Sanford School of Medicine, University of South DakotaSioux FallsUnited States
| | | | - Jennifer Snoozy
- Pediatrics and Rare Diseases Group, Sanford ResearchSioux FallsUnited States
| | - Peter C Breen
- Department of Molecular Biology, Massachusetts General HospitalBostonUnited States
| | - Gary Ruvkun
- Department of Molecular Biology, Massachusetts General HospitalBostonUnited States
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15
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Yasan GT, Gunel-Ozcan A. Hypoxia and Hypoxia Mimetic Agents As Potential Priming Approaches to Empower Mesenchymal Stem Cells. Curr Stem Cell Res Ther 2024; 19:33-54. [PMID: 36642875 DOI: 10.2174/1574888x18666230113143234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/12/2022] [Accepted: 11/04/2022] [Indexed: 01/17/2023]
Abstract
Mesenchymal stem cells (MSC) exhibit self-renewal capacity and multilineage differentiation potential, making them attractive for research and clinical application. The properties of MSC can vary depending on specific micro-environmental factors. MSC resides in specific niches with low oxygen concentrations, where oxygen functions as a metabolic substrate and a signaling molecule. Conventional physical incubators or chemically hypoxia mimetic agents are applied in cultures to mimic the original low oxygen tension settings where MSC originated. This review aims to focus on the current knowledge of the effects of various physical hypoxic conditions and widely used hypoxia-mimetic agents-PHD inhibitors on mesenchymal stem cells at a cellular and molecular level, including proliferation, stemness, differentiation, viability, apoptosis, senescence, migration, immunomodulation behaviors, as well as epigenetic changes.
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Affiliation(s)
| | - Aysen Gunel-Ozcan
- Department of Stem Cell Sciences, Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey
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16
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Barnes EA, Ito R, Che X, Alvira CM, Cornfield DN. Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2023; 325:L741-L755. [PMID: 37847687 PMCID: PMC11068430 DOI: 10.1152/ajplung.00428.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 09/21/2023] [Accepted: 10/11/2023] [Indexed: 10/19/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a disease characterized by increased vasoconstriction and vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) highly express the transcription factor hypoxia-inducible factor-1α (HIF-1α), yet the role of PASMC HIF-1α in the development of PAH remains controversial. To study the role of SMC HIF-1α in the pulmonary vascular response to acute and chronic hypoxia, we used a gain-of-function strategy to stabilize HIF-1α in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22α-expressing cells. This strategy increased HIF-1α expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22α-PHD1/2-/- mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22α-PHD1/2+/+ than in SM22α-PHD1/2-/- mice. In vitro studies demonstrated increased contractility and myosin light chain phosphorylation in isolated PHD1/2+/+ compared with PHD1/2-/- PASMC under both normoxic and hypoxic conditions. After chronic hypoxia, there was more p27 and less vascular remodeling in SM22α-PHD1/2-/- compared with SM22α-PHD1/2+/+ mice. Hypoxia increased p27 in PASMC isolated from control patients, but not in cells from patients with idiopathic pulmonary arterial hypertension (IPAH). These findings highlight an SM22α-expressing cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1α expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH.NEW & NOTEWORTHY In a mouse model wherein hypoxia-inducible factor 1 alpha (HIF-1α) is stabilized in vascular smooth muscle cells, we found that HIF-1α regulates vasoconstriction by limiting phosphorylation of myosin light chain and regulates vascular remodeling through p27 induction. These findings highlight a cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling.
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Affiliation(s)
- Elizabeth A Barnes
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, School of Medicine, Stanford, California, United States
| | - Reiji Ito
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, School of Medicine, Stanford, California, United States
| | - Xibing Che
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, School of Medicine, Stanford, California, United States
| | - Cristina M Alvira
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, School of Medicine, Stanford, California, United States
| | - David N Cornfield
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, School of Medicine, Stanford, California, United States
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17
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Zhao Y, Xiong W, Li C, Zhao R, Lu H, Song S, Zhou Y, Hu Y, Shi B, Ge J. Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets. Signal Transduct Target Ther 2023; 8:431. [PMID: 37981648 PMCID: PMC10658171 DOI: 10.1038/s41392-023-01652-9] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/10/2023] [Accepted: 09/13/2023] [Indexed: 11/21/2023] Open
Abstract
Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases. From the research history and milestone events related to hypoxia in cardiovascular development and diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal and spatial perspectives, encompassing the occurrence and progression of hypoxia (gradual decline in oxygen concentration), the acute and chronic manifestations of hypoxia, and the geographical characteristics of hypoxia (natural selection at high altitudes). Furthermore, hypoxia signaling pathways are associated with natural rhythms, such as diurnal and hibernation processes. In addition to innate factors and natural selection, it has been found that epigenetics, as a postnatal factor, profoundly influences the hypoxic response and progression within the cardiovascular system. Within this intricate process, interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established. Thus, it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more therapeutic targets and make reasonable advancements in clinical research, including FDA-approved drugs and ongoing clinical trials, to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases.
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Affiliation(s)
- Yongchao Zhao
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
| | - Weidong Xiong
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
- Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China
- Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China
| | - Chaofu Li
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
| | - Ranzun Zhao
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Hao Lu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
- Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - Shuai Song
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
- Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - You Zhou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
- Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - Yiqing Hu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China.
| | - Bei Shi
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China.
| | - Junbo Ge
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China.
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China.
- Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China.
- Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China.
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
- Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
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18
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Warnhoff K, Bhattacharya S, Snoozy J, Breen PC, Ruvkun G. Hypoxia-inducible factor induces cysteine dioxygenase and promotes cysteine homeostasis in Caenorhabditis elegans. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.04.538701. [PMID: 37205365 PMCID: PMC10187278 DOI: 10.1101/2023.05.04.538701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Dedicated genetic pathways regulate cysteine homeostasis. For example, high levels of cysteine activate cysteine dioxygenase, a key enzyme in cysteine catabolism in most animal and many fungal species. The mechanism by which cysteine dioxygenase is regulated is largely unknown. In an unbiased genetic screen for mutations that activate cysteine dioxygenase (cdo-1) in the nematode C. elegans, we isolated loss-of-function mutations in rhy-1 and egl-9, which encode proteins that negatively regulate the stability or activity of the oxygen-sensing hypoxia inducible transcription factor (hif-1). EGL-9 and HIF-1 are core members of the conserved eukaryotic hypoxia response. However, we demonstrate that the mechanism of HIF-1-mediated induction of cdo-1 is largely independent of EGL-9 prolyl hydroxylase activity and the von Hippel-Lindau E3 ubiquitin ligase, the classical hypoxia signaling pathway components. We demonstrate that C. elegans cdo-1 is transcriptionally activated by high levels of cysteine and hif-1. hif-1-dependent activation of cdo-1 occurs downstream of an H2S-sensing pathway that includes rhy-1, cysl-1, and egl-9. cdo-1 transcription is primarily activated in the hypodermis where it is also sufficient to drive sulfur amino acid metabolism. Thus, the regulation of cdo-1 by hif-1 reveals a negative feedback loop that maintains cysteine homeostasis. High levels of cysteine stimulate the production of an H2S signal. H2S then acts through the rhy-1/cysl-1/egl-9 signaling pathway to increase HIF-1-mediated transcription of cdo-1, promoting degradation of cysteine via CDO-1.
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Affiliation(s)
- Kurt Warnhoff
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105 USA
| | - Sushila Bhattacharya
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA
| | - Jennifer Snoozy
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA
| | - Peter C. Breen
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Gary Ruvkun
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
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19
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Watanabe K, Sato E, Mishima E, Moriya S, Sakabe T, Sato A, Fujiwara M, Fujimaru T, Ito Y, Taki F, Nagahama M, Tanaka K, Kazama JJ, Nakayama M. Changes in Metabolomic Profiles Induced by Switching from an Erythropoiesis-Stimulating Agent to a Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor in Hemodialysis Patients: A Pilot Study. Int J Mol Sci 2023; 24:12752. [PMID: 37628932 PMCID: PMC10454178 DOI: 10.3390/ijms241612752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/07/2023] [Accepted: 08/12/2023] [Indexed: 08/27/2023] Open
Abstract
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs.
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Affiliation(s)
- Kimio Watanabe
- Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan; (T.S.); (A.S.); (M.F.); (K.T.); (J.J.K.)
