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Yang S, Cui Y, Ma R, Yu S, Zhang H, Zhao P, He J. Hypoxia Regulates the Proliferation and Apoptosis of Coronary Artery Smooth Muscle Cells Through HIF-1α Mediated Autophagy in Yak. Biomolecules 2025; 15:256. [PMID: 40001559 PMCID: PMC11853270 DOI: 10.3390/biom15020256] [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: 01/03/2025] [Revised: 02/07/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025] Open
Abstract
Cell proliferation and migration mediated by hypoxia-inducible factor-1α (HIF-1α) are important processes of hypoxic cardiac vascular remodeling. HIF-1α also regulates the physiological hypoxic adaptation of the coronary artery in the yak heart, but the potential mechanism remains to be completely elucidated. In this study, coronary artery proliferation increased with age and hypoxia adaptation time. In vitro analysis showed that hypoxia can promote the proliferation of coronary vascular smooth muscle cells (CASMCs). Meanwhile, HIF-1α plays an important role in the regulation of proliferation and migration under hypoxia. Autophagy regulates cell proliferation and migration to participate in hypoxia adaptation in plateau animals. Here, the level of autophagy increased significantly in yak coronary arteries with age and was regulated by HIF-1α-mediated hypoxia. In addition, autophagy could also mediate the hypoxic effect on the proliferation and migration of CASMCs. In summary, the results revealed that the increase in yak heart coronary artery thickening with age increases vascular smooth muscle cell proliferation and migration, mainly achieved through hypoxia-mediated HIF-1α-regulated autophagy. These results contribute to understanding how the heart adapts to life in a hypoxic environment.
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Affiliation(s)
- Shanshan Yang
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; (S.Y.); (R.M.); (S.Y.); (H.Z.); (P.Z.); (J.H.)
| | - Yan Cui
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; (S.Y.); (R.M.); (S.Y.); (H.Z.); (P.Z.); (J.H.)
- Gansu Province Livestock Embryo Engineering Research Center, Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Rui Ma
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; (S.Y.); (R.M.); (S.Y.); (H.Z.); (P.Z.); (J.H.)
| | - Sijiu Yu
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; (S.Y.); (R.M.); (S.Y.); (H.Z.); (P.Z.); (J.H.)
- Gansu Province Livestock Embryo Engineering Research Center, Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Hui Zhang
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; (S.Y.); (R.M.); (S.Y.); (H.Z.); (P.Z.); (J.H.)
| | - Pengfei Zhao
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; (S.Y.); (R.M.); (S.Y.); (H.Z.); (P.Z.); (J.H.)
| | - Junfeng He
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; (S.Y.); (R.M.); (S.Y.); (H.Z.); (P.Z.); (J.H.)
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Razavi ZS, Farokhi S, Mahmoudvand G, Karimi-Rouzbahani A, Farasati-Far B, Tahmasebi-Ghorabi S, Pazoki-Toroudi H, Saadat-Fakhr M, Afkhami H. Stem cells and bio scaffolds for the treatment of cardiovascular diseases: new insights. Front Cell Dev Biol 2024; 12:1472103. [PMID: 39726717 PMCID: PMC11669526 DOI: 10.3389/fcell.2024.1472103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 10/01/2024] [Indexed: 12/28/2024] Open
Abstract
Mortality and morbidity from cardiovascular diseases are common worldwide. In order to improve survival and quality of life for this patient population, extensive efforts are being made to establish effective therapeutic modalities. New treatment options are needed, it seems. In addition to treating cardiovascular diseases, cell therapy is one of the most promising medical platforms. One of the most effective therapeutic approaches in this area is stem cell therapy. In stem cell biology, multipotent stem cells and pluripotent stem cells are divided into two types. There is evidence that stem cell therapy could be used as a therapeutic approach for cardiovascular diseases based on multiple lines of evidence. The effectiveness of stem cell therapies in humans has been studied in several clinical trials. In spite of the challenges associated with stem cell therapy, it appears that resolving them may lead to stem cells being used in cardiovascular disease patients. This may be an effective therapeutic approach. By mounting these stem cells on biological scaffolds, their effect can be enhanced.
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Affiliation(s)
- Zahra Sadat Razavi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Simin Farokhi
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Golnaz Mahmoudvand
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Arian Karimi-Rouzbahani
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Bahareh Farasati-Far
- Department of Chemistry, Iran University of Science and Technology, Tehran, Iran
| | - Samaneh Tahmasebi-Ghorabi
- Master of Health Education, Research Expert, Clinical Research Development Unit, Emam Khomeini Hospital, Ilam University of Medical Sciences, Ilam, Iran
| | | | - Masoud Saadat-Fakhr
- Faculty of Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
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Lidonnici J, Oberkersch RE. Reciprocal Dynamics of Metabolism and mRNA Translation in Tumor Angiogenesis. Int J Mol Sci 2024; 25:11284. [PMID: 39457064 PMCID: PMC11508371 DOI: 10.3390/ijms252011284] [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: 09/26/2024] [Revised: 10/17/2024] [Accepted: 10/18/2024] [Indexed: 10/28/2024] Open
Abstract
Angiogenesis, the process of formation of new blood vessels from pre-existing vasculature, is essential for tumor growth and metastasis. Anti-angiogenic treatment targeting vascular endothelial growth factor (VEGF) signaling is a powerful tool to combat tumor growth; however, anti-tumor angiogenesis therapy has shown limited efficacy, with survival benefits ranging from only a few weeks to months. Compensation by upregulation of complementary growth factors and switches to different modes of vascularization have made these types of therapies less effective. Recent evidence suggests that targeting specific players in endothelial metabolism is a valuable therapeutic strategy against tumor angiogenesis. Although it is clear that metabolism can modulate the translational machinery, the reciprocal relationship between metabolism and mRNA translational control during tumor angiogenesis is not fully understood. In this review, we explore emerging examples of how endothelial cell metabolism affects mRNA translation during the formation of blood vessels. A deeper comprehension of these mechanisms could lead to the development of innovative therapeutic strategies for both physiological and pathological angiogenesis.
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Affiliation(s)
- Jacopo Lidonnici
- Department of Surgery, Oncology and Gastroenterology, Section of Oncology and Immunology, University of Padova, 35128 Padova, Italy;
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Rahane D, Dhingra T, Chalavady G, Datta A, Ghosh B, Rana N, Borah A, Saraf S, Bhattacharya P. Hypoxia and its effect on the cellular system. Cell Biochem Funct 2024; 42:e3940. [PMID: 38379257 DOI: 10.1002/cbf.3940] [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: 10/31/2023] [Revised: 01/08/2024] [Accepted: 01/11/2024] [Indexed: 02/22/2024]
Abstract
Eukaryotic cells utilize oxygen for different functions of cell organelles owing to cellular survival. A balanced oxygen homeostasis is an essential requirement to maintain the regulation of normal cellular systems. Any changes in the oxygen level are stressful and can alter the expression of different homeostasis regulatory genes and proteins. Lack of oxygen or hypoxia results in oxidative stress and formation of hypoxia inducible factors (HIF) and reactive oxygen species (ROS). Substantial cellular damages due to hypoxia have been reported to play a major role in various pathological conditions. There are different studies which demonstrated that the functions of cellular system are disrupted by hypoxia. Currently, study on cellular effects following hypoxia is an important field of research as it not only helps to decipher different signaling pathway modulation, but also helps to explore novel therapeutic strategies. On the basis of the beneficial effect of hypoxia preconditioning of cellular organelles, many therapeutic investigations are ongoing as a promising disease management strategy in near future. Hence, the present review discusses about the effects of hypoxia on different cellular organelles, mechanisms and their involvement in the progression of different diseases.
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Affiliation(s)
- Dipali Rahane
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Tannu Dhingra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Guruswami Chalavady
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Aishika Datta
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Bijoyani Ghosh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Nikita Rana
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Shailendra Saraf
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
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Bouhamida E, Morciano G, Pedriali G, Ramaccini D, Tremoli E, Giorgi C, Pinton P, Patergnani S. The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches. Int J Mol Sci 2023; 24:11105. [PMID: 37446282 DOI: 10.3390/ijms241311105] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/26/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023] Open
Abstract
Calcific aortic valve stenosis (CAVS) is among the most common causes of cardiovascular mortality in an aging population worldwide. The pathomechanisms of CAVS are such a complex and multifactorial process that researchers are still making progress to understand its physiopathology as well as the complex players involved in CAVS pathogenesis. Currently, there is no successful and effective treatment to prevent or slow down the disease. Surgical and transcatheter valve replacement represents the only option available for treating CAVS. Insufficient oxygen availability (hypoxia) has a critical role in the pathogenesis of almost all CVDs. This process is orchestrated by the hallmark transcription factor, hypoxia-inducible factor 1 alpha subunit (HIF-1α), which plays a pivotal role in regulating various target hypoxic genes and metabolic adaptations. Recent studies have shown a great deal of interest in understanding the contribution of HIF-1α in the pathogenesis of CAVS. However, it is deeply intertwined with other major contributors, including sustained inflammation and mitochondrial impairments, which are attributed primarily to CAVS. The present review aims to cover the latest understanding of the complex interplay effect of hypoxia signaling pathways, mitochondrial dysfunction, and inflammation in CAVS. We propose further hypotheses and interconnections on the complexity of these impacts in a perspective of better understanding the pathophysiology. These interplays will be examined considering recent studies that shall help us better dissect the molecular mechanism to enable the design and development of potential future therapeutic approaches that can prevent or slow down CAVS processes.
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Affiliation(s)
- Esmaa Bouhamida
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy
| | - Giampaolo Morciano
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Gaia Pedriali
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy
| | - Daniela Ramaccini
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy
| | - Elena Tremoli
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy
| | - Carlotta Giorgi
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Paolo Pinton
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Simone Patergnani
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy
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Gray OA, Yoo J, Sobreira DR, Jousma J, Witonsky D, Sakabe NJ, Peng YJ, Prabhakar NR, Fang Y, Nobréga MA, Di Rienzo A. A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans. SCIENCE ADVANCES 2022; 8:eade1942. [PMID: 36417539 PMCID: PMC9683707 DOI: 10.1126/sciadv.ade1942] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 10/25/2022] [Indexed: 06/16/2023]
Abstract
In Tibetans, noncoding alleles in EPAS1-whose protein product hypoxia-inducible factor 2α (HIF-2α) drives the response to hypoxia-carry strong signatures of positive selection; however, their functional mechanism has not been systematically examined. Here, we report that high-altitude alleles disrupt the activity of four EPAS1 enhancers in one or more cell types. We further characterize one enhancer (ENH5) whose activity is both allele specific and hypoxia dependent. Deletion of ENH5 results in down-regulation of EPAS1 and HIF-2α targets in acute hypoxia and in a blunting of the transcriptional response to sustained hypoxia. Deletion of ENH5 in mice results in dysregulation of gene expression across multiple tissues. We propose that pleiotropic adaptive effects of the Tibetan alleles in EPAS1 underlie the strong selective signal at this gene.
