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Lim KRQ, Amrute J, Kovacs A, Diwan A, Williams DL, Mann DL. Lipopolysaccharide Induces Trained Innate Immune Tolerance in the Heart Through Interferon Signaling in a Model of Stress-Induced Cardiomyopathy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.24.614798. [PMID: 39386701 PMCID: PMC11463458 DOI: 10.1101/2024.09.24.614798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Background Although the ability of the heart to adapt to environmental stress has been studied extensively, the molecular and cellular mechanisms responsible for cardioprotection are not yet fully understood. Methods We administered Toll-like receptor (TLR) agonists or a diluent to wild-type mice and assessed their potential to induce cardiac protection against injury from a high intraperitoneal dose of isoproterenol (ISO) administered 7 days later. Cardioprotective effects were analyzed through serum cardiac troponin I levels, immune cell profiling via flow cytometry, echocardiography, and multiomic single-nuclei RNA and ATAC sequencing. Results Pretreatment with the TLR4 agonist lipopolysaccharide (LPS), but not TLR1/2 or TLR3 agonists, conferred cardioprotection against ISO, as demonstrated by reduced cardiac troponin I leakage, decreased inflammation, preservation of cardiac structure and function, and improved survival. Remarkably, LPS-induced tolerance was reversed by β-glucan treatment. Multiomic analysis showed that LPS-tolerized hearts had greater chromatin accessibility and upregulated gene expression compared to hearts treated with LPS and β-glucan (reverse-tolerized). The LPS tolerance was associated with upregulation of interferon response pathways across various cell types, including cardiac myocytes and stromal cells. Blocking both type 1 and type 2 interferon signaling eliminated LPS-induced tolerance against ISO, while pretreatment with recombinant type 1 and 2 interferons conferred cardiac protection. Multiomic sequencing further revealed enhanced cytoprotective signaling in interferon-treated hearts. Analysis of cell-cell communication networks indicated increased autocrine signaling by cardiac myocytes, as well as greater paracrine signaling between stromal cells and myeloid cells, in LPS-tolerized versus reverse-tolerized hearts. Conclusions LPS pretreatment confers cardiac protection against ISO-induced injury through TLR4 mediated type 1 and 2 interferon signaling, consistent with trained innate immune tolerance. The observation that LPS-induced protection in cardiac myocytes involves both cell-autonomous and non-cell-autonomous mechanisms underscores the complexity of innate immune tolerance in the heart, warranting further investigation into this cardioprotective phenotype. Clinical Perspective What is new?: The Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) confers cardiac protection against isoproterenol-mediated injury in a manner consistent with trained innate immune tolerance, which is reversed by β-glucan treatment.Activation of type 1 and 2 interferon signaling, which is downstream of Toll-like receptor 4, is necessary and sufficient for LPS-induced cardiac protection.LPS-tolerized hearts show heightened autocrine signaling by cardiac myocytes and, to a greater degree, increased cell-cell communication between cardiac myocytes and stromal and myeloid cells compared to reverse-tolerized hearts.What are the clinical implications?: TLR4 and interferon signaling play key roles in the establishment of cardiac protection and LPS-induced trained innate immune tolerance.The protective effects of LPS are mediated by cell-autonomous and non-cell-autonomous mechanisms, suggesting that a deeper understanding of the molecular and cellular signatures of innate immune tolerance is required for the development of targeted approaches to modulate trained innate immunity, and consequently cytoprotection, in the heart.
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Lajqi T, Köstlin-Gille N, Bauer R, Zarogiannis SG, Lajqi E, Ajeti V, Dietz S, Kranig SA, Rühle J, Demaj A, Hebel J, Bartosova M, Frommhold D, Hudalla H, Gille C. Training vs. Tolerance: The Yin/Yang of the Innate Immune System. Biomedicines 2023; 11:766. [PMID: 36979747 PMCID: PMC10045728 DOI: 10.3390/biomedicines11030766] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/26/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
For almost nearly a century, memory functions have been attributed only to acquired immune cells. Lately, this paradigm has been challenged by an increasing number of studies revealing that innate immune cells are capable of exhibiting memory-like features resulting in increased responsiveness to subsequent challenges, a process known as trained immunity (known also as innate memory). In contrast, the refractory state of endotoxin tolerance has been defined as an immunosuppressive state of myeloid cells portrayed by a significant reduction in the inflammatory capacity. Both training as well tolerance as adaptive features are reported to be accompanied by epigenetic and metabolic alterations occurring in cells. While training conveys proper protection against secondary infections, the induction of endotoxin tolerance promotes repairing mechanisms in the cells. Consequently, the inappropriate induction of these adaptive cues may trigger maladaptive effects, promoting an increased susceptibility to secondary infections-tolerance, or contribute to the progression of the inflammatory disorder-trained immunity. This review aims at the discussion of these opposing manners of innate immune and non-immune cells, describing the molecular, metabolic and epigenetic mechanisms involved and interpreting the clinical implications in various inflammatory pathologies.
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Affiliation(s)
- Trim Lajqi
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
| | - Natascha Köstlin-Gille
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
- Department of Neonatology, University of Tübingen, D-72076 Tübingen, Germany
| | - Reinhard Bauer
- Institute of Molecular Cell Biology, Jena University Hospital, D-07745 Jena, Germany
| | - Sotirios G. Zarogiannis
- Department of Physiology, School of Health Sciences, Faculty of Medicine, University of Thessaly, GR-41500 Larissa, Greece
| | - Esra Lajqi
- Department of Radiation Oncology, Heidelberg University Hospital, D-69120 Heidelberg, Germany
| | - Valdrina Ajeti
- Department of Pharmacy, Alma Mater Europaea—Campus College Rezonanca, XK-10000 Pristina, Kosovo
| | - Stefanie Dietz
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
- Department of Neonatology, University of Tübingen, D-72076 Tübingen, Germany
| | - Simon A. Kranig
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
| | - Jessica Rühle
- Department of Neonatology, University of Tübingen, D-72076 Tübingen, Germany
| | - Ardian Demaj
- Faculty of Medical Sciences, University of Tetovo, MK-1200 Tetova, North Macedonia
| | - Janine Hebel
- Department of Neonatology, University of Tübingen, D-72076 Tübingen, Germany
| | - Maria Bartosova
- Center for Pediatric and Adolescent Medicine Heidelberg, University of Heidelberg, D-69120 Heidelberg, Germany
| | - David Frommhold
- Klinik für Kinderheilkunde und Jugendmedizin, D-87700 Memmingen, Germany
| | - Hannes Hudalla
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
| | - Christian Gille
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
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Jena AB, Samal RR, Dandapat J, Subudhi U. Thermodynamics of benzoquinone-induced conformational changes in nucleic acids and human serum albumin. Chem Biol Interact 2023; 369:110281. [PMID: 36436547 DOI: 10.1016/j.cbi.2022.110281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 11/06/2022] [Accepted: 11/21/2022] [Indexed: 11/26/2022]
Abstract
Biological macromolecules such as proteins, nucleic acids, carbohydrates and lipids, play a crucial role in biochemical and molecular processes. Thus, the study of the structure-function relationship of biomolecules in presence of ligands is an important aspect of structural biology. The current communication describes the chemico-biological interaction between benzene metabolite para-benzoquinone (BQ) with B-form of nucleic acids (B-DNA) and human serum albumin (HSA). The binding ability of HSA towards bromocresol green (BCG) was significantly suppressed when exposed to increasing concentrations of BQ in the presence of various physiological buffers. Further, the native fluorescence of HSA was drastically reduced and the secondary structures of HSA were significantly compromised with increasing concentrations of BQ. In vitro and in silico studies also revealed that BQ binds to domains I and II of HSA and thus altering the conformation of HSA which may potentially affect plasma osmotic pressure, as well as the binding and transport of numerous endogenous and exogenous molecules. Similarly, BQ interacts directly to the GC region of B-DNA particularly in the minor groove which was also assessed by computational docking studies. Isothermal titration calorimetry data suggest higher binding affinity of BQ towards DNA than HSA. Various spectroscopic observations also suggest that BQ binds to DNA preferably in the minor grooves. Thus, the results revealed that BQ may play a key role in inducing mutagenicity, either by formation of adducts on GC regions or by accelerating oxidative damage to biomacromolecules through chemico-biological interactions.
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Affiliation(s)
- Atala B Jena
- Department of Biotechnology, Utkal University, Bhubaneswar, 751004, Odisha, India; Centre of Excellence in Integrated Omics & Computational Biology, Utkal University, Bhubaneswar, 751004, Odisha, India
| | - Rashmi R Samal
- Biochemistry & Biophysics Laboratory, CSIR-Institute of Minerals & Materials Technology, Bhubaneswar, 751013, Odisha, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India
| | - Jagneshwar Dandapat
- Department of Biotechnology, Utkal University, Bhubaneswar, 751004, Odisha, India; Centre of Excellence in Integrated Omics & Computational Biology, Utkal University, Bhubaneswar, 751004, Odisha, India.
| | - Umakanta Subudhi
- Biochemistry & Biophysics Laboratory, CSIR-Institute of Minerals & Materials Technology, Bhubaneswar, 751013, Odisha, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India.