- Kidney Center, St Luke’s International Hospital, Tokyo 104-8560, Japan; (T.F.); (Y.I.); (F.T.); (M.N.); (M.N.)
| | - Emiko Sato
- Division of Clinical Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan;
| | - Eikan Mishima
- Division of Nephrology, Rheumatology and Endocrinology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan;
- Institute of Metabolism and Cell Death, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Shinobu Moriya
- Clinical Engineering Center, St Luke’s International Hospital, Tokyo 104-8560, Japan;
| | - Takuma Sakabe
- Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan; (T.S.); (A.S.); (M.F.); (K.T.); (J.J.K.)
| | - Atsuya Sato
- Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan; (T.S.); (A.S.); (M.F.); (K.T.); (J.J.K.)
| | - Momoko Fujiwara
- Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan; (T.S.); (A.S.); (M.F.); (K.T.); (J.J.K.)
| | - Takuya Fujimaru
- Kidney Center, St Luke’s International Hospital, Tokyo 104-8560, Japan; (T.F.); (Y.I.); (F.T.); (M.N.); (M.N.)
| | - Yugo Ito
- Kidney Center, St Luke’s International Hospital, Tokyo 104-8560, Japan; (T.F.); (Y.I.); (F.T.); (M.N.); (M.N.)
| | - Fumika Taki
- Kidney Center, St Luke’s International Hospital, Tokyo 104-8560, Japan; (T.F.); (Y.I.); (F.T.); (M.N.); (M.N.)
| | - Masahiko Nagahama
- Kidney Center, St Luke’s International Hospital, Tokyo 104-8560, Japan; (T.F.); (Y.I.); (F.T.); (M.N.); (M.N.)
| | - Kenichi Tanaka
- Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan; (T.S.); (A.S.); (M.F.); (K.T.); (J.J.K.)
| | - Junichiro James Kazama
- Division of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1295, Japan; (T.S.); (A.S.); (M.F.); (K.T.); (J.J.K.)
| | - Masaaki Nakayama
- Kidney Center, St Luke’s International Hospital, Tokyo 104-8560, Japan; (T.F.); (Y.I.); (F.T.); (M.N.); (M.N.)
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20
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Dang CV. Cancer Metabolism Historical Perspectives: A Chronicle of Controversies and Consensus. Cold Spring Harb Perspect Med 2023; 13:a041530. [PMID: 37553212 PMCID: PMC10691493 DOI: 10.1101/cshperspect.a041530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
A century ago, Otto Warburg's work sparked the field of cancer metabolism, which has since taken a tortuous path. As evidence accumulated over the decades, consensus views of causes of cancer emerged, whereby genetic and epigenetic oncogenic drivers promoted immune evasion and induced new blood vessels and neoplastic metabolism to support tumor growth. Neoplastic cells abandon social cues of intercellular cooperation, escape tissue confinement, metastasize, and ultimately kill the host. Herein, key milestones in the study of cancer metabolism are chronicled with an emphasis on carbohydrate metabolism. The field began with a cancer cell-autonomous view that has been refined by a richer understanding of solid cancers as growing, immune-suppressive, complex organs comprising different cell types that are nourished by a variety of nutrients and variable amounts of oxygen through abnormal neovasculatures. Based on foundational historical studies, our current understanding of cancer metabolism offers a hopeful outlook for targeting metabolism to enhance cancer therapy.
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Affiliation(s)
- Chi V Dang
- Ludwig Institute for Cancer Research, New York, New York 10017, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
- Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21287, USA
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21
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Steinberger KJ, Eubank TD. The Underexplored Landscape of Hypoxia-Inducible Factor 2 Alpha and Potential Roles in Tumor Macrophages: A Review. OXYGEN (BASEL, SWITZERLAND) 2023; 3:45-76. [PMID: 37124241 PMCID: PMC10137047 DOI: 10.3390/oxygen3010005] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
Low tissue oxygenation, termed hypoxia, is a characteristic of solid tumors with negative consequences. Tumor-associated macrophages (TAMs) accumulate in hypoxic tumor regions and correlate with worse outcomes in cancer patients across several tumor types. Thus, the molecular mechanism in which macrophages respond to low oxygen tension has been increasingly investigated in the last decade. Hypoxia stabilizes a group of hypoxia-inducible transcription factors (HIFs) reported to drive transcriptional programs involved in cell survival, metabolism, and angiogenesis. Though both tumor macrophage HIF-1α and HIF-2α correlate with unfavorable tumor microenvironments, most research focuses on HIF-1α as the master regulator of hypoxia signaling, because HIF-1α expression was originally identified in several cancer types and correlates with worse outcome in cancer patients. The relative contribution of each HIFα subunit to cell phenotypes is poorly understood especially in TAMs. Once thought to have overlapping roles, recent investigation of macrophage HIF-2α has demonstrated a diverse function from HIF-1α. Little work has been published on the differential role of hypoxia-dependent macrophage HIF-2α when compared to HIF-1α in the context of tumor biology. This review highlights cellular HIF-2α functions and emphasizes the gap in research investigating oxygen-dependent functions of tumor macrophage HIF-2α.
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Affiliation(s)
- Kayla J. Steinberger
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26505, USA
- In Vivo Multifunctional Magnetic Resonance Center, West Virginia University, Morgantown, WV 26505, USA
- West Virginia University Cancer Institute, Morgantown, WV 26505, USA
| | - Timothy D. Eubank
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26505, USA
- In Vivo Multifunctional Magnetic Resonance Center, West Virginia University, Morgantown, WV 26505, USA
- West Virginia University Cancer Institute, Morgantown, WV 26505, USA
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22
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Chen Z, Han F, Du Y, Shi H, Zhou W. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther 2023; 8:70. [PMID: 36797231 PMCID: PMC9935926 DOI: 10.1038/s41392-023-01332-8] [Citation(s) in RCA: 424] [Impact Index Per Article: 212.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 12/20/2022] [Accepted: 01/18/2023] [Indexed: 02/18/2023] Open
Abstract
Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype of cancer cells, mediates the effects of cancer chemotherapy, radiotherapy, and immunotherapy through complex mechanisms, and is closely associated with poor prognosis in various cancer patients. Accumulating studies have demonstrated that through normalization of the tumor vasculature, nanoparticle carriers and biocarriers can effectively increase the oxygen concentration in the tumor microenvironment, improve drug delivery and the efficacy of radiotherapy. They also increase infiltration of innate and adaptive anti-tumor immune cells to enhance the efficacy of immunotherapy. Furthermore, drugs targeting key genes associated with hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting hypoxia-inducible factors and downstream targets, can be used for visualization and quantitative analysis of tumor hypoxia and antitumor activity. However, the relationship between hypoxia and cancer is an area of research that requires further exploration. Here, we investigated the potential factors in the development of hypoxia in cancer, changes in signaling pathways that occur in cancer cells to adapt to hypoxic environments, the mechanisms of hypoxia-induced cancer immune tolerance, chemotherapeutic tolerance, and enhanced radiation tolerance, as well as the insights and applications of hypoxia in cancer therapy.
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Affiliation(s)
- Zhou Chen
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China.,The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Fangfang Han
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China.,The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yan Du
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Huaqing Shi
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Wence Zhou
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China. .,Lanzhou University Sencond Hospital, Lanzhou, Gansu, China.
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23
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Kim Y, Koh JS, Woo SD, Lee SI, Kang DH, Park D, Chung C, Kwon IS, Lee JE. The Tri-iodothyronine (T3) Level Is a Prognostic Factor for Patients With Advanced NSCLC: Receiving Immune Checkpoint Inhibitors and Is Associated With Liver Metastasis. Clin Med Insights Oncol 2022; 16:11795549221139522. [PMID: 36532699 PMCID: PMC9751177 DOI: 10.1177/11795549221139522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 11/01/2022] [Indexed: 08/22/2023] Open
Abstract
BACKGROUND Endocrine hormones influence tumor progression and the response to treatment. Despite the importance of immune checkpoint inhibitors (ICIs) as treatments for advanced non-small cell lung cancer (NSCLC), few studies have explored the effects of hormone levels in NSCLC patients on the effectiveness of ICI therapies. We thus investigated the effects of baseline blood markers in patients with advanced NSCLC on ICI treatments. METHODS Patients with advanced NSCLC who received programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors at Chungnam National University Hospital between December 2016 and November 2020 and who lacked any history of thyroid gland-related diseases were analyzed retrospectively. We collected clinical information and baseline laboratory data, including the levels of endocrine hormones, cytokines, complete blood counts (CBCs), and peripheral blood chemistry panels. We explored the relationships of hormone levels with clinical outcomes (overall survival [OS], progression-free survival [PFS], and best response), liver metastasis, and blood markers using the Kaplan-Meier method, Cox's proportional hazards regression, and logistic regression. RESULTS A total of 113 patients were enrolled. A shorter PFS was independently associated with liver metastasis, higher cortisol levels, and lower hemoglobin (Hb) levels; a shorter OS was associated with liver metastasis, lower tri-iodothyronine (T3) levels, higher lactate dehydrogenase (LDH) levels, and lower albumin levels. Patients with low T3 levels exhibited a shorter PFS and OS, and a poorer best response. Patients with low T3 levels tended to have higher disease progression rates, lower levels of adrenocorticotropic hormone (ACTH), C-peptide, albumin, Hb, and neutrophil-to-lymphocyte ratio, and higher levels of interleukin (IL)-6, white blood cells, platelets, compared with those with normal T3 levels. We found a significant association between a low T3 level and liver metastasis. CONCLUSIONS We found the baseline T3 level was associated with both prognosis and the response to ICIs in patients with advanced NSCLC, probably reflecting impaired liver function and systemic inflammation induced by the interaction of T3 with other biomarkers, such as IL-6, ACTH, cortisol, C-peptide, Hb, LDH, and albumin.