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Affiliation(s)
- Olivia A. Gray
- Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
| | - Jennifer Yoo
- Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
- Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, IL 60637, USA
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Débora R. Sobreira
- Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
| | - Jordan Jousma
- Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
| | - David Witonsky
- Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
| | - Noboru J. Sakabe
- Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
| | - Ying-Jie Peng
- Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, IL 60637, USA
| | - Nanduri R. Prabhakar
- Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, IL 60637, USA
| | - Yun Fang
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Marcelo A. Nobréga
- Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
| | - Anna Di Rienzo
- Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
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Effects of Six Weeks of Hypoxia Exposure on Hepatic Fatty Acid Metabolism in ApoE Knockout Mice Fed a High-Fat Diet. LIFE (BASEL, SWITZERLAND) 2022; 12:life12101535. [PMID: 36294970 PMCID: PMC9605121 DOI: 10.3390/life12101535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/08/2022] [Accepted: 09/28/2022] [Indexed: 11/05/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease with a characteristic of abnormal lipid metabolism. In the present study, we employed apolipoprotein E knockout (ApoE KO) mice to investigate the effects of hypoxia exposure on hepatic fatty acid metabolism and to test whether a high-fat diet (HFD) would suppress the beneficial effect caused by hypoxia treatment. ApoE KO mice were fed a HFD for 12 weeks, and then were forwarded into a six-week experiment with four groups: HFD + normoxia, normal diet (ND) + normoxia, HFD + hypoxia exposure (HE), and ND + HE. The C57BL/6J wild type (WT) mice were fed a ND for 18 weeks as the baseline control. The hypoxia exposure was performed in daytime with normobaric hypoxia (11.2% oxygen, 1 h per time, three times per week). Body weight, food and energy intake, plasma lipid profiles, hepatic lipid contents, plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and molecular/biochemical makers and regulators of the fatty acid synthesis and oxidation in the liver were measured at the end of interventions. Six weeks of hypoxia exposure decreased plasma triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) contents but did not change hepatic TG and non-esterified fatty acid (NEFA) levels in ApoE KO mice fed a HFD or ND. Furthermore, hypoxia exposure decreased the mRNA expression of Fasn, Scd1, and Srebp-1c significantly in the HFD + HE group compared with those in the HFD + normoxia group; after replacing a HFD with a ND, hypoxia treatment achieved more significant changes in the measured variables. In addition, the protein expression of HIF-1α was increased only in the ND + HE group but not in the HFD + HE group. Even though hypoxia exposure did not affect hepatic TG and NEFA levels, at the genetic level, the intervention had significant effects on hepatic metabolic indices of fatty acid synthesis, especially in the ND + HE group, while HFD suppressed the beneficial effect of hypoxia on hepatic lipid metabolism in male ApoE KO mice. The dietary intervention of shifting HFD to ND could be more effective in reducing hepatic lipid accumulation than hypoxia intervention.
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Marwarha G, Røsand Ø, Slagsvold KH, Høydal MA. GSK3β Inhibition Is the Molecular Pivot That Underlies the Mir-210-Induced Attenuation of Intrinsic Apoptosis Cascade during Hypoxia. Int J Mol Sci 2022; 23:ijms23169375. [PMID: 36012628 PMCID: PMC9409400 DOI: 10.3390/ijms23169375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/09/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Apoptotic cell death is a deleterious consequence of hypoxia-induced cellular stress. The master hypoxamiR, microRNA-210 (miR-210), is considered the primary driver of the cellular response to hypoxia stress. We have recently demonstrated that miR-210 attenuates hypoxia-induced apoptotic cell death. In this paper, we unveil that the miR-210-induced inhibition of the serine/threonine kinase Glycogen Synthase Kinase 3 beta (GSK3β) in AC-16 cardiomyocytes subjected to hypoxia stress underlies the salutary protective response of miR-210 in mitigating the hypoxia-induced apoptotic cell death. Using transient overexpression vectors to augment miR-210 expression concomitant with the ectopic expression of the constitutive active GSK3β S9A mutant (ca-GSK3β S9A), we exhaustively performed biochemical and molecular assays to determine the status of the hypoxia-induced intrinsic apoptosis cascade. Caspase-3 activity analysis coupled with DNA fragmentation assays cogently demonstrate that the inhibition of GSK3β kinase activity underlies the miR-210-induced attenuation in the hypoxia-driven apoptotic cell death. Further elucidation and delineation of the upstream cellular events unveiled an indispensable role of the inhibition of GSK3β kinase activity in mediating the miR-210-induced mitigation of the hypoxia-driven BAX and BAK insertion into the outer mitochondria membrane (OMM) and the ensuing Cytochrome C release into the cytosol. Our study is the first to unveil that the inhibition of GSK3β kinase activity is indispensable in mediating the miR-210-orchestrated protective cellular response to hypoxia-induced apoptotic cell death.
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Affiliation(s)
- Gurdeep Marwarha
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology (NTNU), 7034 Trondheim, Norway
| | - Øystein Røsand
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology (NTNU), 7034 Trondheim, Norway
| | - Katrine Hordnes Slagsvold
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology (NTNU), 7034 Trondheim, Norway
- Department of Cardiothoracic Surgery, St. Olavs University Hospital, 7030 Trondheim, Norway
| | - Morten Andre Høydal
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology (NTNU), 7034 Trondheim, Norway
- Correspondence: ; Tel.: +47-48134843
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Ntagwabira F, Trujillo M, McElroy T, Brown T, Simmons P, Sykes D, Allen AR. Piperlongumine as a Neuro-Protectant in Chemotherapy Induced Cognitive Impairment. Int J Mol Sci 2022; 23:2008. [PMID: 35216124 PMCID: PMC8880369 DOI: 10.3390/ijms23042008] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/05/2022] [Accepted: 02/07/2022] [Indexed: 11/16/2022] Open
Abstract
Advances in the early diagnosis and treatment have led to increases in breast cancer survivorship. Survivors report cognitive impairment symptoms such as loss of concentration and learning and memory deficits which significantly reduce the patient's quality of life. Additional therapies are needed to prevent these side effects and, the precise mechanisms of action responsible are not fully elucidated. However, increasing evidence points toward the use of neuroprotective compounds with antioxidants and anti-inflammatory properties as tools for conserving learning and memory. Here, we examine the ability of piperlongumine (PL), an alkaloid known to have anti-inflammatory and antioxidant effects, to play a neuroprotective role in 16-week-old female C57BL/6J mice treated with a common breast cancer regimen of doxorubicin, cyclophosphamide, and docetaxel (TAC). During social memory testing, TAC-treated mice exhibited impairment, while TAC/PL co-treated mice did not exhibit measurable social memory deficits. Proteomics analysis showed ERK1/2 signaling is involved in TAC and TAC/PL co-treatment. Reduced Nrf2 mRNA expression was also observed. mRNA levels of Gria2 were increased in TAC treated mice and reduced in TAC/PL co-treated mice. In this study, PL protects against social memory impairment when co-administered with TAC via multifactorial mechanisms involving oxidative stress and synaptic plasticity.
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Affiliation(s)
- Fabio Ntagwabira
- Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (F.N.); (M.T.); (T.M.); (T.B.); (P.S.)
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
- Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
| | - Madison Trujillo
- Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (F.N.); (M.T.); (T.M.); (T.B.); (P.S.)
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
- Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
| | - Taylor McElroy
- Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (F.N.); (M.T.); (T.M.); (T.B.); (P.S.)
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
- Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
| | - Taurean Brown
- Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (F.N.); (M.T.); (T.M.); (T.B.); (P.S.)
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
- Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
| | - Pilar Simmons
- Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (F.N.); (M.T.); (T.M.); (T.B.); (P.S.)
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
| | | | - Antiño R. Allen
- Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (F.N.); (M.T.); (T.M.); (T.B.); (P.S.)
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
- Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
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Voulalas G, Tsui J, Candilio L, Baker D. SARS-CoV-2 and Pre-existing Vascular Diseases: Guilt by Association? CLINICAL MEDICINE INSIGHTS-CARDIOLOGY 2021; 15:11795468211010705. [PMID: 34035654 PMCID: PMC8132081 DOI: 10.1177/11795468211010705] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 03/17/2021] [Indexed: 01/08/2023]
Abstract
Severe Acute Respiratory Syndrome coronavirus-2 has rapidly spread and emerged as a pandemic. Although evidence on its pathophysiology is growing, there are still issues that should be taken into consideration, including its effects on pre-existing peripheral vascular disease. The aim of this review is to describe the thrombotic and endothelial dysfunctions caused by SARS-CoV-2, assess if cardiovascular comorbidities render an individual susceptible to the infection and determine the course of pre-existing vascular diseases in infected individuals. A search through MEDLINE, PubMed and EMBASE was conducted and more than 260 articles were identified and 97 of them were reviewed; the rest were excluded because they were not related to the aim of this study. Hypertension, cardiovascular disease, diabetes mellitus and cerebrovascular diseases comprised 24.30% ± 16.23%, 13.29% ± 12.88%, 14.82% ± 7.57% and 10.82% ± 11.64% of the cohorts reviewed, respectively. Arterial and venous thrombotic complications rocketed up to 31% in severely infected individuals in some studies. We suggest that hypertension, cardiovascular diseases, diabetes and cerebrovascular diseases may render an individual susceptible to severe COVID-19 infection. Pre-existing vascular diseases are expected to deteriorate with SARS-CoV-2 infection as a consequence of its increased thrombotic burden and the development of endothelial dysfunction. COVID-19 has emerged only a few months ago and it is premature to predict the long-term effects to the vascular system. Its disturbances of the coagulation mechanisms and effects on vascular endothelium will likely provoke a surge of vascular complications in the coming months.
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Affiliation(s)
- Grigorios Voulalas
- Vascular Surgery Department, Royal Free London NHS Foundation Trust, London, UK
- Division of Surgery & Interventional Science, University College London, UK
| | - Janice Tsui
- Vascular Surgery Department, Royal Free London NHS Foundation Trust, London, UK
- Division of Surgery & Interventional Science, University College London, UK
| | - Luciano Candilio
- Cardiology Department, Royal Free London NHS Foundation Trust, London, UK
| | - Daryll Baker
- Vascular Surgery Department, Royal Free London NHS Foundation Trust, London, UK
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11
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Špaková I, Rabajdová M, Mičková H, Graier WF, Mareková M. Effect of hypoxia factors gene silencing on ROS production and metabolic status of A375 malignant melanoma cells. Sci Rep 2021; 11:10325. [PMID: 33990669 PMCID: PMC8121821 DOI: 10.1038/s41598-021-89792-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 04/29/2021] [Indexed: 01/04/2023] Open
Abstract
The innate response of melanocytes to exogenous or endogenous stress stimuli like extreme pH and temperature, metabolite and oxygen deficiency or a high UV dose initiates a cellular stress response. This process activates adaptive processes to minimize the negative impact of the stressor on the pigment cell. Under physiological conditions, a non-cancer cell is directed to apoptosis if the stressor persists. However, malignant melanoma cells will survive persistent stress thanks to distinct "cancerous" signaling pathways (e.g. MEK) and transcription factors that regulate the expression of so-called "survival genes" (e.g. HIF, MITF). In this survival response of cancer cells, MEK pathway directs melanoma cells to deregulate mitochondrial metabolism, to accumulate reduced species (NADH), and to centralize metabolism in the cytosol. The aim of this work was to study the effect of gene silencing in malignant melanoma A375 cells on metabolic processes in cytosol and mitochondria. Gene silencing of HIF-1α, and miR-210 in normoxia and pseudohypoxia, and analysis of its effect on MITF-M, and PDHA1 expression. Detection of cytosolic NADH by Peredox-mCherry Assay. Detection of OCR, and ECAR using Seahorse XF96. Measurement of produced O2•- with MitoTracker Red CMXRos. 1H NMR analysis of metabolites present in cell suspension, and medium. By gene silencing of HIF-1α and miR-210 the expression of PDHA1 was upregulated while that of MITF-M was downregulated, yielding acceleration of mitochondrial respiratory activity and thus elimination of ROS. Hence, we detected a significantly reduced A375 cell viability, an increase in alanine, inositol, nucleotides, and other metabolites that together define apoptosis. Based on the results of measurements of mitochondrial resipiratory activity, ROS production, and changes in the metabolites obtained in cells under the observed conditions, we concluded that silencing of HIF-1α and miR-210 yields apoptosis and, ultimately, apoptotic cell death in A375 melanoma cells.