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Jena AB, Rath S, Subudhi U, Dandapat J. Molecular interaction of benzo-a-pyrene inhibits the catalytic activity of catalase: Insights from biophysical and computational studies. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.133494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Chen F, Zou L, Williams B, Chao W. Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials. Antioxid Redox Signal 2021; 35:1324-1339. [PMID: 33588628 PMCID: PMC8817700 DOI: 10.1089/ars.2021.0005] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Significance: Sepsis is a critical clinical syndrome with life-threatening organ dysfunction induced by a dysregulated host response to infection. Despite decades of intensive research, sepsis remains a leading cause of in-hospital mortality with few specific treatments. Recent Advances: Toll-like receptors (TLRs) are a part of the innate immune system and play an important role in host defense against invading pathogens such as bacteria, virus, and fungi. Using a combination of genetically modified animal models and pharmacological agents, numerous preclinical studies during the past two decades have demonstrated that dysregulated TLR signaling may contribute to sepsis pathogenesis. However, many clinical trials targeting inflammation and innate immunity such as TLR4 have yielded mixed results. Critical Issues: Here we review various TLRs and the specific molecules these TLRs sense-both the pathogen-associated and host-derived stress molecules, and their converging signaling pathways. We critically analyze preclinical investigations into the role of TLRs in animal sepsis, the complexity of targeting TLRs for sepsis intervention, and the disappointing clinical trials of the TLR4 antagonist eritoran. Future Directions: Future sepsis treatments will depend on better understanding the complex biological mechanisms of sepsis pathogenesis, the high heterogeneity of septic humans as defined by clinical presentations and unique immunological biomarkers, and improved stratifications for targeted interventions.
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Affiliation(s)
- Fengqian Chen
- Translational Research Program, Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Lin Zou
- Translational Research Program, Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Brittney Williams
- Translational Research Program, Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Wei Chao
- Translational Research Program, Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Sun N, Li M, Liu G, Jing M, He F, Cao Z, Zong W, Tang J, Gao C, Liu R. Toxic mechanism of pyrene to catalase and protective effects of vitamin C: Studies at the molecular and cell levels. Int J Biol Macromol 2021; 171:225-233. [PMID: 33418042 DOI: 10.1016/j.ijbiomac.2020.12.169] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/10/2020] [Accepted: 12/22/2020] [Indexed: 11/17/2022]
Abstract
Polycyclic aromatic hydrocarbons, distributing extensively in the soil, would potentially threaten the soil organisms (Eisenia fetida) by triggering oxidative stress. As a ubiquitous antioxidant enzyme, catalase can protect organisms from oxidative damage. To reveal the potential impact of polycyclic aromatic hydrocarbon pyrene (Pyr) on catalase (CAT) and the possible protective effect of Ascorbic acid (vitamin C), multi-spectral and molecular docking techniques were used to investigate the influence of structure and function of catalase by pyrene. Fluorescence and circular dichroism analysis showed that pyrene would induce the microenvironmental changes of CAT amino acid residues and increase the α-helix in the secondary structure. Molecular simulation results indicated that the main binding force of pyrene around the active center of CAT is hydrogen bonding force. Furthermore, pyrene inhibited catalase activity to 69.9% compared with the blank group, but the degree of inhibition was significantly weakened after vitamin C added into the research group. Cell level experiments showed that pyrene can increase the level of ROS in the body cavity cell of earthworms, and put the cells under the threat of potential oxidative damage. Antioxidants-vitamin C has a protective effect on catalase and maintains the stability of intracellular ROS levels to a certain extent.
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Affiliation(s)
- Ning Sun
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, 72# Jimo Binhai Road, Qingdao, Shandong 266237, PR China
| | - Meifei Li
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, 72# Jimo Binhai Road, Qingdao, Shandong 266237, PR China
| | - Guiliang Liu
- Shandong Institute for Food and Drug Control, Jinan 250101, PR China
| | - Mingyang Jing
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, 72# Jimo Binhai Road, Qingdao, Shandong 266237, PR China
| | - Falin He
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, 72# Jimo Binhai Road, Qingdao, Shandong 266237, PR China
| | - Zhaozhen Cao
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, 72# Jimo Binhai Road, Qingdao, Shandong 266237, PR China
| | - Wansong Zong
- College of Geography and Environment, Shandong Normal University, 88# East Wenhua Road, Jinan, Shandong 250014, PR China
| | - Jingchun Tang
- Key Laboratory of Pollution Processes and Environmental Criteria (Ministry of Education), Tianjin Engineering Research Center of Environmental Diagnosis and Contamination Remediation, College of Environmental Science and Engineering, Nankai University, Tianjin 300350, PR China
| | - Canzhu Gao
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, 72# Jimo Binhai Road, Qingdao, Shandong 266237, PR China
| | - Rutao Liu
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, 72# Jimo Binhai Road, Qingdao, Shandong 266237, PR China.
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Jing M, Han G, Wan J, Zhang S, Yang J, Zong W, Niu Q, Liu R. Catalase and superoxide dismutase response and the underlying molecular mechanism for naphthalene. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 736:139567. [PMID: 32479957 DOI: 10.1016/j.scitotenv.2020.139567] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/11/2020] [Accepted: 05/18/2020] [Indexed: 05/21/2023]
Abstract
Naphthalene, a naturally-occurring polyaromatic hydrocarbon, pose potential threats to health for its wide exposures in environment. Naphthalene could disrupt the redox equilibrium resulting in oxidative damage. Antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) are considered to be the efficient defense barriers to protect organisms from negative impacts of toxicants. Limited information is available regarding the underlying molecular mechanism between antioxidant enzymes and naphthalene. In this paper, structural and functional alterations of CAT and SOD for low dose (1.6-25.6 mg/L) naphthalene exposure have been investigated at the molecular and cellular levels. The enzyme activity responses of CAT and SOD in hepatocytes for naphthalene were consistent with the molecular, in which the activity of CAT increased and the activity of SOD slightly inhibited. Spectroscopy methods and molecular docking were carried out to investigate the underlying binding mechanisms. Naphthalene exposure significantly changed the conformation of CAT with secondary structure alteration (α-helix increase) but only changed the skeleton structure of SOD without secondary structure alteration. Naphthalene could bind to CAT and SOD primarily via H-binding force accompanied with the particle size of CAT/SOD agglomerates decreasing. Naphthalene preferentially bound to the surface of CAT and SOD. Besides, naphthalene could also bind directly to the active center of CAT with the key residues Arg364 and Tyr 357 for activity. This paper provides a combined cellular and molecular strategy to research biomarker responses for toxicants exposure. Besides, this study offers detailed basic data for the comprehensive understanding of naphthalene toxicity.
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Affiliation(s)
- Mingyang Jing
- School of Environmental Science and Engineering, Shandong University, America CRC for Environment & Health, 72# Jimo Binhai Road, Qingdao, Shandong 266237, PR China; Penglai Jiaxin Dye Chemical Co., Ltd, 1#Jiaxin Road, Yantai, Shandong 265601, PR China
| | - Guangye Han
- Shandong Huankeyuan Environmental Engineering Co., Ltd, Lixia, 50# Lishan Road, Jinan, Shandong 250100, PR China
| | - Jingqiang Wan
- School of Environmental Science and Engineering, Shandong University, America CRC for Environment & Health, 72# Jimo Binhai Road, Qingdao, Shandong 266237, PR China
| | - Shansheng Zhang
- Penglai Jiaxin Dye Chemical Co., Ltd, 1#Jiaxin Road, Yantai, Shandong 265601, PR China
| | - Junhai Yang
- Penglai Jiaxin Dye Chemical Co., Ltd, 1#Jiaxin Road, Yantai, Shandong 265601, PR China
| | - WanSong Zong
- College of Geography and Environment, Shandong Normal University, 88# East Wenhua Road, Jinan, Shandong 250014, PR China
| | - Qigui Niu
- School of Environmental Science and Engineering, Shandong University, America CRC for Environment & Health, 72# Jimo Binhai Road, Qingdao, Shandong 266237, PR China
| | - Rutao Liu
- School of Environmental Science and Engineering, Shandong University, America CRC for Environment & Health, 72# Jimo Binhai Road, Qingdao, Shandong 266237, PR China.