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Affiliation(s)
- Yoonjoo Kim
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Jeong Suk Koh
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Seong-Dae Woo
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Song-I Lee
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Da Hyun Kang
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Dongil Park
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Chaeuk Chung
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - In-Sun Kwon
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Jeong Eun Lee
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
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24
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Kocianova E, Piatrikova V, Golias T. Revisiting the Warburg Effect with Focus on Lactate. Cancers (Basel) 2022; 14:cancers14246028. [PMID: 36551514 PMCID: PMC9776395 DOI: 10.3390/cancers14246028] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
Rewired metabolism is acknowledged as one of the drivers of tumor growth. As a result, aerobic glycolysis, or the Warburg effect, is a feature of many cancers. Increased glucose uptake and glycolysis provide intermediates for anabolic reactions necessary for cancer cell proliferation while contributing sufficient energy. However, the accompanying increased lactate production, seemingly wasting glucose carbon, was originally explained only by the need to regenerate NAD+ for successive rounds of glycolysis by the lactate dehydrogenase (LDH) reaction in the cytosol. After the discovery of a mitochondrial LDH isoform, lactate oxidation entered the picture, and lactate was recognized as an important oxidative fuel. It has also been revealed that lactate serves a variety of signaling functions and helps cells adapt to the new environment. Here, we discuss recent findings on lactate metabolism and signaling in cancer while attempting to explain why the Warburg effect is adopted by cancer cells.
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Affiliation(s)
- Eva Kocianova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia
| | - Viktoria Piatrikova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 84215 Bratislava, Slovakia
| | - Tereza Golias
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia
- Correspondence:
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25
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Lathuiliere A, Vernet R, Charrier E, Urwyler M, Von Rohr O, Belkouch MC, Saingier V, Bouvarel T, Guillarme D, Engel A, Salmon P, Laumonier T, Grogg J, Mach N. Immortalized human myoblast cell lines for the delivery of therapeutic proteins using encapsulated cell technology. Mol Ther Methods Clin Dev 2022; 26:441-458. [PMID: 36092361 PMCID: PMC9418741 DOI: 10.1016/j.omtm.2022.07.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/31/2022] [Indexed: 12/04/2022]
Abstract
Despite many promising results obtained in previous preclinical studies, the clinical development of encapsulated cell technology (ECT) for the delivery of therapeutic proteins from macrocapsules is still limited, mainly due to the lack of an allogeneic cell line compatible with therapeutic application in humans. In our work, we generated an immortalized human myoblast cell line specifically tailored for macroencapsulation. In the present report, we characterized the immortalized myoblasts and described the engineering process required for the delivery of functional therapeutic proteins including a cytokine, monoclonal antibodies and a viral antigen. We observed that, when encapsulated, the novel myoblast cell line can be efficiently frozen, stored, and thawed, which limits the challenge imposed by the manufacture and supply of encapsulated cell-based therapeutic products. Our results suggest that this versatile allogeneic cell line represents the next step toward a broader development and therapeutic use of ECT.
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Affiliation(s)
- Aurelien Lathuiliere
- Oncology Division, Geneva University Hospital and Medical School, 1211 Geneva, Switzerland
| | - Remi Vernet
- Oncology Division, Geneva University Hospital and Medical School, 1211 Geneva, Switzerland
- Centre for Translational Research in Onco-Hematology, Oncology Division, Geneva University Hospital and University of Geneva, 1211 Geneva, Switzerland
| | - Emily Charrier
- Oncology Division, Geneva University Hospital and Medical School, 1211 Geneva, Switzerland
- Centre for Translational Research in Onco-Hematology, Oncology Division, Geneva University Hospital and University of Geneva, 1211 Geneva, Switzerland
- MaxiVAX SA, 1202 Geneva, Switzerland
| | - Muriel Urwyler
- Oncology Division, Geneva University Hospital and Medical School, 1211 Geneva, Switzerland
- Centre for Translational Research in Onco-Hematology, Oncology Division, Geneva University Hospital and University of Geneva, 1211 Geneva, Switzerland
| | - Olivier Von Rohr
- Oncology Division, Geneva University Hospital and Medical School, 1211 Geneva, Switzerland
- Centre for Translational Research in Onco-Hematology, Oncology Division, Geneva University Hospital and University of Geneva, 1211 Geneva, Switzerland
| | - Marie-Claude Belkouch
- Oncology Division, Geneva University Hospital and Medical School, 1211 Geneva, Switzerland
- Centre for Translational Research in Onco-Hematology, Oncology Division, Geneva University Hospital and University of Geneva, 1211 Geneva, Switzerland
| | - Valentin Saingier
- Oncology Division, Geneva University Hospital and Medical School, 1211 Geneva, Switzerland
- Centre for Translational Research in Onco-Hematology, Oncology Division, Geneva University Hospital and University of Geneva, 1211 Geneva, Switzerland
| | - Thomas Bouvarel
- Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, 1211 Geneva, Switzerland
- School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland
| | - Davy Guillarme
- Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, 1211 Geneva, Switzerland
- School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland
| | | | - Patrick Salmon
- Department of Basic Neurosciences, University of Geneva, 1211 Geneva, Switzerland
| | - Thomas Laumonier
- Cell Therapy and Musculoskeletal Disorders Laboratory, Department of Orthopaedic Surgery, Faculty of Medicine, Geneva University Hospital and University of Geneva, 1211 Geneva, Switzerland
| | | | - Nicolas Mach
- Oncology Division, Geneva University Hospital and Medical School, 1211 Geneva, Switzerland
- Centre for Translational Research in Onco-Hematology, Oncology Division, Geneva University Hospital and University of Geneva, 1211 Geneva, Switzerland
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26
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Hypothermia Alleviates Reductive Stress, a Root Cause of Ischemia Reperfusion Injury. Int J Mol Sci 2022; 23:ijms231710108. [PMID: 36077504 PMCID: PMC9456258 DOI: 10.3390/ijms231710108] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/25/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
Ischemia reperfusion injury is common in transplantation. Previous studies have shown that cooling can protect against hypoxic injury. To date, the protective effects of hypothermia have been largely associated with metabolic suppression. Since kidney transplantation is one of the most common organ transplant surgeries, we used human-derived renal proximal tubular cells (HKC8 cell line) as a model of normal renal cells. We performed a temperature titration curve from 37 °C to 22 °C and evaluated cellular respiration and molecular mechanisms that can counteract the build-up of reducing equivalents in hypoxic conditions. We show that the protective effects of hypothermia are likely to stem both from metabolic suppression (inhibitory component) and augmentation of stress tolerance (activating component), with the highest overlap between activating and suppressing mechanisms emerging in the window of mild hypothermia (32 °C). Hypothermia decreased hypoxia-induced rise in the extracellular lactate:pyruvate ratio, increased ATP/ADP ratio and mitochondrial content, normalized lipid content, and improved the recovery of respiration after anoxia. Importantly, it was observed that in contrast to mild hypothermia, moderate and deep hypothermia interfere with HIF1 (hypoxia inducible factor 1)-dependent HRE (hypoxia response element) induction in hypoxia. This work also demonstrates that hypothermia alleviates reductive stress, a conceptually novel and largely overlooked phenomenon at the root of ischemia reperfusion injury.
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27
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Wei Y, Giunta S, Xia S. Hypoxia in Aging and Aging-Related Diseases: Mechanism and Therapeutic Strategies. Int J Mol Sci 2022; 23:8165. [PMID: 35897741 PMCID: PMC9330578 DOI: 10.3390/ijms23158165] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 07/12/2022] [Accepted: 07/14/2022] [Indexed: 01/27/2023] Open
Abstract
As the global aging process continues to lengthen, aging-related diseases (e.g., chronic obstructive pulmonary disease (COPD), heart failure) continue to plague the elderly population. Aging is a complex biological process involving multiple tissues and organs and is involved in the development and progression of multiple aging-related diseases. At the same time, some of these aging-related diseases are often accompanied by hypoxia, chronic inflammation, oxidative stress, and the increased secretion of the senescence-associated secretory phenotype (SASP). Hypoxia seems to play an important role in the process of inflammation and aging, but is often neglected in advanced clinical research studies. Therefore, we have attempted to elucidate the role played by different degrees and types of hypoxia in aging and aging-related diseases and their possible pathways, and propose rational treatment options based on such mechanisms for reference.