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Affiliation(s)
- Ivana Špaková
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 04011, Košice, Slovakia
| | - Miroslava Rabajdová
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 04011, Košice, Slovakia.
| | - Helena Mičková
- Department of Biology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Košice, Slovakia
| | - Wolfgang F Graier
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.,BioTechMed, Graz, Austria
| | - Mária Mareková
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 04011, Košice, Slovakia
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12
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Walke GR, Meron S, Shenberger Y, Gevorkyan‐Airapetov L, Ruthstein S. Cellular Uptake of the ATSM-Cu(II) Complex under Hypoxic Conditions. ChemistryOpen 2021; 10:486-492. [PMID: 33908707 PMCID: PMC8080296 DOI: 10.1002/open.202100044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/08/2021] [Indexed: 12/21/2022] Open
Abstract
The Cu(II)-diacetyl-bis (N4-methylthiosemicarbazone) complex (ATSM-Cu(II)) has been suggested as a promising positron emission tomography (PET) agent for hypoxia imaging. Several in-vivo studies have shown its potential to detect hypoxic tumors. However, its uptake mechanism and its specificity to various cancer cell lines have been less studied. Herein, we tested ATSM-Cu(II) toxicity, uptake, and reduction, using four different cell types: (1) mouse breast cancer cells (DA-3), (2) human embryonic kidney cells (HEK-293), (3) breast cancer cells (MCF-7), and (4) cervical cancer cells (Hela) under normoxic and hypoxic conditions. We showed that ATSM-Cu(II) is toxic to breast cancer cells under normoxic and hypoxic conditions; however, it is not toxic to normal HEK-293 non-cancer cells. We showed that the Cu(I) content in breast cancer cell after treatment with ATSM-Cu(II) under hypoxic conditions is higher than in normal cells, despite that the uptake of ATSM-Cu(II) is a bit higher in normal cells than in breast cancer cells. This study suggests that the redox potential of ATSM-Cu(II) is higher in breast cancer cells than in normal cells; thus, its toxicity to cancer cells is increased.
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Affiliation(s)
- Gulshan R. Walke
- Department of ChemistryFaculty of Exact Sciences, and theInstitute for Nanotechnology and advanced materials (BINA)Bar-Ilan University5290002Ramat-GanIsrael
| | - Shelly Meron
- Department of ChemistryFaculty of Exact Sciences, and theInstitute for Nanotechnology and advanced materials (BINA)Bar-Ilan University5290002Ramat-GanIsrael
| | - Yulia Shenberger
- Department of ChemistryFaculty of Exact Sciences, and theInstitute for Nanotechnology and advanced materials (BINA)Bar-Ilan University5290002Ramat-GanIsrael
| | - Lada Gevorkyan‐Airapetov
- Department of ChemistryFaculty of Exact Sciences, and theInstitute for Nanotechnology and advanced materials (BINA)Bar-Ilan University5290002Ramat-GanIsrael
| | - Sharon Ruthstein
- Department of ChemistryFaculty of Exact Sciences, and theInstitute for Nanotechnology and advanced materials (BINA)Bar-Ilan University5290002Ramat-GanIsrael
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VandenBrooks JM, Ford CF, Harrison JF. Responses to Alteration of Atmospheric Oxygen and Social Environment Suggest Trade-Offs among Growth Rate, Life Span, and Stress Susceptibility in Giant Mealworms ( Zophobas morio). Physiol Biochem Zool 2021; 93:358-368. [PMID: 32758057 DOI: 10.1086/710726] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Growth rate, development time, and response to environmental stressors vary tremendously across organisms, suggesting trade-offs that are affected by evolutionary or ecological factors, but such trade-offs are poorly understood. Prior studies using artificially selected lines of Manduca sexta suggest that insects with high growth rates, long development time, and large body size are more sensitive to hypoxic or hyperoxic stresses, such as reactive oxygen species (ROS) production, but the mechanisms and specific life-history associations remain unclear. Here, we manipulated the social environment to differentiate the effects of size, growth rate, and development time on oxygen sensitivity of the giant mealworm, Zophobas morio. Crowding reduced growth rates but yielded larger adults as a result of supernumerary molts and longer development times. The juvenile performance (growth rate, development time, adult mass) of crowd-reared mealworms was less sensitive to variation in atmospheric oxygen than it was for individually reared animals, consistent with the hypothesis that high growth rates are associated with increased sensitivity to ROS. Life span in normoxia was extended by crowd rearing, perhaps due to the larger size and/or increased resources of the larger adults. Life spans of crowd-reared animals were more negatively affected by hypoxia or hyperoxia than life spans of individually reared animals, possibly due to the longer total stress exposure of crowd-reared animals. These data suggest that animals with high growth rates experience a negative trade-off of performance with greater sensitivity to stress during the juvenile phase, while animals with long development times or life spans experience a negative trade-off of greater susceptibility of life span to environmental stress.
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He J, Yu Y, Qin XW, Zeng RY, Wang YY, Li ZM, Mi S, Weng SP, Guo CJ, He JG. Identification and functional analysis of the Mandarin fish (Siniperca chuatsi) hypoxia-inducible factor-1α involved in the immune response. FISH & SHELLFISH IMMUNOLOGY 2019; 92:141-150. [PMID: 31176007 DOI: 10.1016/j.fsi.2019.04.298] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 04/24/2019] [Accepted: 04/27/2019] [Indexed: 06/09/2023]
Abstract
Mandarin fish (Siniperca chuatsi) is a popular cultured freshwater fish species due to its high market value in China. With increasing density of breeding, mandarin fish is often cultured under low environmental oxygen concentrations (hypoxia). In this study, the relative expression levels of hypoxia response element (HRE)-luciferase reporter and the HIF signaling pathway downstream genes (scldha, scvegf, and scglut-1) were significantly increased by hypoxic stress, thereby indicating that mandarin fish has an HIF signaling pathway. The mandarin fish HIF-1α (scHIF-1α) was also characterized. Multiple sequence alignments showed that scHIF-1α presented similar architectures to other known vertebrates. Subcellular localization analysis showed that scHIF-1α was mainly located in the nucleus of the mandarin fish fry-1 (MFF-1) cells. The role of scHIF-1α in the regulation of the HIF signaling pathway was confirmed. Overexpression of scHIF-1α could induce the HIF signaling pathway, whereas knockdown of scHIF-1α inhibited the activity of the HIF-1 signaling pathway. Tissue distribution analysis showed that schif-1α was significantly highly expressed in the blood, heart, and liver, which indicated that the main function of scHIF-1α was closely related to the circulatory system. Furthermore, scHIF-1α expression was significantly induced by poly I:C, poly dG:dC or PMA, thereby indicating that scHIF-1α was involved in the immune response. HIF-1α plays an important role in pathogen infections in mammals, but its role in fish is rarely investigated. Overexpression of scHIF-1α could inhibit MRV and SCRV infections, whereas knockdown of scHIF-1α could promote such infections. Those results suggested that scHIF-1α played an important role in fish virus infection. Our study will help understand the hypoxia associated with the outbreaks of aquatic viral disease.
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Affiliation(s)
- Jian He
- State Key Laboratory for Biocontrol / Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, School of Marine Sciences, Sun Yat-sen University, No.132 Waihuan Dong Road, Higher Education Mega Center, Guangzhou, Guangdong, 510006, PR China
| | - Yang Yu
- State Key Laboratory for Biocontrol / Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, School of Marine Sciences, Sun Yat-sen University, No.132 Waihuan Dong Road, Higher Education Mega Center, Guangzhou, Guangdong, 510006, PR China
| | - Xiao-Wei Qin
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China
| | - Ruo-Yun Zeng
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China
| | - Yuan-Yuan Wang
- State Key Laboratory for Biocontrol / Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, School of Marine Sciences, Sun Yat-sen University, No.132 Waihuan Dong Road, Higher Education Mega Center, Guangzhou, Guangdong, 510006, PR China
| | - Zhi-Min Li
- State Key Laboratory for Biocontrol / Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, School of Marine Sciences, Sun Yat-sen University, No.132 Waihuan Dong Road, Higher Education Mega Center, Guangzhou, Guangdong, 510006, PR China
| | - Shu Mi
- State Key Laboratory for Biocontrol / Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, School of Marine Sciences, Sun Yat-sen University, No.132 Waihuan Dong Road, Higher Education Mega Center, Guangzhou, Guangdong, 510006, PR China
| | - Shao-Ping Weng
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China
| | - Chang-Jun Guo
- State Key Laboratory for Biocontrol / Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, School of Marine Sciences, Sun Yat-sen University, No.132 Waihuan Dong Road, Higher Education Mega Center, Guangzhou, Guangdong, 510006, PR China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China; Institute of Aquatic Economic Animals / Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-sen University, 135 Xingang Road West, Guangzhou, 510275, PR China.
| | - Jian-Guo He
- State Key Laboratory for Biocontrol / Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, School of Marine Sciences, Sun Yat-sen University, No.132 Waihuan Dong Road, Higher Education Mega Center, Guangzhou, Guangdong, 510006, PR China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China; Institute of Aquatic Economic Animals / Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-sen University, 135 Xingang Road West, Guangzhou, 510275, PR China
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15
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Gupta N, Zhao YY, Evans CE. The stimulation of thrombosis by hypoxia. Thromb Res 2019; 181:77-83. [DOI: 10.1016/j.thromres.2019.07.013] [Citation(s) in RCA: 372] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 06/19/2019] [Accepted: 07/14/2019] [Indexed: 11/28/2022]
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16
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Li H, Cheng Z, Tang Y, Feng M, Yin A, Zhang H, Xu J, Zhang Q, Zhang J, Qian L. Expression profile of long non‑coding RNAs in cardiomyocytes exposed to acute ischemic hypoxia. Mol Med Rep 2018; 19:302-308. [PMID: 30431112 PMCID: PMC6297740 DOI: 10.3892/mmr.2018.9658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 09/28/2018] [Indexed: 12/02/2022] Open
Abstract
Acute myocardial infarction (AMI) is a life-threatening disease and seriously influences patient quality of life. Long non-coding RNAs (lncRNAs), an emerging class of non-coding genes, have attracted attention in research, however, whether lncRNAs serve a function in acute ischemic hypoxia remains to be elucidated. In the present study, an lncRNA microarray was used to analyze differential lncRNA expression in acute ischemic hypoxia. A total of 323 lncRNAs were identified, 168 of which were upregulated and 155 of which were downregulated. Gene Ontology and Pathway analyses were also used to identify the potential functions of dysregulated lncRNAs; it was predicted that these dysregulated lncRNAs may contribute to the initiation of AMI. It was demonstrated that an lncRNA termed sloyfley may influence acute ischemic hypoxia through its neighboring gene Peg3, which has been linked to brain ischemia hypoxia. In summary, the present study identified numerous lncRNAs, which may provide further opportunities for the development of novel therapeutic strategies.