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Adenine Nucleotide Translocase 1 Expression is Coupled to the HSP27-Mediated TLR4 Signaling in Cardiomyocytes. Cells 2019; 8:cells8121588. [PMID: 31817787 PMCID: PMC6952976 DOI: 10.3390/cells8121588] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 12/03/2019] [Accepted: 12/03/2019] [Indexed: 12/21/2022] Open
Abstract
The cardiac-specific overexpression of the adenine nucleotide translocase 1 (ANT1) has cardioprotective effects in various experimental heart disease models. Here, we analyzed the link between ANT1 expression and heat shock protein 27 (HSP27)-mediated toll-like receptor 4 (TLR4) signaling, which represents a novel communication pathway between mitochondria and the extracellular environment. The interaction between ANT1 and HSP27 was identified by co-immunoprecipitation from neonatal rat cardiomyocytes. ANT1 transgenic (ANT1-TG) cardiomyocytes demonstrated elevated HSP27 expression levels. Increased levels of HSP27 were released from the ANT1-TG cardiomyocytes under both normoxic and hypoxic conditions. Extracellular HSP27 stimulated TLR4 signaling via protein kinase B (AKT). The HSP27-mediated activation of the TLR4 pathway was more pronounced in ANT1-TG cardiomyocytes than in wild-type (WT) cardiomyocytes. HSP27-specific antibodies inhibited TLR4 activation and the expression of HSP27. Inhibition of the HSP27-mediated TLR4 signaling pathway with the TLR4 inhibitor oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) reduced the mitochondrial membrane potential (∆ψm) and increased caspase 3/7 activity, which are both markers for cell stress. Conversely, treating cardiomyocytes with recombinant HSP27 protein stimulated TLR4 signaling, induced HSP27 and ANT1 expression, and stabilized the mitochondrial membrane potential. The activation of HSP27 signaling was verified in ischemic ANT1-TG heart tissue, where it correlated with ANT1 expression and the tightness of the inner mitochondrial membrane. Our study shows a new mechanism by which ANT1 is part of the cardioprotective HSP27-mediated TLR4 signaling.
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Hu S, Yuan D, Liu Y, Zhao L, Guo H, Niu Q, Zong W, Liu R. The toxic effects of alizarin red S on catalase at the molecular level. RSC Adv 2019; 9:33368-33377. [PMID: 35529134 PMCID: PMC9073274 DOI: 10.1039/c9ra02986a] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 10/03/2019] [Indexed: 11/21/2022] Open
Abstract
Alizarin red S (ARS) is a widespread mordant dye derived from alizarin. However, it was reported to be mutagenic and carcinogenic probably because it could induce oxidative damages in organisms. Catalase (CAT) is an important antioxidant enzyme defensing oxidative damages induced by xenobiotics. The underlying mechanisms of ARS interacting with CAT have not been clarified yet. This study is conducted to characterize the functional and conformational changes on CAT by ARS and the binding details to further investigate their interaction mechanisms. Under exposure of ARS at 5 μM, CAT activity was significantly decreased to 76.2%. Inhibition of CAT probably resulted in promotion of intracellular oxidative stress and pro-oxidant property of ARS. The interaction between ARS and CAT was proved to be spontaneous and exothermic. However, limited structural changes were observed according to spectroscopic results. Results showed that ARS prefers to bind with residues buried in the active site and could alter the activity of CAT, which were agree with the molecular docking results. This work proves the adverse effects of ARS on CAT mainly at molecular level and further highlights its potential risks to heath. Alizarin red S is confirmed to be toxic to catalase at molecular level attributing to the structural and functional changes of catalase.![]()
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Affiliation(s)
- Shimeng Hu
- School of Environmental Science and Engineering
- Shandong University
- America CRC for Environment & Health
- Shandong Province
- Qingdao
| | - Dong Yuan
- Department of Chemistry and Chemical Engineering
- Qilu Normal University
- Jinan 250013
- P. R. China
| | - Yang Liu
- Department of Chemistry and Chemical Engineering
- Qilu Normal University
- Jinan 250013
- P. R. China
| | - Lining Zhao
- School of Environmental Science and Engineering
- Shandong University
- America CRC for Environment & Health
- Shandong Province
- Qingdao
| | - Hongli Guo
- School of Environmental Science and Engineering
- Shandong University
- America CRC for Environment & Health
- Shandong Province
- Qingdao
| | - Qigui Niu
- School of Environmental Science and Engineering
- Shandong University
- America CRC for Environment & Health
- Shandong Province
- Qingdao
| | - Wansong Zong
- College of Population, Resources and Environment
- Shandong Normal University
- Jinan 250014
- P. R. China
| | - Rutao Liu
- School of Environmental Science and Engineering
- Shandong University
- America CRC for Environment & Health
- Shandong Province
- Qingdao
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Preconditioning in the Rhesus Macaque Induces a Proteomic Signature Following Cerebral Ischemia that Is Associated with Neuroprotection. Transl Stroke Res 2018; 10:440-448. [PMID: 30341719 DOI: 10.1007/s12975-018-0670-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 09/07/2018] [Accepted: 10/09/2018] [Indexed: 12/28/2022]
Abstract
Each year, thousands of patients are at risk of cerebral ischemic injury, due to iatrogenic responses to surgical procedures. Prophylactic treatment of these patients as standard care could minimize potential neurological complications. We have shown that protection of brain tissue, in a non-human primate model of cerebral ischemic injury, is possible through pharmacological preconditioning using the immune activator D192935. We postulate that preconditioning with D192935 results in neuroprotective reprogramming that is evident in the brain following experimentally induced cerebral ischemia. We performed quantitative proteomic analysis of cerebral spinal fluid (CSF) collected post-stroke from our previously published efficacy study to determine whether CSF protein profiles correlated with induced protection. Four groups of animals were examined: naïve animals (no treatment or stroke); animals treated with vehicle prior to stroke; D192935 treated and stroked animals, further delineated into two groups, ones that were protected (small infarcts) and those that were not protected (large infarcts). We found that distinct protein clusters defined the protected and non-protected animal groups, with a 16-member cluster of proteins induced exclusively in D192935 protected animals. Seventy percent of the proteins induced in the protected animals have functions that would enhance neuroprotection and tissue repair, including several members associated with M2 macrophages, a macrophage phenotype shown to contribute to neuroprotection and repair during ischemic injury. These studies highlight the translational importance of CSF biomarkers in defining mechanism and monitoring responses to treatment in development of stroke therapeutics.
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Lee SM, Hutchinson M, Saint DA. The role of Toll-like receptor 4 (TLR4) in cardiac ischaemic-reperfusion injury, cardioprotection and preconditioning. Clin Exp Pharmacol Physiol 2017; 43:864-71. [PMID: 27249055 DOI: 10.1111/1440-1681.12602] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Revised: 05/26/2016] [Accepted: 05/30/2016] [Indexed: 01/04/2023]
Abstract
Cardiac ischaemic-reperfusion injury (IRI) remains the primary cause of mortality throughout the developed world. Molecular mechanisms underlying IRI are complex and are often interlinked with each other driving a synergistic response. Toll-like receptor 4 (TLR4), an immunosurveillance receptor, is known to enhance tissue injury during IRI by enhancing the inflammatory response. The release of endogenous components during IRI bind onto TLR4 leading to the activation of multiple signalling kinases. Once this event occurs these proteins are defined as danger associated molecular patterns molecules (DAMPs) or alarmins. Examples include heat shock proteins, high mobility group box one (HMGB1) and extracellular matrix proteins, all of which are involved in IRI. However, literature in the last two decades suggests that transient stimulation of TLR4 may suppress IRI and thus improve cardiac recovery. Furthermore, it remains to be seen what role TLR4 plays during ischaemic-preconditioning where acute bouts of ischaemia, preceding a harmful bout of ischaemic-reperfusion, is cardioprotective. The other question which also needs to be considered is that if transient TLR4 signalling drives a preconditioning response then what are the ligands which drive this? Hence the second part of this review explores the possible TLR4 ligands which may promote cardioprotection against IRI.
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Affiliation(s)
- Sam Man Lee
- School of Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Mark Hutchinson
- School of Medicine, University of Adelaide, Adelaide, SA, Australia.,Centre for Nanoscale Biophotonics, University of Adelaide, Adelaide, SA, Australia
| | - David A Saint
- School of Medicine, University of Adelaide, Adelaide, SA, Australia
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Low-Dose Endotoxin Induces Late Preconditioning, Increases Peroxynitrite Formation, and Activates STAT3 in the Rat Heart. Molecules 2017; 22:molecules22030433. [PMID: 28282895 PMCID: PMC6155391 DOI: 10.3390/molecules22030433] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 03/01/2017] [Indexed: 12/22/2022] Open
Abstract
Administration of low-dose endotoxin (lipopolysaccharide, LPS) 24 h before a lethal ischemia induces pharmacological late preconditioning. The exact mechanism of this phenomenon is not clear. Here we aimed to investigate whether low-dose LPS exerts late effects on peroxynitrite formation and activation of Akt, Erk, and STAT3 in the heart. Male Wistar rats were injected with LPS (S. typhimurium; 0.5 mg/kg i.p.) or saline. Twenty-four hours later, hearts were isolated, perfused for 10 min, and then used for biochemical analyses. LPS pretreatment enhanced cardiac formation of the peroxynitrite marker 3-nitrotyrosine. LPS pretreatment also increased cardiac levels of the peroxynitrite precursor nitric oxide (NO) and superoxide. The activities of Ca2+-independent NO synthase and xanthine oxidoreductase increased in LPS-pretreated hearts. LPS pretreatment resulted in significantly enhanced phosphorylation of STAT3 and non-significantly increased phosphorylation of Akt without affecting the activation of Erk. In separate experiments, isolated working hearts were subjected to 30 min global ischemia and 20 min reperfusion. LPS pretreatment significantly improved ischemia-reperfusion-induced deterioration of cardiac function. We conclude that LPS pretreatment enhances cardiac peroxynitrite formation and activates STAT3 24 h later, which may contribute to LPS-induced late preconditioning.