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Affiliation(s)
- Yaqin Wei
- Department of Geriatrics, Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai 200000, China;
| | - Sergio Giunta
- Casa di Cura Prof. Nobili–GHC Garofalo Health Care, 40035 Bologna, Italy;
| | - Shijin Xia
- Department of Geriatrics, Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai 200000, China;
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28
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Hypoxia signaling in human health and diseases: implications and prospects for therapeutics. Signal Transduct Target Ther 2022; 7:218. [PMID: 35798726 PMCID: PMC9261907 DOI: 10.1038/s41392-022-01080-1] [Citation(s) in RCA: 183] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/17/2022] [Accepted: 06/23/2022] [Indexed: 02/07/2023] Open
Abstract
Molecular oxygen (O2) is essential for most biological reactions in mammalian cells. When the intracellular oxygen content decreases, it is called hypoxia. The process of hypoxia is linked to several biological processes, including pathogenic microbe infection, metabolic adaptation, cancer, acute and chronic diseases, and other stress responses. The mechanism underlying cells respond to oxygen changes to mediate subsequent signal response is the central question during hypoxia. Hypoxia-inducible factors (HIFs) sense hypoxia to regulate the expressions of a series of downstream genes expression, which participate in multiple processes including cell metabolism, cell growth/death, cell proliferation, glycolysis, immune response, microbe infection, tumorigenesis, and metastasis. Importantly, hypoxia signaling also interacts with other cellular pathways, such as phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-B (NF-κB) pathway, extracellular signal-regulated kinases (ERK) signaling, and endoplasmic reticulum (ER) stress. This paper systematically reviews the mechanisms of hypoxia signaling activation, the control of HIF signaling, and the function of HIF signaling in human health and diseases. In addition, the therapeutic targets involved in HIF signaling to balance health and diseases are summarized and highlighted, which would provide novel strategies for the design and development of therapeutic drugs.
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29
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Sharma S, Sandhir R, Ganju L, Kumar B, Singh Y. Unique mutations in mitochondrial DNA and associated pathways involved in high altitude pulmonary edema susceptibility in Indian lowlanders. J Biomol Struct Dyn 2022:1-16. [PMID: 35666092 DOI: 10.1080/07391102.2022.2081610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
High altitude pulmonary edema (HAPE) is a life threatening non-cardiogenic pulmonary edema that occurs in an otherwise healthy individuals travelling to altitude above 2500 m. Earlier studies have reported association of mutations in nuclear (nDNA) and mitochondrial DNA (mtDNA) with HAPE susceptibility. However, the molecular mechanisms involved in the pathobiology of HAPE have not been fully understood. The present study investigates the genetic predisposition to HAPE by analyzing the mtDNA mutations in HAPE susceptibles (n = 23) and acclimatized controls (n = 23) using next generation sequencing. Structural analysis of mutations was done using SWISS Model server and stability was determined using ΔΔG values. Meta-analysis of GSE52209 dataset was done to identify differentially expressed genes (DEGs) in HAPE susceptibles and acclimatized controls. Fourteen non-synonymous, conserved and pathogenic mutations were predicted using SIFT and PolyPhen scoring in protein coding genes, whereas six mutations in mt-tRNA genes showed association with HAPE (p ≤ 0.05). The structural analysis of these mutations revealed conformational changes in critical regions in Complexes I-V which are involved in subunit assembly and proton pumping activity. The protein-protein interaction network analysis of DEGs showed that HIF1α, EGLN2, EGLN3, PDK1, TFAM, PPARGC1α and NRF1 genes form highly interconnected cluster. Further, pathway enrichment analysis using DAVID revealed that "HIF-1 signaling", "oxidative phosphorylation" and "Metabolic pathways" had strong association with HAPE. Based on the findings it appears that the identified mtDNA mutations may be a potential risk factor in development of HAPE with the associated pathways providing mechanistic insight into the understanding of pathobiology of HAPE and sites for development of therapeutic targets.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Swati Sharma
- Defence Institute of Physiology and Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, Delhi, India.,Department of Biochemistry, Basic Medical Sciences Block II, Panjab University, Chandigarh, India
| | - Rajat Sandhir
- Department of Biochemistry, Basic Medical Sciences Block II, Panjab University, Chandigarh, India
| | - Lilly Ganju
- Defence Institute of Physiology and Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, Delhi, India
| | - Bhuvnesh Kumar
- Defence Institute of Physiology and Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, Delhi, India
| | - Yamini Singh
- Defence Institute of Physiology and Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, Delhi, India
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30
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Wang Y, Zhang G, Meng Q, Huang S, Guo P, Leng Q, Sun L, Liu G, Huang X, Liu J. Precise tumor immune rewiring via synthetic CRISPRa circuits gated by concurrent gain/loss of transcription factors. Nat Commun 2022; 13:1454. [PMID: 35304449 PMCID: PMC8933567 DOI: 10.1038/s41467-022-29120-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 03/01/2022] [Indexed: 12/14/2022] Open
Abstract
Reinvigoration of antitumor immunity has recently become the central theme for the development of cancer therapies. Nevertheless, the precise delivery of immunotherapeutic activities to the tumors remains challenging. Here, we explore a synthetic gene circuit-based strategy for specific tumor identification, and for subsequently engaging immune activation. By design, these circuits are assembled from two interactive modules, i.e., an oncogenic TF-driven CRISPRa effector, and a corresponding p53-inducible off-switch (NOT gate), which jointly execute an AND-NOT logic for accurate tumor targeting. In particular, two forms of the NOT gate are developed, via the use of an inhibitory sgRNA or an anti-CRISPR protein, with the second form showing a superior performance in gating CRISPRa by p53 loss. Functionally, the optimized AND-NOT logic circuit can empower a highly specific and effective tumor recognition/immune rewiring axis, leading to therapeutic effects in vivo. Taken together, our work presents an adaptable strategy for the development of precisely delivered immunotherapy. “Reinvigoration of antitumor immunity has recently become the central theme for the development of cancer therapies. Here the authors present an adaptable gene circuit to harness the CRISPRa for tumorlocalized immune activation.”
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Affiliation(s)
- Yafeng Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center at Medical School of Nanjing University, Nanjing, 210061, China.,Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Guiquan Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center at Medical School of Nanjing University, Nanjing, 210061, China
| | - Qingzhou Meng
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 78 Hengzhigang Road, Guangzhou, 510095, China
| | - Shisheng Huang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Panpan Guo
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Qibin Leng
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 78 Hengzhigang Road, Guangzhou, 510095, China
| | - Lingyun Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Geng Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center at Medical School of Nanjing University, Nanjing, 210061, China. .,Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China.
| | - Xingxu Huang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. .,Zhejiang Laboratory, Hangzhou, 311100, China.
| | - Jianghuai Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center at Medical School of Nanjing University, Nanjing, 210061, China. .,Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China.
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Sabui S, Ramamoorthy K, Romero JM, Simoes RD, Fleckenstein JM, Said HM. Hypoxia inhibits colonic uptake of the microbiota-generated forms of vitamin B1 via HIF-1α-mediated transcriptional regulation of their transporters. J Biol Chem 2022; 298:101562. [PMID: 34998824 PMCID: PMC8800108 DOI: 10.1016/j.jbc.2022.101562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/29/2021] [Accepted: 01/02/2022] [Indexed: 01/19/2023] Open
Abstract
Hypoxia exerts profound effects on cell physiology, but its effect on colonic uptake of the microbiota-generated forms of vitamin B1 (i.e., thiamin pyrophosphate [TPP] and free thiamine) has not been described. Here, we used human colonic epithelial NCM460 cells and human differentiated colonoid monolayers as in vitro and ex vivo models, respectively, and were subjected to either chamber (1% O2, 5% CO2, and 94% N2) or chemically (desferrioxamine; 250 μM)-induced hypoxia followed by determination of different physiological-molecular parameters. We showed that hypoxia causes significant inhibition in TPP and free thiamin uptake by colonic NCM460 cells and colonoid monolayers; it also caused a significant reduction in the expression of TPP (SLC44A4) and free thiamin (SLC19A2 and SLC19A3) transporters and in activity of their gene promoters. Furthermore, hypoxia caused a significant induction in levels of hypoxia-inducible transcription factor (HIF)-1α but not HIF-2α. Knocking down HIF-1α using gene-specific siRNAs in NCM460 cells maintained under hypoxic conditions, on the other hand, led to a significant reversal in the inhibitory effect of hypoxia on TPP and free thiamin uptake as well as on the expression of their transporters. Finally, a marked reduction in level of expression of the nuclear factors cAMP responsive element-binding protein 1 and gut-enriched Krüppel-like factor 4 (required for activity of SLC44A4 and SLC19A2 promoters, respectively) was observed under hypoxic conditions. In summary, hypoxia causes severe inhibition in colonic TPP and free thiamin uptake that is mediated at least in part via HIF-1α-mediated transcriptional mechanisms affecting their respective transporters.
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Affiliation(s)
- Subrata Sabui
- Department of Physiology and Biophysics, UCI, Irvine, California, USA; Department of Research, VA Medical Center, Long Beach, California, USA
| | | | - Jose M Romero
- Department of Research, VA Medical Center, Long Beach, California, USA; Department of Medicine, UCI, Irvine, California, USA
| | - Rita D Simoes
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
| | - James M Fleckenstein
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA; Department Medicine Service, Veterans Affairs Medical Center, St Louis, Missouri, USA
| | - Hamid M Said
- Department of Physiology and Biophysics, UCI, Irvine, California, USA; Department of Research, VA Medical Center, Long Beach, California, USA; Department of Medicine, UCI, Irvine, California, USA.