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Affiliation(s)
- Hua Li
- Department of Emergency, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Zijie Cheng
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Yuanyuan Tang
- Departmant of General Medicine, Traditional Chinese Medicine Hospital of Jiangsu Province, Nanjing, Jiangsu 210004, P.R. China
| | - Mengwen Feng
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Anwen Yin
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hao Zhang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jia Xu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Qijun Zhang
- Department of Cardiology, YinZhou Hospital Affiliated to Medical School of Ningbo University, Ningbo, Zhejiang 315040, P.R. China
| | - Jinsong Zhang
- Department of Emergency, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Lingmei Qian
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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17
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Fortenbery GW, Sarathy B, Carraway KR, Mansfield KD. Hypoxic stabilization of mRNA is HIF-independent but requires mtROS. Cell Mol Biol Lett 2018; 23:48. [PMID: 30305827 PMCID: PMC6172842 DOI: 10.1186/s11658-018-0112-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 09/25/2018] [Indexed: 01/09/2023] Open
Abstract
Background Tissue ischemia can arise in response to numerous physiologic and pathologic conditions. The cellular response to decreased perfusion, most notably a decrease in glucose and oxygen, is important for cellular survival. In response to oxygen deprivation or hypoxia, one of the key response elements is hypoxia inducible factor (HIF) and a key protein induced by hypoxia is vascular endothelial growth factor (VEGF). Under hypoxia, we and others have reported an increase in the half-life of VEGF and other hypoxia related mRNAs including MYC and CYR61; however, the mediator of this response has yet to be identified. For this study, we sought to determine if HIF-mediated transcriptional activity is involved in the mRNA stabilization induced by hypoxia. Methods HEK293T or C6 cells were cultured in either normoxic or hypoxic (1% oxygen) conditions in the presence of 1 g/L glucose for all experiments. Pharmacological treatments were used to mimic hypoxia (desferroxamine, dimethyloxaloglutamate, CoCl2), inhibit mitochondrial respiration (rotenone, myxothiazol), scavenge reactive oxygen species (ROS; ebselen), or generate mitochondrial ROS (antimycin A). siRNAs were used to knock down components of the HIF transcriptional apparatus. mRNA half-life was determined via actinomycin D decay and real time PCR and western blotting was used to determine mRNA and protein levels respectively. Results Treatment of HEK293T or C6 cells with hypoxic mimetics, desferroxamine, dimethyloxaloglutamate, or CoCl2 showed similar induction of HIF compared to hypoxia treatment, however, in contrast to hypoxia, the mimetics caused no significant increase in VEGF, MYC or CYR61 mRNA half-life. Knockdown of HIF-alpha or ARNT via siRNA also had no effect on hypoxic mRNA stabilization. Interestingly, treatment of HEK293T cells with the mitochondrial inhibitors rotenone and myxothiazol, or the glutathione peroxidase mimetic ebselen did prevent the hypoxic stabilization of VEGF, MYC, and CYR61, suggesting a role for mtROS in the process. Additionally, treatment with antimycin A, which has been shown to generate mtROS, was able to drive the normoxic stabilization of these mRNAs. Conclusion Overall these data suggest that hypoxic mRNA stabilization is independent of HIF transcriptional activity but requires mtROS.
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Affiliation(s)
- Grey W Fortenbery
- 1Brody School of Medicine, East Carolina University, Greenville, NC 27834 USA
| | - Brinda Sarathy
- 2Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834 USA
| | - Kristen R Carraway
- 2Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834 USA
| | - Kyle D Mansfield
- 2Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834 USA
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Gupta A, Sugadev R, Sharma YK, Yahmad Y, Khurana P. Role of miRNAs in hypoxia-related disorders. J Biosci 2018; 43:739-749. [PMID: 30207319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Hypoxia is a complex pathophysiological condition. The physiological and molecular responses to this stress have been extensively studied. However, the management of its ill effects still poses a challenge to clinicians. MicroRNAs (miRNAs) are short non-coding RNA molecules that control post-transcriptional gene expression. The regulatory role of miRNAs in hypoxic environments has been studied in many hypoxia-related disorders, however a comprehensive compilation and analysis of all data and the significance of miRNAs in hypoxia adaption is still lacking. This review summarizes the miRNAs related to various hypoxia-related disorders and highlights the computational approaches to study them. This would help in designing novel strategies toward efficient management of hypoxia-related disorders.
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Affiliation(s)
- A Gupta
- Defence Institute of Physiology and Allied Sciences (DIPAS), Defence R and D Organization (DRDO), Timarpur, Delhi 110 054, India
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Gupta A, Sugadev R, Sharma YK, Ahmad Y, Khurana P. Role of miRNAs in hypoxia-related disorders. J Biosci 2018. [DOI: 10.1007/s12038-018-9789-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Ma Y, Dong Y, Zou L, Shen L, Liu S, Liu S, Huang W, Zhao Q, Wong W. A Probe Based on a Soft Salt Complex for Ratiometric and Lifetime Imaging of Variations in Intracellular Oxygen Content. Eur J Inorg Chem 2018. [DOI: 10.1002/ejic.201800250] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Yun Ma
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors Institute of Advanced Materials (IAM) Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM) Nanjing University of Posts and Telecommunications (NUPT) 210023 Nanjing China
- Institute of Molecular Functional Materials and Department of Chemistry Hong Kong Baptist University Waterloo Road, Kowloon Tong Hong Kong P. R. China
| | - Yafang Dong
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors Institute of Advanced Materials (IAM) Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM) Nanjing University of Posts and Telecommunications (NUPT) 210023 Nanjing China
| | - Liang Zou
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors Institute of Advanced Materials (IAM) Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM) Nanjing University of Posts and Telecommunications (NUPT) 210023 Nanjing China
| | - Liang Shen
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors Institute of Advanced Materials (IAM) Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM) Nanjing University of Posts and Telecommunications (NUPT) 210023 Nanjing China
| | - Suyi Liu
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors Institute of Advanced Materials (IAM) Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM) Nanjing University of Posts and Telecommunications (NUPT) 210023 Nanjing China
| | - Shujuan Liu
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors Institute of Advanced Materials (IAM) Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM) Nanjing University of Posts and Telecommunications (NUPT) 210023 Nanjing China
| | - Wei Huang
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors Institute of Advanced Materials (IAM) Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM) Nanjing University of Posts and Telecommunications (NUPT) 210023 Nanjing China
| | - Qiang Zhao
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors Institute of Advanced Materials (IAM) Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM) Nanjing University of Posts and Telecommunications (NUPT) 210023 Nanjing China
| | - Wai‐Yeung Wong
- Institute of Molecular Functional Materials and Department of Chemistry Hong Kong Baptist University Waterloo Road, Kowloon Tong Hong Kong P. R. China
- Department of Applied Biology and Chemical Technology,
- The Hong Kong Polytechnic University Hung Hom Hong Kong P. R. China
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Oka SI, Hirata T, Suzuki W, Naito D, Chen Y, Chin A, Yaginuma H, Saito T, Nagarajan N, Zhai P, Bhat S, Schesing K, Shao D, Hirabayashi Y, Yodoi J, Sciarretta S, Sadoshima J. Thioredoxin-1 maintains mechanistic target of rapamycin (mTOR) function during oxidative stress in cardiomyocytes. J Biol Chem 2017; 292:18988-19000. [PMID: 28939765 DOI: 10.1074/jbc.m117.807735] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 09/06/2017] [Indexed: 12/19/2022] Open
Abstract
Thioredoxin 1 (Trx1) is a 12-kDa oxidoreductase that catalyzes thiol-disulfide exchange reactions to reduce proteins with disulfide bonds. As such, Trx1 helps protect the heart against stresses, such as ischemia and pressure overload. Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, metabolism, and survival. We have shown previously that mTOR activity is increased in response to myocardial ischemia-reperfusion injury. However, whether Trx1 interacts with mTOR to preserve heart function remains unknown. Using a substrate-trapping mutant of Trx1 (Trx1C35S), we show here that mTOR is a direct interacting partner of Trx1 in the heart. In response to H2O2 treatment in cardiomyocytes, mTOR exhibited a high molecular weight shift in non-reducing SDS-PAGE in a 2-mercaptoethanol-sensitive manner, suggesting that mTOR is oxidized and forms disulfide bonds with itself or other proteins. The mTOR oxidation was accompanied by reduced phosphorylation of endogenous substrates, such as S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1) in cardiomyocytes. Immune complex kinase assays disclosed that H2O2 treatment diminished mTOR kinase activity, indicating that mTOR is inhibited by oxidation. Of note, Trx1 overexpression attenuated both H2O2-mediated mTOR oxidation and inhibition, whereas Trx1 knockdown increased mTOR oxidation and inhibition. Moreover, Trx1 normalized H2O2-induced down-regulation of metabolic genes and stimulation of cell death, and an mTOR inhibitor abolished Trx1-mediated rescue of gene expression. H2O2-induced oxidation and inhibition of mTOR were attenuated when Cys-1483 of mTOR was mutated to phenylalanine. These results suggest that Trx1 protects cardiomyocytes against stress by reducing mTOR at Cys-1483, thereby preserving the activity of mTOR and inhibiting cell death.
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Affiliation(s)
- Shin-Ichi Oka
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Tsuyoshi Hirata
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Wataru Suzuki
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Daichi Naito
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Yanbin Chen
- the Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou 215000, China
| | - Adave Chin
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Hiroaki Yaginuma
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Toshiro Saito
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Narayani Nagarajan
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Peiyong Zhai
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Santosh Bhat
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Kevin Schesing
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Dan Shao
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101
| | - Yoko Hirabayashi
- the Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Tokyo 158-8501, Japan
| | - Junji Yodoi
- the Department of Biological Responses, Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8397, Japan, and
| | - Sebastiano Sciarretta
- the Department of Medical-Surgical Science and Biotechnologies, University of Rome, Latina 04100, Italy
| | - Junichi Sadoshima
- From the Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101,
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22
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Binó L, Procházková J, Radaszkiewicz KA, Kučera J, Kudová J, Pacherník J, Kubala L. Hypoxia favors myosin heavy chain beta gene expression in an Hif-1alpha-dependent manner. Oncotarget 2017; 8:83684-83697. [PMID: 29137374 PMCID: PMC5663546 DOI: 10.18632/oncotarget.19016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 06/18/2017] [Indexed: 11/25/2022] Open
Abstract
The potentiation of the naturally limited regenerative capacity of the heart is dependent on an understanding of the mechanisms that are activated in response to pathological conditions such as hypoxia. Under these conditions, the expression of genes suggested to support cardiomyocyte survival and heart adaptation is triggered. Particularly important are changes in the expression of myosin heavy chain (MHC) isoforms. We propose here that alterations in the expression profiles of MHC genes are induced in response to hypoxia and are primarily mediated by hypoxia inducible factor (HIF). In in vitro models of mouse embryonic stem cell-derived cardiomyocytes, we showed that hypoxia (1% O2) or the pharmacological stabilization of HIFs significantly increased MHCbeta (Myh7) gene expression. The key role of HIF-1alpha is supported by the absence of these effects in HIF-1alpha-deficient cells, even in the presence of HIF-2alpha. Interestingly, ChIP analysis did not confirm the direct interaction of HIF-1alpha with putative HIF response elements predicted in the MHCalpha and beta encoding DNA region. Further analyses showed the significant effect of the mTOR signaling inhibitor rapamycin in inducing Myh7 expression and a hypoxia-triggered reduction in the levels of antisense RNA transcripts associated with the Myh7 gene locus. Overall, the recognized and important role of HIF in the regulation of heart regenerative processes could be highly significant for the development of novel therapeutic interventions in heart failure.