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Domínguez Fernández E, Flohé S, Siemers F, Nau M, Ackermann M, Ruwe M, Schade FU. Endotoxin tolerance protects against local hepatic ischemia/reperfusion injury in the rat. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519000060040801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Liver surgery and liver transplantation as well as circulatory shock are often associated with hepatic ischemia/reperfusion (I/R) injury. Recent evidence suggests that TNF-α plays a central role in I/R injury and, therefore, down-regulation of TNF-α seems to be a promising way to protect against the deleterious consequences of I/R. Endotoxin tolerance represents a state of unresponsiveness to endotoxin and is associated with diminished TNF-α production. Thus, the effect of endotoxin tolerance on hepatic I/R injury of the liver was investigated in a rat model. I/R injury was induced by temporary ischemia of the left lateral liver lobe for 90 min followed by a 3 h observation period of reperfusion. I/R injury resulted in functional hepatic disorder characterized by a decrease both in bile flow and bile acid concentration and 50% mortality. This was prevented by induction of endotoxin tolerance. Hepatic TNF-α mRNA expression after I/R of the liver was determined by RT-PCR. In untreated rats, TNF-α mRNA was induced in the liver 60 min after reperfusion and further increased until 3 h after reperfusion. In contrast, in endotoxin-tolerant rats, no increases in TNF-α mRNA expression were detected. This suggests that induction of endotoxin tolerance protects against hepatic I/R injury possibly via down-regulation of intra-organ TNF-α expression.
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Affiliation(s)
- Emilio Domínguez Fernández
- Department of General Surgery, Mannheim Medical School, University of Heidelberg, Mannheim, Germany, Clinical Research Group for Shock and Multi Organ Failure, University of Essen, Essen, Germany, -heidelberg.de
| | - Sascha Flohé
- Clinical Research Group for Shock and Multi Organ Failure, University of Essen, Essen, Germany
| | - Frank Siemers
- Clinical Research Group for Shock and Multi Organ Failure, University of Essen, Essen, Germany
| | - Michael Nau
- Clinical Research Group for Shock and Multi Organ Failure, University of Essen, Essen, Germany
| | - Markus Ackermann
- Clinical Research Group for Shock and Multi Organ Failure, University of Essen, Essen, Germany
| | - Markus Ruwe
- Department of Pathology, University of Essen, Essen, Germany
| | - Fritz Ulrich Schade
- Clinical Research Group for Shock and Multi Organ Failure, University of Essen, Essen, Germany
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Flach R, Schade F. Peritoneal macrophages from endotoxin-tolerant mice produce an inhibitor of tumor necrosis factor α synthesis and protect against endotoxin shock. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/096805199700400401] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
In the present study it was found that development of early endotoxin-tolerance is associated with the capacity of mouse peritoneal macrophages (MPM) to produce an activity interfering with the synthesis of tumor necrosis factor α. Peritoneal macrophages from LPS-tolerant mice (tMPM), treated with LPS in vitro produced less TNFα, IL-10 and TGFβ than LPS-treated macrophages from normal mice (nMPM). The supernatants of LPS-activated tMPM contained activities which suppressed formation of TNF in nMPM and RAW 264.7 cells as determined by bioassay, ELISA and PCR. Supernatants of nMPM and unstimulated tMPM were devoid of the inhibitory activity. The inhibitor did not interfere with the bioactivity of TNFα in WEHI cells. It also suppressed PMA/IFN-γ induced TNF synthesis in macrophage cultures. The transfer of macrophages isolated from endotoxin-tolerant mice into normal mice protected against endotoxin shock, whereas macrophages from normal mice increased susceptibility to endotoxin.
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Affiliation(s)
- R. Flach
- Klinische Forschergruppe Schock und Multiorganversagen, Department for Surgery, University Hospital Essen, Essen, Germany
| | - F.U. Schade
- Klinische Forschergruppe Schock und Multiorganversagen, Department for Surgery, University Hospital Essen, Essen, Germany
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Abstract
SIGNIFICANCE Peroxisomes are organelles present in most eukaryotic cells. The organs with the highest density of peroxisomes are the liver and kidneys. Peroxisomes possess more than fifty enzymes and fulfill a multitude of biological tasks. They actively participate in apoptosis, innate immunity, and inflammation. In recent years, a considerable amount of evidence has been collected to support the involvement of peroxisomes in the pathogenesis of kidney injury. RECENT ADVANCES The nature of the two most important peroxisomal tasks, beta-oxidation of fatty acids and hydrogen peroxide turnover, functionally relates peroxisomes to mitochondria. Further support for their communication and cooperation is furnished by the evidence that both organelles share the components of their division machinery. Until recently, the majority of studies on the molecular mechanisms of kidney injury focused primarily on mitochondria and neglected peroxisomes. CRITICAL ISSUES The aim of this concise review is to introduce the reader to the field of peroxisome biology and to provide an overview of the evidence about the contribution of peroxisomes to the development and progression of kidney injury. The topics of renal ischemia-reperfusion injury, endotoxin-induced kidney injury, diabetic nephropathy, and tubulointerstitial fibrosis, as well as the potential therapeutic implications of peroxisome activation, are addressed in this review. FUTURE DIRECTIONS Despite recent progress, further studies are needed to elucidate the molecular mechanisms induced by dysfunctional peroxisomes and the role of the dysregulated mitochondria-peroxisome axis in the pathogenesis of renal injury. Antioxid. Redox Signal. 25, 217-231.
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Affiliation(s)
- Radovan Vasko
- Department of Nephrology and Rheumatology, University Medical Center Göttingen , Göttingen, Germany
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Soraya H, Masoud WGT, Gandhi M, Garjani A, Clanachan AS. Myocardial mechanical dysfunction following endotoxemia: role of changes in energy substrate metabolism. Basic Res Cardiol 2016; 111:24. [DOI: 10.1007/s00395-016-0544-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 02/17/2016] [Indexed: 01/06/2023]
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Walshe CM, Laffey JG, Kevin L, O’Toole D. Sepsis protects the myocardium and other organs from subsequent ischaemic/reperfusion injury via a MAPK-dependent mechanism. Intensive Care Med Exp 2015; 3:35. [PMID: 26215802 PMCID: PMC4513033 DOI: 10.1186/s40635-014-0035-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 12/09/2014] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Sepsis has been shown to precondition the intact heart against ischaemia/reperfusion (IR) injury, and prior endotoxin exposure of cells in in vitro models has shown evidence of protection against subsequent simulated ischaemia. Our aim in this study is to validate these findings and further investigate the signaling pathways involved. METHODS Adult male Sprague Dawley rats were randomised to control (n = 7) or caecal ligation and perforation (CLP)-induced sepsis (n = 7). Hearts were harvested at 48 h, suspended in Langendorff mode and subjected to 30-min global ischaemia followed by 90-min reperfusion. In subsequent experiments, designed to determine the mechanisms by which sepsis protected against ischaemic injury, endotoxin-stimulated isolated cardiomyocytes, pulmonary A549 cells and renal HK2 cells were subjected to normoxic and hypoxic conditions. The roles of key pathways, including mitogen-activated protein (MAP) kinases extracellular-regulated protein kinase (ERK) 1/2, p38 MAPK (p38), c-Jun NH2-terminal protein kinase (JNK)), and nuclear factor-kappaB (NF-κB) were examined. RESULTS Systemic sepsis protected isolated hearts from subsequent ischaemic/reperfusion-induced injury, enhancing functional recovery on reperfusion [developed left ventricular pressure ((d)LVP) mean(SE) 66.63(±10.7) mmHg vs. 54.13(±9.9) mmHg; LVPmax at 60 min 67.29(±11.9) vs. 72.48(±9.3), sepsis vs. control] despite significantly reduced baseline LV function in CLP animals (p < 0.001). Septic preconditioning significantly reduced infarct size after IR injury (p < 0.05). Endotoxin exposure protected isolated cardiomyocytes against hypoxia-induced cell death (p < 0.001). This effect appeared mediated in part via the p38, JNK and NF-κB pathways, but was independent of the ERK pathway, and did not appear to be mediated via HMGB1. The preconditioning effect of endotoxin was also demonstrated in isolated kidney and lung cells, suggesting that this preconditioning effect of sepsis is not confined to the myocardium. CONCLUSIONS Sepsis preconditions the isolated rat heart against myocardial IR injury. These effects appeared to be mediated in part via the p38, JNK and NF-κB and pathways, but were independent of the ERK and HMGB pathways.