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Lactate Supply from Astrocytes to Neurons and its Role in Ischemic Stroke-induced Neurodegeneration. Neuroscience 2022; 481:219-231. [PMID: 34843897 DOI: 10.1016/j.neuroscience.2021.11.035] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/19/2021] [Accepted: 11/22/2021] [Indexed: 01/10/2023]
Abstract
Glucose transported to the brain is metabolized to lactate in astrocytes and supplied to neuronal cells via a monocarboxylic acid transporter (MCT). Lactate is used in neuronal cells for various functions, including learning and memory formation. Furthermore, lactate can block stroke-induced neurodegeneration. We aimed to clarify the effect of astrocyte-produced lactate on stroke-induced neurodegeneration. Previously published in vivo and in vitro animal and cell studies, respectively, were searched in PubMed, ScienceDirect, and Web of Science. Under physiological conditions, lactate production and release by astrocytes are regulated by changes in lactate dehydrogenase (LDH) and MCT expression. Moreover, considering stroke, lactate production and supply are regulated through hypoxia-inducible factor (HIF)-1α expression, especially with hypoxic stimulation, which may promote neuronal apoptosis; contrastingly, neuronal survival may be promoted via HIF-1α. Stroke stimulation could prevent neurodegeneration through the strong enhancement of lactate production, as well as upregulation of MCT4 expression to accelerate lactate supply. However, studies using astrocytes derived from animal stroke models revealed significantly reduced lactate production and MCT expression. These findings suggest that the lack of lactate supply may strongly contribute to hypoxia-induced neurodegeneration. Furthermore, diminished lactate supply from astrocytes could facilitate stroke-induced neurodegeneration. Therefore, astrocyte-derived lactate may contribute to stroke prevention.
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Ratcliffe PJ. Harveian Oration 2020: Elucidation of molecular oxygen sensing mechanisms in human cells: implications for medicine. Clin Med (Lond) 2022; 22:23-33. [PMID: 34921056 PMCID: PMC8813027 DOI: 10.7861/clinmed.ed.22.1.harv] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Peter J Ratcliffe
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK, and director of clinical research, Francis Crick Institute, London, UK
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Škodová-Sveráková I, Záhonová K, Juricová V, Danchenko M, Moos M, Baráth P, Prokopchuk G, Butenko A, Lukáčová V, Kohútová L, Bučková B, Horák A, Faktorová D, Horváth A, Šimek P, Lukeš J. Highly flexible metabolism of the marine euglenozoan protist Diplonema papillatum. BMC Biol 2021; 19:251. [PMID: 34819072 PMCID: PMC8611851 DOI: 10.1186/s12915-021-01186-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/08/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The phylum Euglenozoa is a group of flagellated protists comprising the diplonemids, euglenids, symbiontids, and kinetoplastids. The diplonemids are highly abundant and speciose, and recent tools have rendered the best studied representative, Diplonema papillatum, genetically tractable. However, despite the high diversity of diplonemids, their lifestyles, ecological functions, and even primary energy source are mostly unknown. RESULTS We designed a metabolic map of D. papillatum cellular bioenergetic pathways based on the alterations of transcriptomic, proteomic, and metabolomic profiles obtained from cells grown under different conditions. Comparative analysis in the nutrient-rich and nutrient-poor media, as well as the absence and presence of oxygen, revealed its capacity for extensive metabolic reprogramming that occurs predominantly on the proteomic rather than the transcriptomic level. D. papillatum is equipped with fundamental metabolic routes such as glycolysis, gluconeogenesis, TCA cycle, pentose phosphate pathway, respiratory complexes, β-oxidation, and synthesis of fatty acids. Gluconeogenesis is uniquely dominant over glycolysis under all surveyed conditions, while the TCA cycle represents an eclectic combination of standard and unusual enzymes. CONCLUSIONS The identification of conventional anaerobic enzymes reflects the ability of this protist to survive in low-oxygen environments. Furthermore, its metabolism quickly reacts to restricted carbon availability, suggesting a high metabolic flexibility of diplonemids, which is further reflected in cell morphology and motility, correlating well with their extreme ecological valence.
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Affiliation(s)
- Ingrid Škodová-Sveráková
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic.
- Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia.
| | - Kristína Záhonová
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic
- Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic
| | - Valéria Juricová
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic
- Faculty of Sciences, University of South Bohemia, České Budějovice (Budweis), Czech Republic
| | - Maksym Danchenko
- Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Martin Moos
- Institute of Entomology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic
| | - Peter Baráth
- Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia
- Medirex Group Academy n.o., Trnava, Slovakia
| | - Galina Prokopchuk
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic
| | - Anzhelika Butenko
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic
- Faculty of Science, University of Ostrava, Ostrava, Czech Republic
| | | | - Lenka Kohútová
- Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Barbora Bučková
- Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia
| | - Aleš Horák
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic
- Faculty of Sciences, University of South Bohemia, České Budějovice (Budweis), Czech Republic
| | - Drahomíra Faktorová
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic
- Faculty of Sciences, University of South Bohemia, České Budějovice (Budweis), Czech Republic
| | - Anton Horváth
- Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia
| | - Petr Šimek
- Institute of Entomology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic
| | - Julius Lukeš
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis), Czech Republic.
- Faculty of Sciences, University of South Bohemia, České Budějovice (Budweis), Czech Republic.
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35
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Todd VM, Vecchi LA, Clements ME, Snow KP, Ontko CD, Himmel L, Pinelli C, Rafat M, Johnson RW. Hypoxia inducible factor signaling in breast tumors controls spontaneous tumor dissemination in a site-specific manner. Commun Biol 2021; 4:1122. [PMID: 34556788 PMCID: PMC8460839 DOI: 10.1038/s42003-021-02648-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 09/08/2021] [Indexed: 02/07/2023] Open
Abstract
Hypoxia is a common feature in tumors and induces signaling that promotes tumor cell survival, invasion, and metastasis, but the impact of hypoxia inducible factor (HIF) signaling in the primary tumor on dissemination to bone in particular remains unclear. To better understand the contributions of hypoxia inducible factor 1 alpha (HIF1α), HIF2α, and general HIF pathway activation in metastasis, we employ a PyMT-driven spontaneous murine mammary carcinoma model with mammary specific deletion of Hif1α, Hif2α, or von Hippel-Lindau factor (Vhl) using the Cre-lox system. Here we show that Hif1α or Hif2α deletion in the primary tumor decreases metastatic tumor burden in the bone marrow, while Vhl deletion increases bone tumor burden, as hypothesized. Unexpectedly, Hif1α deletion increases metastatic tumor burden in the lung, while deletion of Hif2α or Vhl does not affect pulmonary metastasis. Mice with Hif1α deleted tumors also exhibit reduced bone volume as measured by micro computed tomography, suggesting that disruption of the osteogenic niche may be involved in the preference for lung dissemination observed in this group. Thus, we reveal that HIF signaling in breast tumors controls tumor dissemination in a site-specific manner.
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Affiliation(s)
- Vera M Todd
- Graduate Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
- Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, TN, USA
| | - Lawrence A Vecchi
- Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, TN, USA
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Miranda E Clements
- Tumor Microenvironment and Metastasis Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Katherine P Snow
- Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, TN, USA
- Department of Medicine, Health, and Society, Vanderbilt University, Nashville, TN, USA
| | - Cayla D Ontko
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Lauren Himmel
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Christopher Pinelli
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Marjan Rafat
- Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, TN, USA
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA
| | - Rachelle W Johnson
- Graduate Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA.
- Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, TN, USA.
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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Gala D, Mohak S, Fábián Z. Extracellular Vehicles of Oxygen-Depleted Mesenchymal Stromal Cells: Route to Off-Shelf Cellular Therapeutics? Cells 2021; 10:cells10092199. [PMID: 34571848 PMCID: PMC8465344 DOI: 10.3390/cells10092199] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 08/23/2021] [Accepted: 08/24/2021] [Indexed: 11/16/2022] Open
Abstract
Cellular therapy is a promising tool of human medicine to successfully treat complex and challenging pathologies such as cardiovascular diseases or chronic inflammatory conditions. Bone marrow-derived mesenchymal stromal cells (BMSCs) are in the limelight of these efforts, initially, trying to exploit their natural properties by direct transplantation. Extensive research on the therapeutic use of BMSCs shed light on a number of key aspects of BMSC physiology including the importance of oxygen in the control of BMSC phenotype. These efforts also led to a growing number of evidence indicating that the beneficial therapeutic effects of BMSCs can be mediated by BMSC-secreted agents. Further investigations revealed that BMSC-excreted extracellular vesicles could mediate the potentially therapeutic effects of BMSCs. Here, we review our current understanding of the relationship between low oxygen conditions and the effects of BMSC-secreted extracellular vesicles focusing on the possible medical relevance of this interplay.