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Affiliation(s)
- Lucia Binó
- Institute of Biophysics of the CAS, Brno, Czech Republic.,Institute of Experimental Biology, Department of Physiology and Immunology of Animals, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Jiřina Procházková
- Institute of Biophysics of the CAS, Brno, Czech Republic.,Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Katarzyna Anna Radaszkiewicz
- Institute of Experimental Biology, Department of Physiology and Immunology of Animals, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Jan Kučera
- Institute of Experimental Biology, Department of Physiology and Immunology of Animals, Faculty of Science, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, Center of Biomolecular and Cellular Engineering, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - Jana Kudová
- Institute of Biophysics of the CAS, Brno, Czech Republic.,Institute of Experimental Biology, Department of Physiology and Immunology of Animals, Faculty of Science, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, Center of Biomolecular and Cellular Engineering, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - Jiří Pacherník
- Institute of Experimental Biology, Department of Physiology and Immunology of Animals, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Lukáš Kubala
- Institute of Biophysics of the CAS, Brno, Czech Republic.,Institute of Experimental Biology, Department of Physiology and Immunology of Animals, Faculty of Science, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, Center of Biomolecular and Cellular Engineering, St. Anne's University Hospital Brno, Brno, Czech Republic
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23
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Carraway KR, Johnson EM, Kauffmann TC, Fry NJ, Mansfield KD. Hypoxia and Hypoglycemia synergistically regulate mRNA stability. RNA Biol 2017; 14:938-951. [PMID: 28362162 PMCID: PMC5546718 DOI: 10.1080/15476286.2017.1311456] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Ischemic events, common in many diseases, result from decreased blood flow and impaired delivery of oxygen and glucose to tissues of the body. While much is known about the cellular transcriptional response to ischemia, much less is known about the posttranscriptional response to oxygen and glucose deprivation. The goal of this project was to investigate one such posttranscriptional response, the regulation of mRNA stability. To that end, we have identified several novel ischemia-related mRNAs that are synergistically stabilized by oxygen and glucose deprivation including VEGF, MYC, MDM2, and CYR61. This increase in mRNA half-life requires the synergistic effects of both low oxygen (1%) as well as low glucose (≤ 1 g/L) conditions. Oxygen or glucose deprivation alone fails to initiate the response, as exposure to either high glucose (4 g/L) or normoxic conditions inhibits the response. Furthermore, in response to hypoxia/hypoglycemia, the identified mRNAs are released from the RNA binding protein KHSRP which likely contributes to their stabilization.
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Affiliation(s)
- Kristen R Carraway
- a Biochemistry and Molecular Biology, Brody School of Medicine , East Carolina University , Greenville , NC , USA
| | - Ellen M Johnson
- a Biochemistry and Molecular Biology, Brody School of Medicine , East Carolina University , Greenville , NC , USA
| | - Travis C Kauffmann
- b Brody School of Medicine , East Carolina University , Greenville , NC , USA
| | - Nate J Fry
- a Biochemistry and Molecular Biology, Brody School of Medicine , East Carolina University , Greenville , NC , USA
| | - Kyle D Mansfield
- a Biochemistry and Molecular Biology, Brody School of Medicine , East Carolina University , Greenville , NC , USA
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24
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Feuer S, Liu X, Donjacour A, Simbulan R, Maltepe E, Rinaudo P. Common and specific transcriptional signatures in mouse embryos and adult tissues induced by in vitro procedures. Reproduction 2016; 153:REP-16-0473. [PMID: 27799627 PMCID: PMC5411347 DOI: 10.1530/rep-16-0473] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 10/26/2016] [Indexed: 12/17/2022]
Abstract
Stressful environmental exposures incurred early in development can affect postnatal metabolic health and susceptibility to non-communicable diseases in adulthood, although the molecular mechanisms by which this occurs have yet to be elucidated. Here we use a mouse model to investigate how assorted in vitro exposures restricted exclusively to the preimplantation period affect transcription both acutely in embryos and long-term in subsequent offspring adult tissues, to determine if reliable transcriptional markers of in vitro stress are present at specific developmental time points and throughout development. Each in vitro fertilization or embryo culture environment led to a specific and unique blastocyst transcriptional profile, but we identified a common 18-gene and 9-pathway signature of preimplantation embryo manipulation that was present in all in vitro embryos irrespective of culture condition or method of fertilization. This fingerprint did not persist throughout development and there was no clear transcriptional cohesion between adult IVF offspring tissues or compared to their preceding embryos, indicating a tissue-specific impact of in vitro stress on gene expression. However, the transcriptional changes present in each IVF tissue were targeted by the same upstream transcriptional regulators, which provide insight as to how acute transcriptional responses to stressful environmental exposures might be preserved throughout development to influence adult gene expression.
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Affiliation(s)
- Sky Feuer
- S Feuer, Obstetrics and Gynecology, University of California, San Francisco, San Francisco, United States
| | - Xiaowei Liu
- X Liu, Obstetrics and Gynecology, University of California, San Francisco, San Francisco, United States
| | - Annemarie Donjacour
- A Donjacour, Obstetrics and Gynecology, University of California, San Francisco, San Francisco, United States
| | - Rhodel Simbulan
- R Simbulan, Obstetrics and Gynecology, University of California, San Francisco, San Francisco, United States
| | - Emin Maltepe
- E Maltepe, Obstetrics and Gynecology, University of California, San Francisco, San Francisco, United States
| | - Paolo Rinaudo
- P Rinaudo, Obstetrics and Gynecology, University of California, San Francisco, San Francisco, 94115, United States
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25
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Harrison JF, Shingleton AW, Callier V. Stunted by Developing in Hypoxia: Linking Comparative and Model Organism Studies. Physiol Biochem Zool 2015; 88:455-70. [PMID: 26658244 DOI: 10.1086/682216] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Animals develop in atmospheric hypoxia in a wide range of habitats, and tissues may experience O2 limitation of ATP production during postembryonic development if O2 supply structures do not keep pace with growing O2 demand during ontogeny. Most animal species are stunted by postembryonic development in hypoxia, showing reduced growth rates and size in moderate hypoxia (5-15 kPa Po2). In mammals, the critical Po2 that limits resting metabolic rate also falls in this same moderate hypoxic range, so stunted growth may simply be due to hypoxic limits on ATP production. However, in most invertebrates and at least some lower vertebrates, hypoxic stunting occurs at Po2 values well above those that limit resting metabolism. Studies with diverse model organisms have identified multiple homologous O2-sensing signaling pathways that can inhibit feeding and growth during moderate hypoxia. Together, these comparative and model organism-based studies suggest that hypoxic stunting of growth and size can occur as programmed inhibition of growth, often by inhibition of insulin stimulation of growth processes. Furthermore, there is increasing evidence that these same O2 signaling pathways can be utilized during normal animal development to ensure matching of O2 supply and demand structures and in mediation of variation in animal performance.
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Affiliation(s)
- Jon F Harrison
- School of Life Sciences, Arizona State University, Tempe, Arizona 85287; 2Department of Biology, Lake Forest College, Lake Forest, Illinois 60045
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26
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Robin E, Marcillac F, Raddatz E. A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance. Am J Physiol Regul Integr Comp Physiol 2015; 308:R614-26. [PMID: 25632022 DOI: 10.1152/ajpregu.00423.2014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 01/19/2015] [Indexed: 11/22/2022]
Abstract
To what extent hypoxia alters the adenosine (ADO) system and impacts on cardiac function during embryogenesis is not known. Ectonucleoside triphosphate diphosphohydrolase (CD39), ecto-5'-nucleotidase (CD73), adenosine kinase (AdK), adenosine deaminase (ADA), equilibrative (ENT1,3,4), and concentrative (CNT3) transporters and ADO receptors A1, A2A, A2B, and A3 constitute the adenosinergic system. During the first 4 days of development chick embryos were exposed in ovo to normoxia followed or not followed by 6 h hypoxia. ADO and glycogen content and mRNA expression of the genes were determined in the atria, ventricle, and outflow tract of the normoxic (N) and hypoxic (H) hearts. Electrocardiogram and ventricular shortening of the N and H hearts were recorded ex vivo throughout anoxia/reoxygenation ± ADO. Under basal conditions, CD39, CD73, ADK, ADA, ENT1,3,4, CNT3, and ADO receptors were differentially expressed in the atria, ventricle, and outflow tract. In H hearts ADO level doubled, glycogen decreased, and mRNA expression of all the investigated genes was downregulated by hypoxia, except for A2A and A3 receptors. The most rapid and marked downregulation was found for ADA in atria. H hearts were arrhythmic and more vulnerable to anoxia-reoxygenation than N hearts. Despite downregulation of the genes, exposure of isolated hearts to ADO 1) preserved glycogen through activation of A1 receptor and Akt-GSK3β-GS pathway, 2) prolonged activity and improved conduction under anoxia, and 3) restored QT interval in H hearts. Thus hypoxia-induced downregulation of the adenosinergic system can be regarded as a coping response, limiting the detrimental accumulation of ADO without interfering with ADO signaling.
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Affiliation(s)
- Elodie Robin
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Switzerland; and National Center for Scientific Research, Center for Molecular Biophysics, Orléans, France
| | - Fabrice Marcillac
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Switzerland; and
| | - Eric Raddatz
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Switzerland; and
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27
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Suzuki T, Shinjo S, Arai T, Kanai M, Goda N. Hypoxia and fatty liver. World J Gastroenterol 2014; 20:15087-15097. [PMID: 25386057 PMCID: PMC4223242 DOI: 10.3748/wjg.v20.i41.15087] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 02/14/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.