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Affiliation(s)
- Criona M Walshe
- Department of Anaesthesia, Galway University Hospitals and National University of Ireland, University Road, Galway, Ireland
| | - John G Laffey
- Department of Anaesthesia, Galway University Hospitals and National University of Ireland, University Road, Galway, Ireland
| | - Leo Kevin
- Department of Anaesthesia, Galway University Hospitals and National University of Ireland, University Road, Galway, Ireland
| | - Daniel O’Toole
- Department of Anaesthesia, Galway University Hospitals and National University of Ireland, University Road, Galway, Ireland
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Zhang M, Zou L, Feng Y, Chen YJ, Zhou Q, Ichinose F, Chao W. Toll-like receptor 4 is essential to preserving cardiac function and survival in low-grade polymicrobial sepsis. Anesthesiology 2015; 121:1270-80. [PMID: 24937074 DOI: 10.1097/aln.0000000000000337] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Toll-like receptor 4 (TLR4), the receptor for endotoxin, mediates hyperinflammatory response and contributes to high mortality during both endotoxin shock and severe sepsis. However, little is known about the role of TLR4 in the pathogenesis of low-grade polymicrobial sepsis, which is often associated with immunosuppression. METHODS Low-grade polymicrobial sepsis was generated by cecum ligation and puncture. Mortality was monitored in wild- type (C57BL/10ScSn) and TLR4def (C57BL/10ScCr) mice. Ex vivo heart and individual cardiomyocyte function were assessed in Langendorff (Hugo Sachs Elektronik; Harvard Apparatus, Holliston, MA) and IonOptix systems (IonOptix, Milton, MA), respectively. Serum chemistry was tested for liver and kidney injury. Cytokines were examined using a multiplex immunoassay. Neutrophil migratory and phagocytic functions were assessed using flow cytometry. Reactive oxygen species were measured using redox-sensitive dichlorodihydrofluorescein dye. RESULTS Following cecum ligation and puncture, wild-type mice developed bacterial peritonitis with mild cardiac dysfunction (n=3 in sham and n=8 in cecum ligation and puncture) and a mortality of 23% within 14 days (n=22). In comparison, septic TLR4def mice had deleterious cardiac dysfunction (n=6 in sham and n=10 in cecum ligation and puncture), kidney and liver injury (n=7), and much higher mortality at 81% (n=21). The deleterious effects observed in septic TLR4def mice were associated with increased local and systemic cytokine response, reduced neutrophil migratory and phagocytic function, increased reactive oxygen species generation in leukocytes, and impaired bacterial clearance. CONCLUSION TLR4 plays an essential role in host defense against low-grade polymicrobial sepsis by mediating neutrophil migratory/phagocytic functions, attenuating inflammation, reducing reactive oxygen species generation, and enhanced bacterial clearance.
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Affiliation(s)
- Ming Zhang
- From the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (M.Z., L.Z., Y.F., Y.-J.C., F.I., W.C.); and Department of Ultrasound Medicine, Second Xiangya Hospital, Xiangya School of Medicine, Changsha, China (M.Z., Q.Z.)
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Sun H, Yang B, Cui E, Liu R. Spectroscopic investigations on the effect of N-acetyl-L-cysteine-capped CdTe Quantum Dots on catalase. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2014; 132:692-699. [PMID: 24910977 DOI: 10.1016/j.saa.2014.04.157] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 04/17/2014] [Accepted: 04/23/2014] [Indexed: 06/03/2023]
Abstract
Quantum dots (QDs) are recognized as some of the most promising semiconductor nanocrystals in biomedical applications. However, the potential toxicity of QDs has aroused wide public concern. Catalase (CAT) is a common enzyme in animal and plant tissues. For the potential application of QDs in vivo, it is important to investigate the interaction of QDs with CAT. In this work, the effect of N-Acetyl-L-cysteine-Capped CdTe Quantum Dots with fluorescence emission peak at 612 nm (QDs-612) on CAT was investigated by fluorescence, synchronous fluorescence, fluorescence lifetime, ultraviolet-visible (UV-vis) absorption and circular dichroism (CD) techniques. Binding of QDs-612 to CAT caused static quenching of the fluorescence, the change of the secondary structure of CAT and the alteration of the microenvironment of tryptophan residues. The association constants K were determined to be K288K=7.98×10(5)Lmol(-1) and K298K=7.21×10(5)Lmol(-1). The interaction between QDs-612 and CAT was spontaneous with 1:1 stoichiometry approximately. The CAT activity was also inhibited for the bound QDs-612. This work provides direct evidence about enzyme toxicity of QDs-612 to CAT in vitro and establishes a new strategy to investigate the interaction between enzyme and QDs at a molecular level, which is helpful for clarifying the bioactivities of QDs in vivo.
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Affiliation(s)
- Haoyu Sun
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, Shandong Province, 27# Shanda South Road, Jinan 250100, PR China
| | - Bingjun Yang
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, Shandong Province, 27# Shanda South Road, Jinan 250100, PR China
| | - Erqian Cui
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, Shandong Province, 27# Shanda South Road, Jinan 250100, PR China
| | - Rutao Liu
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, Shandong Province, 27# Shanda South Road, Jinan 250100, PR China.
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Kuhn H, Petzold K, Hammerschmidt S, Wirtz H. Interaction of cyclic mechanical stretch and toll-like receptor 4-mediated innate immunity in rat alveolar type II cells. Respirology 2014; 19:67-73. [PMID: 23796194 DOI: 10.1111/resp.12149] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 02/14/2013] [Accepted: 05/30/2013] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND OBJECTIVE In cases of infection-induced acute lung injury, mechanical ventilation might be necessary to maintain oxygenation. Although low tidal volume ventilation is applied, alveolar over-distension may occur and result in ventilator-induced lung injury. In this study, we investigate (i) the influence of lipopolysaccharide (LPS) stimulation on high-amplitude stretching; and (ii) the effect of stretching on LPS-mediated immune response in isolated rat alveolar type II cells. METHODS Type II cells were incubated with LPS and stretched for 24 h on elastic membranes. Initially we examined apoptosis and lactic acid dehydrogenase release in LPS-treated stretched cells. Furthermore we determined toll-like receptor (TLR) 4 expression, TLR4 signalling by analysis of nuclear factor κB (NF-κB) activation and the secretion of inflammatory cytokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interleukin-1 beta, tumour necrosis factor alpha). RESULTS Our results show that LPS increases apoptosis and cytotoxicity in high amplitude stretched cells. Stretching and LPS activate NF-κB. The LPS influence is the prevailing one while no synergistic effects were observed by additional stretching. LPS stimulates an increased secretion of the inflammatory mediators only. Stretching had no influence on cytokines secretion. CONCLUSIONS We conclude that activation of TLR4 mediated immunity intensifies cell damage caused by stretching whereas in return stretching had no influence on TLR4 mediated innate immunity.
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Affiliation(s)
- Hartmut Kuhn
- Department of Respiratory Medicine, University of Leipzig, Leipzig, Germany
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Wagner KB, Felix SB, Riad A. Innate immune receptors in heart failure: Side effect or potential therapeutic target? World J Cardiol 2014; 6:791-801. [PMID: 25228958 PMCID: PMC4163708 DOI: 10.4330/wjc.v6.i8.791] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 04/18/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a leading cause of mortality and morbidity in western countries and occasions major expenses for public health systems. Although optimal medical treatment is widely available according to current guidelines, the prognosis of patients with HF is still poor. Despite the etiology of the disease, increased systemic or cardiac activation of the innate immune system is well documented in several types of HF. In some cases there is evidence of an association between innate immune activation and clinical outcome of patients with this disease. However, the few large trials conducted with the use of anti-inflammatory medication in HF have not revealed its benefits. Thus, greater understanding of the relationship between alteration in the immune system and development and progression of HF is urgently necessary: prior to designing therapeutic interventions that target pathological inflammatory processes in preventing harmful cardiac effects of immune modulatory therapy. In this regard, relatively recently discovered receptors of the innate immune system, i.e., namely toll-like receptors (TLRs) and nod-like receptors (NLRs)-are the focus of intense cardiovascular research. These receptors are main up-stream regulators of cytokine activation. This review will focus on current knowledge of the role of TLRs and NLRs, as well as on downstream cytokine activation, and will discuss potential therapeutic implications.
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Tzeng HP, Evans S, Gao F, Chambers K, Topkara VK, Sivasubramanian N, Barger PM, Mann DL. Dysferlin mediates the cytoprotective effects of TRAF2 following myocardial ischemia reperfusion injury. J Am Heart Assoc 2014; 3:e000662. [PMID: 24572254 PMCID: PMC3959693 DOI: 10.1161/jaha.113.000662] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background We have demonstrated that tumor necrosis factor (TNF) receptor‐associated factor 2 (TRAF2), a scaffolding protein common to TNF receptors 1 and 2, confers cytoprotection in the heart. However, the mechanisms for the cytoprotective effects of TRAF2 are not known. Methods/Results Mice with cardiac‐restricted overexpression of low levels of TRAF2 (MHC‐TRAF2LC) and a dominant negative TRAF2 (MHC‐TRAF2DN) were subjected to ischemia (30‐minute) reperfusion (60‐minute) injury (I/R), using a Langendorff apparatus. MHC‐TRAF2LC mice were protected against I/R injury as shown by a significant ≈27% greater left ventricular (LV) developed pressure after I/R, whereas mice with impaired TRAF2 signaling had a significantly ≈38% lower LV developed pressure, a ≈41% greater creatine kinase (CK) release, and ≈52% greater Evans blue dye uptake after I/R, compared to LM. Transcriptional profiling of MHC‐TRAF2LC and MHC‐TRAF2DN mice identified a calcium‐triggered exocytotic membrane repair protein, dysferlin, as a potential cytoprotective gene responsible for the cytoprotective effects of TRAF2. Mice lacking dysferlin had a significant ≈39% lower LV developed pressure, a ≈20% greater CK release, and ≈29% greater Evans blue dye uptake after I/R, compared to wild‐type mice, thus phenocopying the response to tissue injury in the MHC‐TRAF2DN mice. Moreover, breeding MHC‐TRAF2LC onto a dysferlin‐null background significantly attenuated the cytoprotective effects of TRAF2 after I/R injury. Conclusion The study shows that dysferlin, a calcium‐triggered exocytotic membrane repair protein, is required for the cytoprotective effects of TRAF2‐mediated signaling after I/R injury.