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37
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Duarte TL, Talbot NP, Drakesmith H. NRF2 and Hypoxia-Inducible Factors: Key Players in the Redox Control of Systemic Iron Homeostasis. Antioxid Redox Signal 2021; 35:433-452. [PMID: 32791852 DOI: 10.1089/ars.2020.8148] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Significance: Oxygen metabolism and iron homeostasis are closely linked. Iron facilitates the oxygen-carrying capacity of blood, and its deficiency causes anemia. Conversely, excess free iron is detrimental for stimulating the formation of reactive oxygen species, causing tissue damage. The amount and distribution of iron thus need to be tightly regulated by the liver-expressed hormone hepcidin. This review analyzes the roles of key oxygen-sensing pathways in cellular and systemic regulation of iron homeostasis; specifically, the prolyl hydroxylase domain (PHD)/hypoxia-inducible factor (HIF) and the Kelch-like ECH-associated protein 1/NF-E2 p45-related factor 2 (KEAP1/NRF2) pathways, which mediate tissue adaptation to low and high oxygen, respectively. Recent Advances: In macrophages, NRF2 regulates genes involved in hemoglobin catabolism, iron storage, and iron export. NRF2 was recently identified as the molecular sensor of iron-induced oxidative stress and is responsible for BMP6 expression by liver sinusoidal endothelial cells, which in turn activates hepcidin synthesis by hepatocytes to restore systemic iron levels. Moreover, NRF2 orchestrates the activation of antioxidant defenses that are crucial to protect against iron toxicity. On the contrary, low iron/hypoxia stabilizes renal HIF2a via inactivation of iron-dependent PHD dioxygenases, causing an erythropoietic stimulus that represses hepcidin via an inhibitory effect of erythroferrone on bone morphogenetic proteins. Intestinal HIF2a is also stabilized, increasing the expression of genes involved in dietary iron absorption. Critical Issues: An intimate crosstalk between oxygen-sensing pathways and iron regulatory mechanisms ensures that fluctuations in systemic iron levels are promptly detected and restored. Future Directions: The realization that redox-sensitive transcription factors regulate systemic iron levels suggests novel therapeutic approaches. Antioxid. Redox Signal. 35, 433-452.
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Affiliation(s)
- Tiago L Duarte
- Instituto de Biologia Molecular e Celular, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
| | - Nick P Talbot
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom
| | - Hal Drakesmith
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
- Haematology Theme, Oxford Biomedical Research Centre, Oxford, United Kingdom
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Pathological Role of Phosphoglycerate Kinase 1 in Balloon Angioplasty-Induced Neointima Formation. Int J Mol Sci 2021; 22:ijms22168822. [PMID: 34445528 PMCID: PMC8396187 DOI: 10.3390/ijms22168822] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/15/2021] [Accepted: 08/16/2021] [Indexed: 02/07/2023] Open
Abstract
Restenosis is a common vascular complication after balloon angioplasty. Catheter balloon inflation-induced transient ischemia (hypoxia) of local arterial tissues plays a pathological role in neointima formation. Phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate (ATP)-generating glycolytic enzyme, has been reported to associate with cell survival and can be triggered under hypoxia. The purposes of this study were to investigate the possible role and regulation of PGK1 in vascular smooth muscle cells (VSMCs) and balloon-injured arteries under hypoxia. Neointimal hyperplasia was induced by a rat carotid artery injury model. The cellular functions and regulatory mechanisms of PGK1 in VSMCs were investigated using small interfering RNAs (siRNAs), chemical inhibitors, or anaerobic cultivation. Our data indicated that protein expression of PGK1 can be rapidly induced at a very early stage after balloon angioplasty, and the silencing PGK1-induced low cellular energy circumstance resulted in the suppressions of VSMC proliferation and migration. Moreover, the experimental results demonstrated that blockage of PDGF receptor-β (PDGFRB) or its downstream pathway, the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis, effectively reduced hypoxia-induced factor-1 (HIF-1α) and PGK1 expressions in VSMCs. In vivo study evidenced that PGK1 knockdown significantly reduced neointima hyperplasia. PGK1 was expressed at the early stage of neointimal formation, and suppressing PGK1 has a potential beneficial effect for preventing restenosis.
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Ghasemishahrestani Z, Melo Mattos LM, Tilli TM, Santos ALSD, Pereira MD. Pieces of the Complex Puzzle of Cancer Cell Energy Metabolism: An Overview of Energy Metabolism and Alternatives for Targeted Cancer Therapy. Curr Med Chem 2021; 28:3514-3534. [PMID: 32814521 DOI: 10.2174/0929867327999200819123357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/17/2020] [Accepted: 07/22/2020] [Indexed: 11/22/2022]
Abstract
Over the past decades, several advances in cancer cell biology have led to relevant details about a phenomenon called the 'Warburg effect'. Currently, it has been accepted that the Warburg effect is not compatible with all cancer cells, and thus the process of aerobic glycolysis is now challenged by the knowledge of a large number of cells presenting mitochondrial function. The energy metabolism of cancer cells is focused on the bioenergetic and biosynthetic pathways in order to meet the requirements of rapid proliferation. Changes in the metabolism of carbohydrates, amino acids and lipids have already been reported for cancer cells and this might play an important role in cancer progression. To the best of our knowledge, these changes are mainly attributed to genetic reprogramming which leads to the transformation of a healthy into a cancerous cell. Indeed, several enzymes that are highly relevant for cellular energy are targets of oncogenes (e.g. PI3K, HIF1, and Myc) and tumor suppressor proteins (e.g. p53). As a consequence of extensive studies on cancer cell metabolism, some new therapeutic strategies have appeared that aim to interrupt the aberrant metabolism, in addition to influencing genetic reprogramming in cancer cells. In this review, we present an overview of cancer cell metabolism (carbohydrate, amino acid, and lipid), and also describe oncogenes and tumor suppressors that directly affect the metabolism. We also discuss some of the potential therapeutic candidates which have been designed to target and disrupt the main driving forces associated with cancer cell metabolism and proliferation.
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Affiliation(s)
- Zeinab Ghasemishahrestani
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Larissa Maura Melo Mattos
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tatiana Martins Tilli
- Centro de Desenvolvimento Tecnologico em Saude, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil
| | - André Luis Souza Dos Santos
- Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcos Dias Pereira
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Nguyen T, Zheng M, Knapp M, Sladojevic N, Zhang Q, Ai L, Harrison D, Chen A, Sitikov A, Shen L, Gonzalez FJ, Zhao Q, Fang Y, Liao JJK, Wu R. Endothelial Aryl Hydrocarbon Receptor Nuclear Translocator Mediates the Angiogenic Response to Peripheral Ischemia in Mice With Type 2 Diabetes Mellitus. Front Cell Dev Biol 2021; 9:691801. [PMID: 34179020 PMCID: PMC8222825 DOI: 10.3389/fcell.2021.691801] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/17/2021] [Indexed: 11/13/2022] Open
Abstract
Hypoxia-inducible factors (HIFs) are the master regulators of angiogenesis, a process that is impaired in patients with diabetes mellitus (DM). The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF1β) has been implicated in the development and progression of diabetes. Angiogenesis is driven primarily by endothelial cells (ECs), but both global and EC-specific loss of ARNT-cause are associated with embryonic lethality. Thus, we conducted experiments in a line of mice carrying an inducible, EC-specific ARNT-knockout mutation (Arnt Δ EC, ERT2) to determine whether aberrations in ARNT expression might contribute to the vascular deficiencies associated with diabetes. Mice were first fed with a high-fat diet to induce diabetes. Arnt Δ EC, ERT2 mice were then adminstrated with oral tamoxifen to disrupt Arnt and peripheral angiogenesis was evaluated by using laser-Doppler perfusion imaging to monitor blood flow after hindlimb ischemia. The Arnt Δ EC, ERT2 mice had impaired blood flow recovery under both non-diabetic and diabetic conditions, but the degree of impairment was greater in diabetic animals. In addition, siRNA-mediated knockdown of ARNT activity reduced measurements of tube formation, and cell viability in human umbilical vein endothelial cells (HUVECs) cultured under high-glucose conditions. The Arnt Δ EC, ERT2 mutation also reduced measures of cell viability, while increasing the production of reactive oxygen species (ROS) in microvascular endothelial cells (MVECs) isolated from mouse skeletal muscle, and the viability of Arnt Δ EC, ERT2 MVECs under high-glucose concentrations increased when the cells were treated with an ROS inhibitor. Collectively, these observations suggest that declines in endothelial ARNT expression contribute to the suppressed angiogenic phenotype in diabetic mice, and that the cytoprotective effect of ARNT expression in ECs is at least partially mediated by declines in ROS production.