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28
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Wang RS, Oldham WM, Loscalzo J. Network-based association of hypoxia-responsive genes with cardiovascular diseases. NEW JOURNAL OF PHYSICS 2014; 16:105014. [PMID: 25530704 PMCID: PMC4270352 DOI: 10.1088/1367-2630/16/10/105014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Molecular oxygen is indispensable for cellular viability and function. Hypoxia is a stress condition in which oxygen demand exceeds supply. Low cellular oxygen content induces a number of molecular changes to activate regulatory pathways responsible for increasing the oxygen supply and optimizing cellular metabolism under limited oxygen conditions. Hypoxia plays critical roles in the pathobiology of many diseases, such as cancer, heart failure, myocardial ischemia, stroke, and chronic lung diseases. Although the complicated associations between hypoxia and cardiovascular (and cerebrovascular) diseases (CVD) have been recognized for some time, there are few studies that investigate their biological link from a systems biology perspective. In this study, we integrate hypoxia genes, CVD genes, and the human protein interactome in order to explore the relationship between hypoxia and cardiovascular diseases at a systems level. We show that hypoxia genes are much closer to CVD genes in the human protein interactome than that expected by chance. We also find that hypoxia genes play significant bridging roles in connecting different cardiovascular diseases. We construct an hypoxia-CVD bipartite network and find several interesting hypoxia-CVD modules with significant Gene Ontology (GO) similarity. Finally, we show that hypoxia genes tend to have more CVD interactors in the human interactome than in random networks of matching topology. Based on these observations, we can predict novel genes that may be associated with CVD. This network-based association study gives us a broad view of the relationships between hypoxia and cardiovascular diseases and provides new insights into the role of hypoxia in cardiovascular biology.
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Affiliation(s)
| | | | - Joseph Loscalzo
- Address correspondence to: Dr. Joseph Loscalzo, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, NRB0630, Boston, MA 02115, USA. Tel: 1-617-525-4833. Fax: 1-617-525-4830.
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29
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The metabolic cooperation between cells in solid cancer tumors. Biochim Biophys Acta Rev Cancer 2014; 1846:216-25. [PMID: 24983675 DOI: 10.1016/j.bbcan.2014.06.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 05/12/2014] [Accepted: 06/24/2014] [Indexed: 12/11/2022]
Abstract
Cancer cells cooperate with stromal cells and use their environment to promote tumor growth. Energy production depends on nutrient availability and O₂ concentration. Well-oxygenated cells are highly proliferative and reorient the glucose metabolism towards biosynthesis, whereas glutamine oxidation replenishes the TCA cycle coupled with OXPHOS-ATP production. Glucose, glutamine and alanine transformations sustain nucleotide and fatty acid synthesis. In contrast, hypoxic cells slow down their proliferation, enhance glycolysis to produce ATP and reject lactate which is recycled as fuel by normoxic cells. Thus, glucose is spared for biosynthesis and/or for hypoxic cell function. Environmental cells, such as fibroblasts and adipocytes, serve as food donors for cancer cells, which reject waste products (CO₂ , H⁺, ammoniac, polyamines…) promoting EMT, invasion, angiogenesis and proliferation. This metabolic-coupling can be considered as a form of commensalism whereby non-malignant cells support the growth of cancer cells. Understanding these cellular cooperations within tumors may be a source of inspiration to develop new anti-cancer agents.
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30
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Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 2014; 15:243-56. [PMID: 24651542 DOI: 10.1038/nrm3772] [Citation(s) in RCA: 781] [Impact Index Per Article: 71.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A distinctive feature of stem cells is their capacity to self-renew to maintain pluripotency. Studies of genetically-engineered mouse models and recent advances in metabolomic analysis, particularly in haematopoietic stem cells, have deepened our understanding of the contribution made by metabolic cues to the regulation of stem cell self-renewal. Many types of stem cells heavily rely on anaerobic glycolysis, and stem cell function is also regulated by bioenergetic signalling, the AKT-mTOR pathway, Gln metabolism and fatty acid metabolism. As maintenance of a stem cell pool requires a finely-tuned balance between self-renewal and differentiation, investigations into the molecular mechanisms and metabolic pathways underlying these decisions hold great therapeutic promise.
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31
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Karcher JR, Greene AS. Bone marrow mononuclear cell angiogenic competency is suppressed by a high-salt diet. Am J Physiol Cell Physiol 2013; 306:C123-31. [PMID: 24259418 DOI: 10.1152/ajpcell.00164.2013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Autologous bone marrow-derived mononuclear cell (BM-MNC) transplantation is a potential therapy for inducing revascularization in ischemic tissues providing the underlying disease process had not negatively affected BM-MNC function. Previously, we have shown that skeletal muscle angiogenesis induced by electrical stimulation is impaired by a high-salt diet (HSD; 4% NaCl) in Sprague-Dawley (SD) rats. In this study we tested the hypothesis that BM-MNC angiogenic function is impaired by an elevated dietary sodium intake. Following 1 wk on HSD, either vehicle or BM-MNCs derived from SD donor rats on HSD or normal salt diet (NSD; 0.4% NaCl) were injected into male SD rats undergoing hindlimb stimulation. Administration of BM-MNCs (intramuscular or intravenous) from NSD donors, but not HSD donors, restored the angiogenic response in HSD recipients. Angiotensin II (3 ng · kg(-1) · min(-1)) infusion of HSD donor rats restored angiogenic capacity of BM-MNCs, and treatment of NSD donor rats with losartan, an angiotensin II receptor-1 antagonist, inhibited BM-MNC angiogenic competency. HSD BM-MNCs and NSD losartan BM-MNCs exhibited increased apoptosis in vitro following an acute 6-h hypoxic stimulus. HSD BM-MNCs also had increased apoptosis following injection into skeletal muscle. This study suggests that BM-MNC transplantation can restore skeletal muscle angiogenesis and that HSD impairs the angiogenic competency of BM-MNCs due to suppression of the renin-angiotensin system causing increased apoptosis.
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Affiliation(s)
- Jamie R Karcher
- Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and
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33
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Dastidar RG, Hooda J, Shah A, Cao TM, Henke RM, Zhang L. The nuclear localization of SWI/SNF proteins is subjected to oxygen regulation. Cell Biosci 2012; 2:30. [PMID: 22932476 PMCID: PMC3489556 DOI: 10.1186/2045-3701-2-30] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Accepted: 08/17/2012] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hypoxia is associated with many disease conditions in humans, such as cancer, stroke and traumatic injuries. Hypoxia elicits broad molecular and cellular changes in diverse eukaryotes. Our recent studies suggest that one likely mechanism mediating such broad changes is through changes in the cellular localization of important regulatory proteins. Particularly, we have found that over 120 nuclear proteins with important functions ranging from transcriptional regulation to RNA processing exhibit altered cellular locations under hypoxia. In this report, we describe further experiments to identify and evaluate the role of nuclear protein relocalization in mediating hypoxia responses in yeast. RESULTS To identify regulatory proteins that play a causal role in mediating hypoxia responses, we characterized the time courses of relocalization of hypoxia-altered nuclear proteins in response to hypoxia and reoxygenation. We found that 17 nuclear proteins relocalized in a significantly shorter time period in response to both hypoxia and reoxygenation. Particularly, several components of the SWI/SNF complex were fast responders, and analysis of gene expression data show that many targets of the SWI/SNF proteins are oxygen regulated. Furthermore, confocal fluorescent live cell imaging showed that over 95% of hypoxia-altered SWI/SNF proteins accumulated in the cytosol in hypoxic cells, while over 95% of the proteins were nuclear in normoxic cells, as expected. CONCLUSIONS SWI/SNF proteins relocalize in response to hypoxia and reoxygenation in a quick manner, and their relocalization likely accounts for, in part or in whole, oxygen regulation of many SWI/SNF target genes.
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Affiliation(s)
- Ranita Ghosh Dastidar
- Department of Molecular and Cell Biology, Center for Systems Biology, University of Texas at Dallas, Mail Stop RL11 800 W Campbell Road, Richardson, TX, 75080, USA
| | - Jagmohan Hooda
- Department of Molecular and Cell Biology, Center for Systems Biology, University of Texas at Dallas, Mail Stop RL11 800 W Campbell Road, Richardson, TX, 75080, USA
| | - Ajit Shah
- Department of Molecular and Cell Biology, Center for Systems Biology, University of Texas at Dallas, Mail Stop RL11 800 W Campbell Road, Richardson, TX, 75080, USA
| | - Thai M Cao
- Department of Molecular and Cell Biology, Center for Systems Biology, University of Texas at Dallas, Mail Stop RL11 800 W Campbell Road, Richardson, TX, 75080, USA
| | - Robert Michael Henke
- Department of Molecular and Cell Biology, Center for Systems Biology, University of Texas at Dallas, Mail Stop RL11 800 W Campbell Road, Richardson, TX, 75080, USA
| | - Li Zhang
- Department of Molecular and Cell Biology, Center for Systems Biology, University of Texas at Dallas, Mail Stop RL11 800 W Campbell Road, Richardson, TX, 75080, USA
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34
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A global view of the biochemical pathways involved in the regulation of the metabolism of cancer cells. Biochim Biophys Acta Rev Cancer 2012; 1826:423-33. [PMID: 22841746 DOI: 10.1016/j.bbcan.2012.07.001] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 07/09/2012] [Accepted: 07/10/2012] [Indexed: 02/08/2023]
Abstract
Cancer cells increase glucose uptake and reject lactic acid even in the presence of oxygen (Warburg effect). This metabolism reorients glucose towards the pentose phosphate pathway for ribose synthesis and consumes great amounts of glutamine to sustain nucleotide and fatty acid synthesis. Oxygenated and hypoxic cells cooperate and use their environment in a manner that promotes their development. Coenzymes (NAD(+), NADPH,H(+)) are required in abundance, whereas continuous consumption of ATP and citrate precludes the negative feedback of these molecules on glycolysis, a regulation supporting the Pasteur effect. Understanding the metabolism of cancer cells may help to develop new anti-cancer treatments.
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35
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Synergistic effects of hypoxia and extracellular matrix cues in cardiomyogenesis. Biomaterials 2012; 33:6313-9. [PMID: 22717366 DOI: 10.1016/j.biomaterials.2012.05.063] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Accepted: 05/27/2012] [Indexed: 11/23/2022]
Abstract
Limited characterization of how the stem cell niche evolves has hindered our ability to mimic the physiological environment. In this paper, we hypothesized that hypoxia-induced extracellular matrix (ECM) cues may facilitate cardiomyogenesis. We evaluated the expression of four ECM proteins - fibronectin, collagen I, collagen IV, and laminin - over a period of 20 days in H1 and H9 human embryonic stem cell-derived embryoid bodies (EBs) under hypoxic (5% oxygen) and normoxic (21% oxygen) conditions. Hypoxic EBs exhibited increased collagen I, collagen IV and fibronectin expression relative to normoxic EBs between days 9-13, which coincided with increased expression of mesoderm genes. The effect of ECM cues was confirmed by plating day 9 EBs on collagen IV, gelatin, and fibronectin-rich substrates for 11 days. Hypoxia/gelatin cultures synergistically increased the cardiomyocyte yield by 1.7 and 5.5 fold relative to normoxia/gelatin and normoxia/collagen IV cultures, respectively. Current differentiation protocols may underestimate the contribution of hypoxia and ECM cues that evolve during EB maturation.