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Affiliation(s)
- Huei-Ping Tzeng
- Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
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Grote K, Sonnenschein K, Kapopara PR, Hillmer A, Grothusen C, Salguero G, Kotlarz D, Schuett H, Bavendiek U, Schieffer B. Toll-like receptor 2/6 agonist macrophage-activating lipopeptide-2 promotes reendothelialization and inhibits neointima formation after vascular injury. Arterioscler Thromb Vasc Biol 2013; 33:2097-104. [PMID: 23868938 DOI: 10.1161/atvbaha.113.301799] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVE Reendothelialization after vascular injury (ie, balloon angioplasty or stent implantation) is clinically extremely relevant to promote vascular healing. We here investigated the therapeutic potential of the toll-like receptor 2/6 agonist macrophage-activating lipopeptide (MALP)-2 on reendothelialization and neointima formation in a murine model of vascular injury. APPROACH AND RESULTS The left common carotid artery was electrically injured, and reendothelialization was quantified by Evans blue staining after 3 days. A single injection of MALP-2 (1 or 10 µg, IV) after vascular injury accelerated reendothelialization (P<0.001). Proliferation of endothelial cells at the wound margins determined by 5-ethynyl-2'-deoxyuridine incorporation was significantly higher in MALP-2-treated animals (P<0.05). Furthermore, wire injury-induced neointima formation of the left common carotid artery was completely prevented by a single injection of MALP-2 (10 µg, IV). In vitro, MALP-2 induced proliferation (BrdU incorporation) and closure of an artificial wound of endothelial cells (P<0.05) but not of smooth muscle cells. Protein array and ELISA analysis of isolated primary endothelial cells and ex vivo stimulated carotid segments revealed that MALP-2 stimulated the release of multiple growth factors and cytokines predominantly from endothelial cells. MALP-2 induced a strong activation of the mitogen-activated protein kinase cascade in endothelial cells, which was attenuated in smooth muscle cells. Furthermore, MALP-2 significantly enhanced circulating monocytes and hematopoietic progenitor cells. CONCLUSIONS The toll-like receptor 2/6 agonist MALP-2 promotes reendothelialization and inhibits neointima formation after experimental vascular injury via enhanced proliferation and migration of endothelial cells. Thus, MALP-2 represents a novel therapeutic option to accelerate reendothelialization after vascular injury.
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Affiliation(s)
- Karsten Grote
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
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Castegren M, Skorup P, Lipcsey M, Larsson A, Sjölin J. Endotoxin tolerance variation over 24 h during porcine endotoxemia: association with changes in circulation and organ dysfunction. PLoS One 2013; 8:e53221. [PMID: 23326400 PMCID: PMC3542331 DOI: 10.1371/journal.pone.0053221] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Accepted: 11/27/2012] [Indexed: 01/05/2023] Open
Abstract
Endotoxin tolerance (ET), defined as reduced inflammatory responsiveness to endotoxin challenge following a first encounter with endotoxin, is an extensively studied phenomenon. Although reduced mortality and morbidity in the presence of ET has been demonstrated in animal studies, little is known about the temporal development of ET. Further, in acute respiratory distress syndrome ET correlates to the severity of the disease, suggesting a complicated relation between ET and organ dysfunction. Eighteen pigs were subjected to intensive care and a continuous endotoxin infusion for 24 h with the aim to study the time course of early ET and to relate ET to outcome in organ dysfunction. Three animals served as non-endotoxemic controls. Blood samples for cytokine analyses were taken and physiological variables registered every third hour. Production of TNF-α, IL-6, and IL-10 before and after endotoxin stimulation ex vivo was measured. The difference between cytokine values after and before ex vivo LPS stimulation (Δ-values) was calculated for all time points. ΔTNF-α was employed as the principal marker of ET and lower ΔTNF-α values were interpreted as higher levels of ET. During endotoxin infusion, there was suppression of ex vivo productions of TNF-α and IL-6 but not of IL-10 in comparison with that at 0 h. The ex vivo TNF-α values followed another time concentration curve than those in vivo. ΔTNF-α was at the lowest already at 6 h, followed by an increase during the ensuing hours. ΔTNF-α at 6 h correlated positively to blood pressure and systemic vascular resistance and negatively to cardiac index at 24 h. In this study a temporal variation of ET was demonstrated that did not follow changes in plasma TNF-α concentrations. Maximal ET occurred early in the course and the higher the ET, the more hyperdynamic the circulation 18 h later.
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Affiliation(s)
- Markus Castegren
- Centre for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden.
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Differences in organ dysfunction in endotoxin-tolerant pigs under intensive care exposed to a second hit of endotoxin. Shock 2012; 37:501-10. [PMID: 22266970 DOI: 10.1097/shk.0b013e318249bb0d] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Endotoxin tolerance is a well-studied phenomenon associated with a reduced inflammatory response. In the switch from an inflammatory to an anti-inflammatory response in clinical sepsis, the concept of endotoxin tolerance is of obvious interest. However, only limited data exist regarding the effect of endotoxin tolerance on organ dysfunction, and therefore, this was investigated in a porcine intensive care sepsis model. Twenty-seven healthy pigs, including nine control animals, were included in the study. Twelve pigs pre-exposed to 24 h of intravenous endotoxin infusion and intensive care and six unexposed pigs were given either a high- or low-dose endotoxin challenge for 6 h. Inflammatory, circulatory, hypoperfusion, and organ dysfunction parameters were followed. The inflammatory responses as well as parameters representing circulation, hypoperfusion, and cardiac and renal function were all markedly attenuated in animals pre-exposed to endotoxin and intensive care as compared with animals not pre-exposed. In animals pre-exposed to endotoxin and given the high-dose of endotoxin challenge, deterioration in pulmonary function was equal to or even worse than in animals not pre-exposed. In contrast to the overall protective effect of endotoxin tolerance observed in other organ systems, the lungs of endotoxin-tolerant animals demonstrated an increased responsiveness to high-dose endotoxin challenge.
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Chen T, Jin X, Crawford BH, Cheng H, Saafir TB, Wagner MB, Yuan Z, Ding G. Cardioprotection from oxidative stress in the newborn heart by activation of PPARγ is mediated by catalase. Free Radic Biol Med 2012; 53:208-15. [PMID: 22609424 DOI: 10.1016/j.freeradbiomed.2012.05.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 04/03/2012] [Accepted: 05/11/2012] [Indexed: 12/20/2022]
Abstract
Regulation of catalase (CAT) by peroxisome proliferator-activated receptor-γ (PPARγ) was investigated to determine if PPARγ activation provides cardioprotection from oxidative stress caused by hydrogen peroxide (H(2)O(2)) in an age-dependent manner. Left ventricular developed pressure (LVDP) was measured in Langendorff perfused newborn or adult rabbit hearts, exposed to 200μM H(2)O(2), with perfusion of rosiglitazone (RGZ) or pioglitazone (PGZ), PPARγ agonists. We found: (1) H(2)O(2) significantly decreased sarcomere shortening in newborn ventricular cells but not in adult cells. Lactate dehydrogenase (LDH) release occurred earlier in newborn than in adult heart, which may be due, in part, to the lower expression of CAT in newborn heart. (2) RGZ increased CAT mRNA and protein as well as activity in newborn but not in adult heart. GW9662 (PPARγ blocker) eliminated the increased CAT mRNA by RGZ. (3) In newborn heart, RGZ and PGZ treatment inhibited release of LDH in response to H(2)O(2) compared to H(2)O(2) alone. GW9662 decreased this inhibition. (4) LVDP was significantly higher in both RGZ+H(2)O(2) and PGZ+H(2)O(2) groups than in the H(2)O(2) group. Block of PPARγ abolished this effect. In contrast, there was no effect of RGZ in adult. (5) The cardioprotective effects of RGZ were abolished by inhibition of CAT. In conclusion, PPARγ activation is cardioprotective to H(2)O(2)-induced stress in the newborn heart by upregulation of catalase. These data suggest that PPARγ activation may be an effective therapy for the young cardiac patient.