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Affiliation(s)
- Tu Nguyen
- Biological Sciences Division – Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Mei Zheng
- Biological Sciences Division – Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Maura Knapp
- Biological Sciences Division – Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Nikola Sladojevic
- Biological Sciences Division – Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Qin Zhang
- Biological Sciences Division – Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Lizhuo Ai
- Biological Sciences Division – Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Devin Harrison
- Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Anna Chen
- Biological Sciences Division – Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Albert Sitikov
- Biological Sciences Division – Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Le Shen
- Section of General Surgery, Department of Surgery, University of Chicago, Chicago, IL, United States
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Qiong Zhao
- Division of Cardiology, Department of Medicine, Inova Heart and Vascular Institute, Annandale, VA, United States
| | - Yun Fang
- Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - James J. K. Liao
- Biological Sciences Division – Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Rongxue Wu
- Biological Sciences Division – Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States
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Kuwano A, Kurokawa M, Kohjima M, Imoto K, Tashiro S, Suzuki H, Tanaka M, Okada S, Kato M, Ogawa Y. Microcirculatory disturbance in acute liver injury. Exp Ther Med 2021; 21:596. [PMID: 33884034 PMCID: PMC8056117 DOI: 10.3892/etm.2021.10028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 10/19/2020] [Indexed: 12/23/2022] Open
Abstract
Microcirculatory disturbance is thought to be involved in the pathogenesis of acute liver injury (ALI). The current study examined the pathophysiologic role of hepatic microcirculatory disturbance in patients with ALI and in mouse models of ALI. Using serum aminotransferase (ALT)/lactate dehydrogenase (LDH) ratio as a hypoxic marker, 279 patients with ALI were classified into the low ALT/LDH ratio (ALT/LDH ≤1.5) and high ALT/LDH ratio group (ALT/LDH >1.5). In the low ALT/LDH ratio group, serum ALT, LDH, fibrinogen degradation products and prothrombin time-international normalized ratio were increased relative to the high ALT/LDH ratio group. Histologically, hepatic expression of tissue factor (TF) and hypoxia-related proteins was enhanced in the low ALT/LDH ratio group, and this was accompanied by sinusoidal fibrin deposition. Sinusoidal hypercoagulation and intrahepatic hypoxia was also analyzed in two different mouse models of ALI; Concanavalin A (ConA) mice and Galactosamine/tumor necrosis factor (TNF)-α (G/T) mice. Serum ALT/LDH ratio in ConA mice was significantly lower compared with G/T mice. Pimonidazole staining revealed the upregulation of hypoxia-related proteins in ConA mice. Recombinant human soluble thrombomodulin improved liver damage in ConA mice in association with reduced sinusoidal hypercoagulation and intrahepatic hypoxia. The present study provides evidence that serum ALT/LDH ratio aids in the identification of patients with ALI and intrahepatic hypoxia as a result of microcirculatory disturbance. The results facilitate the improved understanding of the pathogenesis of ALI, thereby offering a novel therapeutic strategy against ALI, which arises from sinusoidal hypercoagulation.
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Affiliation(s)
- Akifumi Kuwano
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Miho Kurokawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Motoyuki Kohjima
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Koji Imoto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Shigeki Tashiro
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hideo Suzuki
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Masatake Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.,Department of Pathophysiology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Seiji Okada
- Department of Pathophysiology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.,Core Research for Evolutionary Science and Technology (CREST), Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan
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42
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Haase VH. Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease. Kidney Int Suppl (2011) 2021; 11:8-25. [PMID: 33777492 PMCID: PMC7983025 DOI: 10.1016/j.kisu.2020.12.002] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/18/2020] [Accepted: 12/29/2020] [Indexed: 12/11/2022] Open
Abstract
Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) are a promising new class of orally administered drugs currently in late-stage global clinical development for the treatment of anemia of chronic kidney disease (CKD). HIF-PHIs activate the HIF oxygen-sensing pathway and are efficacious in correcting and maintaining hemoglobin levels in patients with non-dialysis- and dialysis-dependent CKD. In addition to promoting erythropoiesis through the increase in endogenous erythropoietin production, HIF-PHIs reduce hepcidin levels and modulate iron metabolism, providing increases in total iron binding capacity and transferrin levels, and potentially reducing the need for i.v. iron supplementation. Furthermore, HIF-activating drugs are predicted to have effects that extend beyond erythropoiesis. This review summarizes clinical data from current HIF-PHI trials in patients with anemia of CKD, discusses mechanisms of action and pharmacologic properties of HIF-PHIs, and deliberates over safety concerns and potential impact on anemia management in patients with CKD.
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Affiliation(s)
- Volker H. Haase
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- Department of Molecular Physiology and Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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43
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Terešak P, Lapao A, Subic N, Boya P, Elazar Z, Simonsen A. Regulation of PRKN-independent mitophagy. Autophagy 2021; 18:24-39. [PMID: 33570005 DOI: 10.1080/15548627.2021.1888244] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Mitochondria are dynamic, multifunctional cellular organelles that play a fundamental role in maintaining cellular homeostasis. Keeping the quality of mitochondria in check is of essential importance for functioning and survival of the cells. Selective autophagic clearance of flawed mitochondria, a process termed mitophagy, is one of the most prominent mechanisms through which cells maintain a healthy mitochondrial pool. The best-studied pathway through which mitophagy is exerted is the PINK1-PRKN pathway. However, an increasing number of studies have shown an existence of alternative pathways, where different proteins and lipids are able to recruit autophagic machinery independently of PINK1 and PRKN. The significance of PRKN-independent mitophagy pathways is reflected in various physiological and pathophysiological processes, but many questions regarding the regulation and the interplay between these pathways remain open. Here we review the current knowledge and recent progress made in the field of PRKN-independent mitophagy. Particularly we focus on the regulation of various receptors that participate in targeting impaired mitochondria to autophagosomes independently of PRKN.AbbreviationsAMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BH: BCL2 homology; CCCP: Carbonyl cyanide m-chlorophenylhydrazone; CL: cardiolipin; ER: endoplasmic reticulum; FCCP: carbonyl cyanide p-trifluoromethoxyphenylhydrazone; IMM: inner mitochondrial membrane; IMS: mitochondrial intermembrane space; LIR: LC3-interacting region; MDVs: mitochondrial-derived vesicles; MTORC1: mechanistic target of rapamycin kinase complex 1; OMM: outer mitochondrial membrane; OXPHOS: oxidative phosphorylation; PD: Parkinson disease; PtdIns3K: phosphatidylinositol 3-kinase; RGC: retinal ganglion cell; RING: really interesting new gene; ROS: reactive oxygen species; SUMO: small ubiquitin like modifier; TBI: traumatic brain injury; TM: transmembrane.
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Affiliation(s)
- Petra Terešak
- Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Ana Lapao
- Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Nemanja Subic
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Patricia Boya
- Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Zvulun Elazar
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Anne Simonsen
- Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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44
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Tumor Cells and Cancer-Associated Fibroblasts: An Updated Metabolic Perspective. Cancers (Basel) 2021; 13:cancers13030399. [PMID: 33499022 PMCID: PMC7865797 DOI: 10.3390/cancers13030399] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/16/2021] [Accepted: 01/18/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Tumors are a complex ecosystem including not only cancer cells, but also many distinct cell types of the tumor micro-environment. While the Warburg effect assessing high glucose uptake in tumors was recognized a long time ago, metabolic heterogeneity within tumors has only recently been demonstrated. Indeed, several recent studies have highlighted other sources of carbon than glucose, including amino acids, fatty acids and lactate. These newly identified metabolic trajectories modulate key cancer cell features, such as invasion capacities. In addition, cancer metabolic heterogeneity is not restricted to cancer cells. Here, we also describe heterogeneity of Cancer-Associated Fibroblast (CAF) subpopulations and their complex metabolic crosstalk with cancer cells. Abstract During the past decades, metabolism and redox imbalance have gained considerable attention in the cancer field. In addition to the well-known Warburg effect occurring in tumor cells, numerous other metabolic deregulations have now been reported. Indeed, metabolic reprograming in cancer is much more heterogeneous than initially thought. In particular, a high diversity of carbon sources used by tumor cells has now been shown to contribute to this metabolic heterogeneity in cancer. Moreover, the molecular mechanisms newly highlighted are multiple and shed light on novel actors. Furthermore, the impact of this metabolic heterogeneity on tumor microenvironment has also been an intense subject of research recently. Here, we will describe the new metabolic pathways newly uncovered in tumor cells. We will also have a particular focus on Cancer-Associated Fibroblasts (CAF), whose identity, function and metabolism have been recently under profound investigation. In that sense, we will discuss about the metabolic crosstalk between tumor cells and CAF.