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36
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Hu XQ, Xiao D, Zhu R, Huang X, Yang S, Wilson SM, Zhang L. Chronic hypoxia suppresses pregnancy-induced upregulation of large-conductance Ca2+-activated K+ channel activity in uterine arteries. Hypertension 2012; 60:214-22. [PMID: 22665123 DOI: 10.1161/hypertensionaha.112.196097] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Our previous study demonstrated that increased Ca(2+)-activated K(+) (BK(Ca)) channel activity played a key role in the normal adaptation of reduced myogenic tone of uterine arteries in pregnancy. The present study tested the hypothesis that chronic hypoxia during gestation inhibits pregnancy-induced upregulation of BK(Ca) channel function in uterine arteries. Resistance-sized uterine arteries were isolated from nonpregnant and near-term pregnant sheep maintained at sea level (≈ 300 m) or exposed to high-altitude (3801 m) hypoxia for 110 days. Hypoxia during gestation significantly inhibited pregnancy-induced upregulation of BK(Ca) channel activity and suppressed BK(Ca) channel current density in pregnant uterine arteries. This was mediated by a selective downregulation of BK(Ca) channel β1 subunit in the uterine arteries. In accordance, hypoxia abrogated the role of the BK(Ca) channel in regulating pressure-induced myogenic tone of uterine arteries that was significantly elevated in pregnant animals acclimatized to chronic hypoxia. In addition, hypoxia abolished the steroid hormone-mediated increase in the β1 subunit and BK(Ca) channel current density observed in nonpregnant uterine arteries. Although the activation of protein kinase C inhibited BK(Ca) channel current density in pregnant uterine arteries of normoxic sheep, this effect was ablated in the hypoxic animals. The results demonstrate that selectively targeting BK(Ca) channel β1 subunit plays a critical role in the maladaption of uteroplacental circulation caused by chronic hypoxia, which contributes to the increased incidence of preeclampsia and fetal intrauterine growth restriction associated with gestational hypoxia.
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Affiliation(s)
- Xiang-Qun Hu
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA.
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Abstract
PURPOSE OF REVIEW Microvesicles (also known as microparticles) are small membranous structures that are released from platelets and cells upon activation or during apoptosis. Microvesicles have been found in blood, urine, synovial fluid, extracellular spaces of solid organs, atherosclerotic plaques, tumors, and elsewhere. Here, we focus on new clinical and basic work that implicates microvesicles as markers and mediators of endothelial dysfunction and hence novel contributors to cardiovascular and other diseases. RECENT FINDINGS Advances in the detection of microvesicles and the use of cell type-specific markers to determine their origin have allowed studies that associated plasma concentrations of specific microvesicles with major types of endothelial dysfunction - namely, inappropriate or maladaptive vascular tone, leukocyte recruitment, and thrombosis. Recent investigations have highlighted microvesicular transport of key biologically active molecules besides tissue factor, such as ligands for pattern-recognition receptors, elements of the inflammasome, and morphogens. Microvesicles generated from human cells under different pathologic circumstances, for example, during cholesterol loading or exposure to endotoxin, carry different subsets of these molecules and thereby alter endothelial function through several distinct, well characterized molecular pathways. SUMMARY Clinical and basic studies indicate that microvesicles may be novel markers and mediators of endothelial dysfunction. This work has advanced our understanding of the development of cardiovascular and other diseases. Opportunities and obstacles to clinical applications are discussed.
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Affiliation(s)
- Ming-Lin Liu
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
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Dietary nitrite attenuates oxidative stress and activates antioxidant genes in rat heart during hypobaric hypoxia. Nitric Oxide 2011; 26:61-73. [PMID: 22197744 DOI: 10.1016/j.niox.2011.12.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Revised: 12/02/2011] [Accepted: 12/08/2011] [Indexed: 01/19/2023]
Abstract
The nitrite anion represents the circulatory and tissue storage form of nitric oxide (NO) and a signaling molecule, capable of conferring cardioprotection and many other health benefits. However, molecular mechanisms for observed cardioprotective properties of nitrite remain largely unknown. We have evaluated the NO-like bioactivity and cardioprotective efficacies of sodium nitrite supplemented in drinking water in rats exposed to short-term chronic hypobaric hypoxia. We observed that, nitrite significantly attenuates hypoxia-induced oxidative stress, modulates HIF-1α stability and promotes NO-cGMP signaling in hypoxic heart. To elucidate potential downstream targets of nitrite during hypoxia, we performed a microarray analysis of nitrite supplemented hypoxic hearts and compared with both hypoxic and nitrite supplemented normoxic hearts respectively. The analysis revealed a significant increase in the expression of many antioxidant genes, transcription factors and cardioprotective signaling pathways which was subsequently confirmed by qRT-PCR and Western blotting. Conversely, hypoxia exposure increased oxidative stress, activated inflammatory cytokines, downregulated ion channels and altered expression of both pro- and anti-oxidant genes. Our results illustrate the physiological function of nitrite as an eNOS-independent source of NO in heart profoundly modulating the oxidative status and cardiac transcriptome during hypoxia.
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Gawlitta D, Fledderus JO, van Rijen MHP, Dokter I, Alblas J, Verhaar MC, Dhert WJA. Hypoxia impedes vasculogenesis of in vitro engineered bone. Tissue Eng Part A 2011; 18:208-18. [PMID: 21859278 DOI: 10.1089/ten.tea.2010.0731] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
To ensure the survival of engineered bone after implantation, we combined human endothelial colony forming cells (ECFCs) and multipotent stromal cells (MSCs) as a proof of concept in a co-culture model to create in vitro prevascularized bone constructs. We hypothesized that a hypoxic stimulus will contribute to prevascularization of engineered bone. Bone marrow-derived MSCs and ECFCs from human adult peripheral blood were allowed to form co-culture pellets containing ECFCs and MSCs (1:4) or MSCs only in controls. After culture under normoxia or hypoxia (5%), pellets were harvested and processed for immunohistochemistry of CD31, α-smooth muscle actin, and osteocalcin. Expression of vascular endothelial growth factor and SDF-1α was analyzed by PCR to elucidate their involvement in hypoxic stimulation of prevascularization. The normoxic condition in co-cultures of MSCs and ECFCs supported the formation and maintenance of prevascular structures, including organized CD31-positive cells embraced by differentiated mural cells. These structures failed to form in hypoxic conditions, thereby rejecting the hypothesis that hypoxia stimulates prevasculogenesis in three-dimensional engineered bone constructs. Further, the formation of prevascular structures was paralleled by increased SDF-1α expression. It is suggested that actual oxygen levels were below 5% in the hypoxic co-cultures, which prevented prevascular structure formation. In conclusion, our normoxic co-culture model containing cells from clinically relevant sources sustained simultaneous endothelial, smooth muscle, and osteogenic differentiation.
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Affiliation(s)
- Debby Gawlitta
- Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands.
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40
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Hong SJ, Jin DP, Buck DW, Galiano RD, Mustoe TA. Impaired response of mature adipocytes of diabetic mice to hypoxia. Exp Cell Res 2011; 317:2299-307. [DOI: 10.1016/j.yexcr.2011.07.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2011] [Revised: 06/01/2011] [Accepted: 07/06/2011] [Indexed: 01/14/2023]
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Koos BJ. Adenosine A₂a receptors and O₂ sensing in development. Am J Physiol Regul Integr Comp Physiol 2011; 301:R601-22. [PMID: 21677265 DOI: 10.1152/ajpregu.00664.2010] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Reduced mitochondrial oxidative phosphorylation, via activation of adenylate kinase and the resulting exponential rise in the cellular AMP/ATP ratio, appears to be a critical factor underlying O₂ sensing in many chemoreceptive tissues in mammals. The elevated AMP/ATP ratio, in turn, activates key enzymes that are involved in physiologic adjustments that tend to balance ATP supply and demand. An example is the conversion of AMP to adenosine via 5'-nucleotidase and the resulting activation of adenosine A(₂A) receptors, which are involved in acute oxygen sensing by both carotid bodies and the brain. In fetal sheep, A(₂A) receptors associated with carotid bodies trigger hypoxic cardiovascular chemoreflexes, while central A(₂A) receptors mediate hypoxic inhibition of breathing and rapid eye movements. A(₂A) receptors are also involved in hypoxic regulation of fetal endocrine systems, metabolism, and vascular tone. In developing lambs, A(₂A) receptors play virtually no role in O₂ sensing by the carotid bodies, but brain A(₂A) receptors remain critically involved in the roll-off ventilatory response to hypoxia. In adult mammals, A(₂A) receptors have been implicated in O₂ sensing by carotid glomus cells, while central A(₂A) receptors likely blunt hypoxic hyperventilation. In conclusion, A(₂A) receptors are crucially involved in the transduction mechanisms of O₂ sensing in fetal carotid bodies and brains. Postnatally, central A(₂A) receptors remain key mediators of hypoxic respiratory depression, but they are less critical for O₂ sensing in carotid chemoreceptors, particularly in developing lambs.
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Affiliation(s)
- Brian J Koos
- Department of Obstetrics and Gynecology; Brain Research Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.
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Xue Y, Li NL, Yang JY, Chen Y, Yang LL, Liu WC. Phosphatidylinositol 3′-kinase signaling pathway is essential for Rac1-induced hypoxia-inducible factor-1α and vascular endothelial growth factor expression. Am J Physiol Heart Circ Physiol 2011; 300:H2169-76. [DOI: 10.1152/ajpheart.00970.2010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We have previously demonstrated the roles of RhoA, Rac1, and Cdc42 in hypoxia-driven angiogenesis. However, the role of oncogenes in hypoxia signaling is poorly understood. Given the importance of Rho proteins in the hypoxic response, we hypothesized that Rho family members could act as mediators of hypoxic signal transduction. We investigated the cross-talk between hypoxia and oncogene-driven signal transduction pathways and explored the role of Rac1 on hypoxia-induced hypoxia-inducible factor (HIF)-1α and VEGF expression. Since the phosphatidylinositol 3′-kinase (PI3K) pathway is involved in signal transduction of many oncogenes, we explored the role of PI3K on Rac1-mediated expression of HIF-1α and VEGF in hypoxia. We showed that LY-294002, a PI3K inhibitor, suppressed HIF-1α and VEGF induction under hypoxic conditions by up to 50%. Activation of Rac1 resulted in an upregulation of hypoxia-induced HIF-1α expression, which was blocked by LY-294002. These data suggested that Rac1 is an intermediate in the PI3K-mediated induction of HIF-1α. Interestingly, there was a significant downregulation of the tumor suppressor genes p53 and von Hippel-Lindau tumor suppressor (VHL) in cells expressing a constitutively active form of Rac1. Rac1-mediated inhibition of p53 and VHL could therefore be implicated in the upregulation of HIF-1α expression.