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Affiliation(s)
- Tao Chen
- Emory-Children's Center for Cardiovascular Biology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA
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27
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Graves BM, Simerly T, Li C, Williams DL, Wondergem R. Phosphoinositide-3-kinase/akt - dependent signaling is required for maintenance of [Ca(2+)](i), I(Ca), and Ca(2+) transients in HL-1 cardiomyocytes. J Biomed Sci 2012; 19:59. [PMID: 22715995 PMCID: PMC3464604 DOI: 10.1186/1423-0127-19-59] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Accepted: 06/20/2012] [Indexed: 01/27/2023] Open
Abstract
The phosphoinositide 3-kinases (PI3K/Akt) dependent signaling pathway plays an important role in cardiac function, specifically cardiac contractility. We have reported that sepsis decreases myocardial Akt activation, which correlates with cardiac dysfunction in sepsis. We also reported that preventing sepsis induced changes in myocardial Akt activation ameliorates cardiovascular dysfunction. In this study we investigated the role of PI3K/Akt on cardiomyocyte function by examining the role of PI3K/Akt-dependent signaling on [Ca2+]i, Ca2+ transients and membrane Ca2+ current, ICa, in cultured murine HL-1 cardiomyocytes. LY294002 (1–20 μM), a specific PI3K inhibitor, dramatically decreased HL-1 [Ca2+]i, Ca2+ transients and ICa. We also examined the effect of PI3K isoform specific inhibitors, i.e. α (PI3-kinase α inhibitor 2; 2–8 nM); β (TGX-221; 100 nM) and γ (AS-252424; 100 nM), to determine the contribution of specific isoforms to HL-1 [Ca2+]i regulation. Pharmacologic inhibition of each of the individual PI3K isoforms significantly decreased [Ca2+]i, and inhibited Ca2+ transients. Triciribine (1–20 μM), which inhibits AKT downstream of the PI3K pathway, also inhibited [Ca2+]i, and Ca2+ transients and ICa. We conclude that the PI3K/Akt pathway is required for normal maintenance of [Ca2+]i in HL-1 cardiomyocytes. Thus, myocardial PI3K/Akt-PKB signaling sustains [Ca2+]i required for excitation-contraction coupling in cardiomyoctyes.
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Affiliation(s)
- Bridget M Graves
- Departments of Surgery, James H. Quillen College of Medicine, East Tennessee State Universitycpr, Johnson City, TN 37614, USA
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28
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Ha T, Liu L, Kelley J, Kao R, Williams D, Li C. Toll-like receptors: new players in myocardial ischemia/reperfusion injury. Antioxid Redox Signal 2011; 15:1875-93. [PMID: 21091074 PMCID: PMC3159106 DOI: 10.1089/ars.2010.3723] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Innate immune and inflammatory responses have been implicated in myocardial ischemia/reperfusion (I/R) injury. However, the mechanisms by which innate immunity and inflammatory response are involved in myocardial I/R have not been elucidated completely. Recent studies highlight the role of Toll-like receptors (TLRs) in the induction of innate immune and inflammatory responses. Growing evidence has demonstrated that TLRs play a critical role in myocardial I/R injury. Specifically, deficiency of TLR4 protects the myocardium from ischemic injury, whereas modulation of TLR2 induces cardioprotection against ischemic insult. Importantly, cardioprotection induced by modulation of TLRs involves activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, suggesting that there is a crosstalk between TLRs and PI3K/Akt signaling pathways. In addition, TLRs also associate with other coreceptors, such as macrophage scavenger receptors in the recognition of their ligands. TLRs are also involved in the induction of angiogenesis, modulation of stem cell function, and expression of microRNA, which are currently important topic areas in myocardial I/R. Understanding how TLRs contribute to myocardial I/R injury could provide basic scientific knowledge for the development of new therapeutic approaches for the treatment and management of patients with heart attack.
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Affiliation(s)
- Tuanzhu Ha
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
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29
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Hypothermia down-regulates the LPS-induced norepinephrine (NE) release in ischaemic human heart cells. Brain Res Bull 2011; 87:67-73. [PMID: 21963948 DOI: 10.1016/j.brainresbull.2011.09.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Revised: 09/17/2011] [Accepted: 09/19/2011] [Indexed: 11/21/2022]
Abstract
Hypothermia has been widely acknowledged as the fundamental component of myocardial protection during cardiac operations. In this work, we studied in human atrial tissue the effect of the common hypothermic protection used in cardiac surgery, and we assessed this effect by comparing catecholamine release among normoxic, ischaemic, and inflammatory conditions. Our results provide the first evidence that lipopolysaccharide treatment results in an extremely dramatic and significant increase in the resting norepinephrine release under ischaemic conditions that can be normalised by hypothermia. These findings demonstrate that inflammatory conditions increase the temperature sensitivity of the norepinephrine transporter in human cardiac tissue. When the possible pharmacological interventions are taken into consideration, the results presented here provide new insight into the protection against ischaemia/reperfusion injury during cardiac surgery.
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30
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Li Y, Si R, Feng Y, Chen HH, Zou L, Wang E, Zhang M, Warren HS, Sosnovik DE, Chao W. Myocardial ischemia activates an injurious innate immune signaling via cardiac heat shock protein 60 and Toll-like receptor 4. J Biol Chem 2011; 286:31308-19. [PMID: 21775438 DOI: 10.1074/jbc.m111.246124] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Innate immune response after transient ischemia is the most common cause of myocardial inflammation and may contribute to injury, yet the detailed signaling mechanisms leading to such a response are not well understood. Herein we tested the hypothesis that myocardial ischemia activates interleukin receptor-associated kinase-1 (IRAK-1), a kinase critical for the innate immune signaling such as that of Toll-like receptors (TLRs), via a mechanism that involves heat shock proteins (HSPs) and TLRs. Coronary artery occlusion induced a rapid myocardial IRAK-1 activation within 30 min in wild-type (WT), TLR2(-/-), or Trif(-/-) mice, but not in TLR4(def) or MyD88(-/-) mice. HSP60 protein was markedly increased in serum or in perfusate of isolated heart following ischemia/reperfusion (I/R). In vitro, recombinant HSP60 induced IRAK-1 activation in cells derived from WT, TLR2(-/-), or Trif(-/-) mice, but not from TLR4(def) or MyD88(-/-) mice. Both myocardial ischemia- and HSP60-induced IRAK-1 activation was abolished by anti-HSP60 antibody. Moreover, HSP60 treatment of cardiomyocytes (CMs) led to marked activation of caspase-8 and -3, but not -9. Expression of dominant-negative mutant of Fas-associated death domain protein or a caspase-8 inhibitor completely blocked HSP60-induced caspase-8 activation, suggesting that HSP60 likely activates an apoptotic program via the death-receptor pathway. In vivo, I/R-induced myocardial apoptosis and cytokine expression were significantly attenuated in TLR4(def) mice or in WT mice treated with anti-HSP60 antibody compared with WT controls. Taken together, the current study demonstrates that myocardial ischemia activates an innate immune signaling via HSP60 and TLR4, which plays an important role in mediating apoptosis and inflammation during I/R.
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Affiliation(s)
- Yan Li
- Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
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31
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Abstract
Recent studies suggest that the heart possesses an innate immune system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses, within the heart. The extant literature suggests that this intrinsic stress response system is mediated, at least in part, by a family of pattern recognition receptors, most notably the Toll-like receptors. Although the innate immune system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if innate immune signaling becomes sustained and/or excessive; in which case, the salutary effects of activation of these pathways are contravened by the known deleterious effects of inflammatory signaling. Herein, the biology of innate immune signaling in the heart is reviewed, as well as the literature suggesting that the innate immune system is involved in the pathogenesis of atherosclerosis, acute coronary syndromes, stroke, viral myocarditis, sepsis, ischemia/reperfusion injury, and heart failure. The review concludes by discussing new therapies that are being developed to modulate the innate immune system.
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Affiliation(s)
- Douglas L Mann
- Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
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32
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Yao YW, Zhang GH, Zhang YY, Li WD, Wang CH, Yin CY, Zhang FM. Lipopolysaccharide pretreatment protects against ischemia/reperfusion injury via increase of HSP70 and inhibition of NF-κB. Cell Stress Chaperones 2011; 16:287-96. [PMID: 21080136 PMCID: PMC3077230 DOI: 10.1007/s12192-010-0242-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2010] [Revised: 10/25/2010] [Accepted: 10/27/2010] [Indexed: 11/24/2022] Open
Abstract
It has been reported that pretreatment of rats with lipopolysaccharide (LPS) increases myocardial functional recovery in ischemia/reperfusion (I/R) hearts. However, the mechanisms by which LPS induces cardioprotection against I/R injury have not been fully elucidated. In this study, we pretreated rats with LPS (1.0 mg/kg) 24 h before they were subjected to I/R injury, and then examined the roles of heat shock protein-70 (HSP70) and nucleus factor-κB (NF-κB) in LPS-induced cardioprotection. We observed that pretreatment with low-dose LPS resulted in significantly increased levels of HSP70 in the myocardium, which could dramatically inhibit NF-κB translocation and reduce degradation of inhibitory κB. Inhibition of NF-κB, in turn, attenuated release of inflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-1β, and IL-6) and reduced apoptosis of myocardium and infarct area following I/R injury. Moreover, HSP70 could ameliorate oxidative stress following I/R injury. To further investigate whether increase of HSP70 might be responsible for protection of the myocardium against I/R injury, we co-administered the HSP70 inhibitor, quercetin, with LPS before I/R injury. We found that LPS-induced cardioprotection was attenuated by co-administration with quercetin. Herein, we concluded that increased levels of HSP70 through LPS pretreatment led to inhibition of NF-κB activity in the myocardium after I/R injury. Our results indicated that LPS-induced cardioprotection was mediated partly through inhibition of NF-κB via increase of HSP70, and LPS pretreatment could provide a means of reducing myocardial I/R injury.