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45
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Hypoxia-Mediated Decrease of Ovarian Cancer Cells Reaction to Treatment: Significance for Chemo- and Immunotherapies. Int J Mol Sci 2020; 21:ijms21249492. [PMID: 33327450 PMCID: PMC7764929 DOI: 10.3390/ijms21249492] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 11/30/2020] [Accepted: 12/08/2020] [Indexed: 12/20/2022] Open
Abstract
Hypoxia, a common factor ruling the microenvironment composition, leads to tumor progression. In this hypoxic context, cytokines and cells cooperate to favor cancer development and metastasis. Tumor hypoxia is heterogeneously distributed. Oxygen gradients depend on the vicinity, functionality of blood vessels, and oxygen ability to diffuse into surrounding tissues. Thus, the vasculature state modulates the microenvironment of the tumor cells. Cells sense and react to small variations in oxygen tension, which explains the lack of tumor cells’ unicity in their reaction to drugs. Ovarian cancers are highly hypoxia-dependent, ascites worsening the access to oxygen, in their reactions to both chemotherapy and new immunotherapy. Consequently, hypoxia affects the results of immunotherapy, and is thus, crucial for the design of treatments. Controlling key immunosuppressive factors and receptors, as well as immune checkpoint molecule expression on tumor, immune and stromal cells, hypoxia induces immunosuppression. Consequently, new approaches to alleviate hypoxia in the tumor microenvironment bring promises for ovarian cancer immunotherapeutic strategies. This review focuses on the effects of hypoxia in the microenvironment and its consequences on tumor treatments. This opens the way to innovative combined treatments to the advantage of immunotherapy outcome in ovarian cancers.
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46
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Lin Z, King R, Tang V, Myers G, Balbin-Cuesta G, Friedman A, McGee B, Desch K, Ozel AB, Siemieniak D, Reddy P, Emmer B, Khoriaty R. The Endoplasmic Reticulum Cargo Receptor SURF4 Facilitates Efficient Erythropoietin Secretion. Mol Cell Biol 2020; 40:e00180-20. [PMID: 32989016 PMCID: PMC7652404 DOI: 10.1128/mcb.00180-20] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/20/2020] [Accepted: 09/24/2020] [Indexed: 12/16/2022] Open
Abstract
Erythropoietin (EPO) stimulates erythroid differentiation and maturation. Though the transcriptional regulation of EPO has been well studied, the molecular determinants of EPO secretion remain unknown. Here, we generated a HEK293T reporter cell line that provides a quantifiable and selectable readout of intracellular EPO levels and performed a genome-scale CRISPR screen that identified SURF4 as an important mediator of EPO secretion. Targeting SURF4 with multiple independent single guide RNAs (sgRNAs) resulted in intracellular accumulation and extracellular depletion of EPO. Both of these phenotypes were rescued by expression of SURF4 cDNA. Additionally, we found that disruption of SURF4 resulted in accumulation of EPO in the endoplasmic reticulum (ER) compartment and that SURF4 and EPO physically interact. Furthermore, SURF4 disruption in Hep3B cells also caused a defect in the secretion of endogenous EPO under conditions mimicking hypoxia, ruling out an artifact of heterologous overexpression. This work demonstrates that SURF4 functions as an ER cargo receptor that mediates the efficient secretion of EPO. Our findings also suggest that modulating SURF4 may be an effective treatment for disorders of erythropoiesis that are driven by aberrant EPO levels. Finally, we show that SURF4 overexpression results in increased secretion of EPO, suggesting a new strategy for more efficient production of recombinant EPO.
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Affiliation(s)
- Zesen Lin
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
| | - Richard King
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Vi Tang
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Greggory Myers
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ginette Balbin-Cuesta
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA
- Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, USA
| | - Ann Friedman
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Beth McGee
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Karl Desch
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA
- Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA
| | - Ayse Bilge Ozel
- Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
| | - David Siemieniak
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA
| | - Pavan Reddy
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA
- University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA
| | - Brian Emmer
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Rami Khoriaty
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA
- University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA
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Xu M, Wang P, Sun S, Gao L, Sun L, Zhang L, Zhang J, Wang S, Liang X. Smart strategies to overcome tumor hypoxia toward the enhancement of cancer therapy. NANOSCALE 2020; 12:21519-21533. [PMID: 33095224 DOI: 10.1039/d0nr05501h] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Hypoxia, as a typical factor in a tumor microenvironment, plays a vital role in tumor treatment resistance, tumor invasion and migration. Hypoxia inducible factor (HIF), as the vital response element of hypoxia, mediates these untoward effects through a series of downstream reactions. Cancer treatments such as photodynamic therapy (PDT), radiotherapy (RT) and chemotherapy are severely hindered by hypoxia and HIF, back, however, could be intelligently manipulated through nanocomposite materials for their great potentiality to combine different functions. Herein, we reviewed the smart strategies in emerging research studies to overcome hypoxia toward the enhancement of tumor therapy.
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Affiliation(s)
- Menghong Xu
- Department of Ultrasound, Peking University Third Hospital, Beijing 100191, P. R. China.
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Iranparast S, Tayebi S, Ahmadpour F, Yousefi B. Tumor-Induced Metabolism and T Cells Located in Tumor Environment. Curr Cancer Drug Targets 2020; 20:741-756. [PMID: 32691710 DOI: 10.2174/1568009620666200720010647] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/30/2020] [Accepted: 05/04/2020] [Indexed: 12/14/2022]
Abstract
Several subtypes of T cells are located in a tumor environment, each of which supplies their energy using different metabolic mechanisms. Since the cancer cells require high levels of glucose, the conditions of food poverty in the tumor environment can cause inactivation of immune cells, especially the T-effector cells, due to the need for glucose in the early stages of these cells activity. Different signaling pathways, such as PI3K-AKt-mTOR, MAPK, HIF-1α, etc., are activated or inactivated by the amount and type of energy source or oxygen levels that determine the fate of T cells in a cancerous environment. This review describes the metabolites in the tumor environment and their effects on the function of T cells. It also explains the signaling pathway of T cells in the tumor and normal conditions, due to the level of access to available metabolites and subtypes of T cells in the tumor environment.
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Affiliation(s)
- Sara Iranparast
- Department of Immunology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran,Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sanaz Tayebi
- Department of Immunology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Fatemeh Ahmadpour
- Department of Biochemistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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49
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Kling L, Schreiber A, Eckardt KU, Kettritz R. Hypoxia-inducible factors not only regulate but also are myeloid-cell treatment targets. J Leukoc Biol 2020; 110:61-75. [PMID: 33070368 DOI: 10.1002/jlb.4ri0820-535r] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 12/19/2022] Open
Abstract
Hypoxia describes limited oxygen availability at the cellular level. Myeloid cells are exposed to hypoxia at various bodily sites and even contribute to hypoxia by consuming large amounts of oxygen during respiratory burst. Hypoxia-inducible factors (HIFs) are ubiquitously expressed heterodimeric transcription factors, composed of an oxygen-dependent α and a constitutive β subunit. The stability of HIF-1α and HIF-2α is regulated by oxygen-sensing prolyl-hydroxylases (PHD). HIF-1α and HIF-2α modify the innate immune response and are context dependent. We provide a historic perspective of HIF discovery, discuss the molecular components of the HIF pathway, and how HIF-dependent mechanisms modify myeloid cell functions. HIFs enable myeloid-cell adaptation to hypoxia by up-regulating anaerobic glycolysis. In addition to effects on metabolism, HIFs control chemotaxis, phagocytosis, degranulation, oxidative burst, and apoptosis. HIF-1α enables efficient infection defense by myeloid cells. HIF-2α delays inflammation resolution and decreases antitumor effects by promoting tumor-associated myeloid-cell hibernation. PHDs not only control HIF degradation, but also regulate the crosstalk between innate and adaptive immune cells thereby suppressing autoimmunity. HIF-modifying pharmacologic compounds are entering clinical practice. Current indications include renal anemia and certain cancers. Beneficial and adverse effects on myeloid cells should be considered and could possibly lead to drug repurposing for inflammatory disorders.
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Affiliation(s)
- Lovis Kling
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Adrian Schreiber
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.,Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Ralph Kettritz
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.,Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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50
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Todd VM, Johnson RW. Hypoxia in bone metastasis and osteolysis. Cancer Lett 2020; 489:144-154. [PMID: 32561416 PMCID: PMC7429356 DOI: 10.1016/j.canlet.2020.06.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 05/15/2020] [Accepted: 06/01/2020] [Indexed: 12/19/2022]
Abstract
Hypoxia is a common feature in tumors, driving pathways that promote epithelial-to-mesenchymal transition, invasion, and metastasis. Clinically, high levels of hypoxia-inducible factor (HIF) expression and stabilization at the primary site in many cancer types is associated with poor patient outcomes. Experimental evidence suggests that HIF signaling in the primary tumor promotes their dissemination to the bone, as well as the release of factors such as LOX that act distantly on the bone to stimulate osteolysis and form a pre-metastatic niche. Additionally, the bone itself is a generally hypoxic organ, fueling the activation of HIF signaling in bone resident cells, promoting tumor cell homing to the bone as well as osteoclastogenesis. The hypoxic microenvironment of the bone also stimulates the vicious cycle of tumor-induced bone destruction, further fueling tumor cell growth and osteolysis. Furthermore, hypoxia appears to regulate key tumor dormancy factors. Thus, hypoxia acts both on the tumor cells as well as the metastatic site to promote tumor cell metastasis.
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Affiliation(s)
- Vera M Todd
- Graduate Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA; Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rachelle W Johnson
- Graduate Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA; Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
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