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Affiliation(s)
- Yan Xue
- Departments of 1Clinical Oncology and
| | - Nan-Lin Li
- Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China
| | | | - Yan Chen
- Departments of 1Clinical Oncology and
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Bryan S, Yang G, Wang R, Khaper N. Cystathionine gamma-lyase-deficient smooth muscle cells exhibit redox imbalance and apoptosis under hypoxic stress conditions. Exp Clin Cardiol 2011; 16:e36-e41. [PMID: 22131857 PMCID: PMC3206107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Accepted: 07/21/2011] [Indexed: 05/31/2023]
Abstract
BACKGROUND Hydrogen sulphide (H(2)S) has recently emerged as a novel and important gasotransmitter in the cardiovascular system, where it is generated mainly by cystathionine gamma-lyase (CSE). Abnormal metabolism and functions of the CSE/H(2)S pathway have been linked to various cardiovascular diseases including atherosclerosis and hypertension. An important role for H(2)S in regulating the balance between cellular growth and death has been demonstrated whereby inhibition of the endogenous CSE/H(2)S pathway results in greater apoptosis of vascular smooth muscle cells (SMCs). H(2)S is increasingly recognized as a critical regulator of vascular integrity, but its role in SMCs during hypoxia has not been explored in a model of CSE deficiency. METHODS Cell viability, apoptosis, redox status and mitochondrial activity in hypoxia-exposed (12 h at 1% O(2)) SMCs derived from the mesenteric artery of CSE-knockout (CSE-KO) mice were analyzed. These were compared with those from CSE-wild-type (CSE-WT) mice. RESULTS CSE-KO cells exhibited redox imbalance and aberrant mitochondrial activity versus CSE-WT cells, indicating an essential regulatory role for the endogenous CSE/H(2)S pathway on SMC function. CSE-KO cells were also more susceptible to hypoxia-induced cell death, indicating a critical contribution of endogenous CSE/H(2)S pathway to the protective hypoxia stress response. CONCLUSION These findings support the concept that H(2)S is a crucial regulator of vascular homeostasis, the deficiency of which is associated with various pathologies, and provide further evidence that H(2)S is a potent vasculoprotectant.
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Affiliation(s)
| | | | | | - Neelam Khaper
- Department of Biology
- Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, Ontario
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Li M, Bertout JA, Ratcliffe SJ, Eckenhoff MF, Simon MC, Floyd TF. Acute anemia elicits cognitive dysfunction and evidence of cerebral cellular hypoxia in older rats with systemic hypertension. Anesthesiology 2010; 113:845-58. [PMID: 20808217 PMCID: PMC3233697 DOI: 10.1097/aln.0b013e3181eaaef9] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Postoperative cognitive dysfunction occurs frequently after cardiac, major vascular, and major orthopedic surgery. Aging and hypertensive cerebrovascular disease are leading risk factors for this disorder. Acute anemia, common to major surgery, has been identified as a possible contributor to postoperative cognitive dysfunction. The effect of hypoxia upon cognition and the cellular and molecular processes involved in learning and memory has been well described. Cerebrovascular changes related to chronic hypertension may expose cells to increased hypoxia with anemia. METHODS Young to aged spontaneously hypertensive rats underwent testing for visuospatial memory and learning in the Morris water maze, measurement of cerebral tissue oxygenation via tissue oxygen probe, and measurement of hypoxia-sensitive genes and proteins, under conditions of sham and experimental isovolemic anemia. RESULTS Acute isovolemic anemia elicited evidence of aging-dependent visuospatial working memory and learning impairment. Isovolemic anemia did not result in cerebral tissue hypoxia, when measured via tissue oxygen probe. Evidence of cellular hypoxia was, however, identified in response to the anemic challenge, as hypoxia-sensitive genes and proteins were up-regulated. Importantly, cellular hypoxic gene responses were increased with anemia in an age-dependent manner in this model of aging with chronic hypertension. CONCLUSIONS In a translational model of chronic hypertension, clinically relevant levels of acute anemia were associated with an age-dependent visuospatial working memory and learning impairment that was matched by an age-dependent cellular sensitivity to anemic hypoxia. These data offer support for a possible link between anemic hypoxia and postoperative cognitive dysfunction in humans.
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Affiliation(s)
- Min Li
- Department of Anesthesiology and Critical Care, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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Han Y, Kuang SZ, Gomer A, Ramirez-Bergeron DL. Hypoxia influences the vascular expansion and differentiation of embryonic stem cell cultures through the temporal expression of vascular endothelial growth factor receptors in an ARNT-dependent manner. Stem Cells 2010; 28:799-809. [PMID: 20135683 DOI: 10.1002/stem.316] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Adaptive responses to low oxygen (O(2)) tension (hypoxia) are mediated by the heterodimeric transcription factor hypoxia inducible factor (HIF). When stabilized by hypoxia, bHLH-PAS alpha- and beta- (HIF-1beta or ARNT) HIF complex regulate the expression of multiple genes, including vascular endothelial growth factor (VEGF). To investigate the mechanism(s) through which hypoxia contributes to blood vessel development, we used embryonic stem cell (ESC) differentiation cultures that develop into embryoid bodies (EBs) mimicking early embryonic development. Significantly, low O(2) levels promote vascular development and maturation in wild-type (WT) ESC cultures measured by an increase in the numbers of CD31(+) endothelial cells (ECs) and sprouting angiogenic EBs, but refractory in Arnt(-/-) and Vegf(-/-) ESC cultures. Thus, we propose that hypoxia promotes the production of ECs and contributes to the development and maturation of vessels. Our findings further demonstrate that hypoxia alters the temporal expression of VEGF receptors Flk-1 (VEGFR-2) and the membrane and soluble forms of the antagonistic receptor Flt-1 (VEGFR-1). Moreover, these receptors are distinctly expressed in differentiating Arnt(-/-) and Vegf(-/-) EBs. These results support existing models in which VEGF signaling is tightly regulated during specific biologic events, but also provide important novel evidence that, in response to physiologic hypoxia, HIF mediates a distinct stoichiometric pattern of VEGF receptors throughout EB differentiation analogous to the formation of vascular networks during embryogenesis.
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Affiliation(s)
- Yu Han
- Case Cardiovascular Research Institute, University Hospitals Harrington-McLaughlin Heart and Vascular Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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McLaughlin KJ, Strain-Damerell CM, Xie K, Brekasis D, Soares AS, Paget MSB, Kielkopf CL. Structural basis for NADH/NAD+ redox sensing by a Rex family repressor. Mol Cell 2010; 38:563-75. [PMID: 20513431 DOI: 10.1016/j.molcel.2010.05.006] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2009] [Revised: 02/21/2010] [Accepted: 05/11/2010] [Indexed: 01/26/2023]
Abstract
Nicotinamide adenine dinucleotides have emerged as key signals of the cellular redox state. Yet the structural basis for allosteric gene regulation by the ratio of reduced NADH to oxidized NAD(+) is poorly understood. A key sensor among Gram-positive bacteria, Rex represses alternative respiratory gene expression until a limited oxygen supply elevates the intracellular NADH:NAD(+) ratio. Here we investigate the molecular mechanism for NADH/NAD(+) sensing among Rex family members by determining structures of Thermus aquaticus Rex bound to (1) NAD(+), (2) DNA operator, and (3) without ligand. Comparison with the Rex/NADH complex reveals that NADH releases Rex from the DNA site following a 40 degrees closure between the dimeric subunits. Complementary site-directed mutagenesis experiments implicate highly conserved residues in NAD-responsive DNA-binding activity. These rare views of a redox sensor in action establish a means for slight differences in the nicotinamide charge, pucker, and orientation to signal the redox state of the cell.
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Affiliation(s)
- Krystle J McLaughlin
- Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
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47
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Endotoxin-induced HIF-1α stabilisation in equine endothelial cells: synergistic action with hypoxia. Inflamm Res 2010; 59:689-98. [DOI: 10.1007/s00011-010-0180-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2009] [Revised: 02/08/2010] [Accepted: 02/15/2010] [Indexed: 10/19/2022] Open
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Generating specificity and diversity in the transcriptional response to hypoxia. Nat Rev Genet 2009; 10:821-32. [PMID: 19884889 DOI: 10.1038/nrg2665] [Citation(s) in RCA: 275] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The sensing of oxygen levels and maintenance of oxygen homeostasis is crucial for cells. The hypoxic-sensitive regulation of gene expression allows information about the oxygen status to be converted into appropriate cellular responses. Although there is a core transcriptional pathway, the signalling cascade can be modified to allow diversity and specificity in the transcriptional output. In this Review, we discuss recent advances in our understanding of the mechanisms and factors that contribute to the observed diversity and specificity. A deeper knowledge about how hypoxic signalling is tuned will further our understanding of the cellular hypoxic response in normal physiology and how it becomes derailed in disease.
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Li Q, Liu J, Michaud M, Schwartz ML, Madri JA. Strain differences in behavioral and cellular responses to perinatal hypoxia and relationships to neural stem cell survival and self-renewal: Modeling the neurovascular niche. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 175:2133-46. [PMID: 19815710 DOI: 10.2353/ajpath.2009.090354] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Premature infants have chronic hypoxia, resulting in cognitive and motor neurodevelopmental handicaps caused by suboptimal neural stem cell (NSC) repair/recovery in neurogenic zones (including the subventricular and the subgranular zones). Understanding the variable central nervous system repair response is crucial to identifying "at risk" infants and to increasing survival and clinical improvement of affected infants. Using mouse strains found to span the range of responsiveness to chronic hypoxia, we correlated differential NSC survival and self-renewal with differences in behavior. We found that C57BL/6 (C57) pups displayed increased hyperactivity after hypoxic insult; CD-1 NSCs exhibited increased hypoxia-induced factor 1alpha (HIF-1alpha) mRNA and protein, increased HIF-1alpha, and decreased prolyl hydroxylase domain 2 in nuclear fractions, which denotes increased transcription/translation and decreased degradation of HIF-1alpha. C57 NSCs exhibited blunted stromal-derived factor 1-induced migratory responsiveness, decreased matrix metalloproteinase-9 activity, and increased neuronal differentiation. Adult C57 mice exposed to hypoxia from P3 to P11 exhibited learning impairment and increased anxiety. These findings support the concept that behavioral differences between C57 and CD-1 mice are a consequence of differential responsiveness to hypoxic insult, leading to differences in HIF-1alpha signaling and resulting in lower NSC proliferative/migratory and higher apoptosis rates in C57 mice. Information gained from these studies will aid in design and effective use of preventive therapies in the very low birth weight infant population.
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Affiliation(s)
- Qi Li
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA
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50
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Taghibiglou C, Martin HGS, Rose JK, Ivanova N, Lin CHC, Lau HL, Rai S, Wang YT, Rankin CH. Essential role of SBP-1 activation in oxygen deprivation induced lipid accumulation and increase in body width/length ratio in Caenorhabditis elegans. FEBS Lett 2009; 583:831-4. [PMID: 19187779 DOI: 10.1016/j.febslet.2009.01.045] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2008] [Revised: 01/15/2009] [Accepted: 01/24/2009] [Indexed: 11/29/2022]
Abstract
Epidemiological evidence suggests a link between chronic oxygen starvation and fat accumulation/obesity, however the underlying mechanism remains unclear. Using Caenorhabditis elegans we found extended oxygen deprivation resulted in activation of SBP-1, the worm homologue of SREBP1, a transcription factor important in maintaining lipid homeostasis. SBP-1 knockdown prevented hypoxia-induced fat accumulation and the associated increase in worm width/length ratio, demonstrating that SBP-1/SREBP1 plays an essential role in hypoxia-induced lipid accumulation and body shape alteration. This study provides the first evidence suggesting that activation of SREBP1 may be a critical pathogenic factor contributing to chronic hypoxia associated excessive fat accumulation/obesity in humans.
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Affiliation(s)
- Changiz Taghibiglou
- Department of Medicine, UBC, Canada; Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5
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