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Affiliation(s)
- Yong-wei Yao
- Department of Cardiology, Affiliated People’s Hospital of Jiangsu University, No.8, DianLi Road, Zhenjiang, Jiangsu Province 212000 People’s Republic of China
| | - Guo-hui Zhang
- Department of Cardiology, Affiliated People’s Hospital of Jiangsu University, No.8, DianLi Road, Zhenjiang, Jiangsu Province 212000 People’s Republic of China
| | - Ying-yu Zhang
- Department of Cardiology, Affiliated People’s Hospital of Jiangsu University, No.8, DianLi Road, Zhenjiang, Jiangsu Province 212000 People’s Republic of China
| | - Wei-dong Li
- Department of Cardiology, Affiliated People’s Hospital of Jiangsu University, No.8, DianLi Road, Zhenjiang, Jiangsu Province 212000 People’s Republic of China
| | - Cheng-hua Wang
- Department of Cardiology, Affiliated People’s Hospital of Jiangsu University, No.8, DianLi Road, Zhenjiang, Jiangsu Province 212000 People’s Republic of China
| | - Chun-yang Yin
- Department of Cardiology, Affiliated People’s Hospital of Jiangsu University, No.8, DianLi Road, Zhenjiang, Jiangsu Province 212000 People’s Republic of China
| | - Fu-min Zhang
- Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province 210029 People’s Republic of China
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33
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Toll-like receptor 4 signaling confers cardiac protection against ischemic injury via inducible nitric oxide synthase- and soluble guanylate cyclase-dependent mechanisms. Anesthesiology 2011; 114:603-13. [PMID: 21270629 DOI: 10.1097/aln.0b013e31820a4d5b] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Prior administration of a small dose of lipopolysaccharide confers a cardiac protection against ischemia-reperfusion injury. However, the signaling mechanisms that control the protection are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) mediates the ability of lipopolysaccharide to protect against cardiac ischemia-reperfusion injury through distinct intracellular pathways involving myeloid differentiation factor 88 (MyD88), TIR-domain-containing adaptor protein-inducing interferon-β-mediated transcription factor (Trif), inducible nitric oxide synthase (iNOS), and soluble guanylate cyclase (sGC). METHODS Wild-type mice and genetically modified mice, that is TLR4-deficient (TLR4(-def)), TLR2 knockout (TLR2(-/-)), MyD88(-/-), Trif(-/-), iNOS(-/-), and sGCα1(-/-), were treated with normal saline or 0.1 mg/kg lipopolysaccharide intraperitoneally. Twenty-four hours later, isolated hearts were perfused in a Langendorff apparatus and subsequently subjected to 30 min global ischemia and reperfusion for as long as 60 min. Left ventricular function and myocardial infarction sizes were examined. RESULTS Compared with saline-treated mice, lipopolysaccharide-treated mice had markedly improved left ventricular developed pressure and dP/dt(max) (P < 0.01) and reduced myocardial infarction sizes (37.2 ± 3.4% vs. 19.8 ± 4.9%, P < 0.01) after ischemia-reperfusion. The cardiac protective effect of lipopolysaccharide was abolished in the TLR4(-def) and MyD88(-/-) mice but remained intact in TLR2(-/-) or Trif(-/-) mice. iNOS(-/-) mice or wild-type mice treated with the iNOS inhibitor 1400W failed to respond to the TLR4-induced nitric oxide production and were not protected by the lipopolysaccharide preconditioning. Although sGCα(1)(-/-) mice had robust nitric oxide production in response to lipopolysaccharide, they were not protected by the TLR4-elicited cardiac protection. CONCLUSIONS TLR4 activation confers a potent cardiac protection against ischemia-reperfusion injury via a MyD88-dependent, but Trif-independent, mechanism. iNOS/sGC are essential for the TLR4-induced cardiac protection.
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Abstract
A wide variety of cardiac disease states can induce remodelling and lead to the functional consequence of heart failure. These complex disease states involve a plethora of parallel signal transduction events, which may be associated with tissue injury or tissue repair. Innate immunity is activated in hearts injured in different ways, evident as cytokine release from the heart, activation of toll-like receptors involved in recognizing danger, and activation of the transcription factor nuclear factor kappa B. Nuclear factor kappa B regulates gene programmes involved in inflammation as well as the resolution of inflammation. The impact of this is an enigma; while cytokines, toll-like receptors, and nuclear factor kappa B appear to elicit myocardial protection in studies of preconditioning, the literature strongly indicates a detrimental role for activation of innate immunity in studies of acute ischaemia–reperfusion injury. The impact of activation of cardiac innate immunity on the long-term outcome in in vivo models of hypertrophy and remodelling is less clear, with conflicting results as to whether it is beneficial or detrimental. More research using genetically engineered mice as tools, different models of evoking remodelling, and long-term follow-up is required for us to conclude whether activation of the innate immune system is good, bad, or unimportant in chronic injury models.
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Affiliation(s)
- Guro Valen
- Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Postbox 1103 Blindern, 0317, Oslo, Norway.
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35
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Topkara VK, Evans S, Zhang W, Epelman S, Staloch L, Barger PM, Mann DL. Therapeutic targeting of innate immunity in the failing heart. J Mol Cell Cardiol 2010; 51:594-9. [PMID: 21074541 DOI: 10.1016/j.yjmcc.2010.11.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2010] [Revised: 10/22/2010] [Accepted: 11/02/2010] [Indexed: 12/22/2022]
Abstract
Recent studies suggest that the heart possesses an intrinsic system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses within the heart. The extant literature suggests that this intrinsic stress response is mediated, at least in part, by a family of pattern recognition receptors that belong to the innate immune system, including CD14, the soluble pattern recognition receptor for lipopolysaccharide, and Toll-like receptors 2, 3, 4, 5, 6, 7, and 9. Although this intrinsic stress response system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if myocardial expression of these molecules either becomes sustained and/or excessive, in which case the salutary effects of activation of these pathways are contravened by the known deleterious effects of inflammatory signaling. Herein we present new information with regard to activation of innate immune gene expression in the failing human heart, as well as review the novel TLR antagonists that are being developed for other indications outside of heart failure. This review will discuss the interesting possibility that the TLR pathway may represent a new target for the development of novel heart failure therapeutics. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."
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Affiliation(s)
- Veli K Topkara
- Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8086, St. Louis, MO 63110, USA
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36
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Mersmann J, Habeck K, Latsch K, Zimmermann R, Jacoby C, Fischer JW, Hartmann C, Schrader J, Kirschning CJ, Zacharowski K. Left ventricular dilation in toll-like receptor 2 deficient mice after myocardial ischemia/reperfusion through defective scar formation. Basic Res Cardiol 2010; 106:89-98. [PMID: 20967453 DOI: 10.1007/s00395-010-0127-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2010] [Revised: 09/23/2010] [Accepted: 10/06/2010] [Indexed: 12/15/2022]
Abstract
Restoration of myocardial blood flow after ischemia triggers an inflammatory response involving toll-like receptors (TLRs). TLR2(-/-)-mice show short-term advantages upon reperfusion injury as compared with WT controls. Accordingly, it has been shown that transient TLR2-blockade prior to reperfusion is associated with improved left-ventricular performance after myocardial scar formation. We present here adverse myocardial remodeling due to a chronic lack of TLR2 expression. Myocardial ischemia/reperfusion (MI/R) was surgically induced in C3HeN-mice by ligation of the left anterior descending coronary artery for 20 min, followed by 24 h or 28 days of reperfusion. TLR2(-/-)-mice and TLR2-Ab treated (T2.5) WT-mice displayed a reduction of infarct size, plasma troponin T concentrations, and leukocyte infiltration as compared with untreated controls after 24 h of reperfusion. After 28 days, however, magnetic resonance imaging revealed a marked left ventricular dilation in TLR2(-/-)-animals, which was associated with pronounced matrix remodeling characterized by reduced collagen and decorin density in the infarct scar. Our data show adverse effects on myocardial remodeling in TLR2(-/-)-mice. Although interception with TLR2 signaling is a promising concept for the prevention of reperfusion injury after myocardial ischemia, these data give cause for serious concern with respect to the time-point and duration of the potential treatment.
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Affiliation(s)
- Jan Mersmann
- Clinic of Anaesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany
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Chi Z, Liu R, Zhang H. Potential enzyme toxicity of oxytetracycline to catalase. THE SCIENCE OF THE TOTAL ENVIRONMENT 2010; 408:5399-5404. [PMID: 20800878 DOI: 10.1016/j.scitotenv.2010.08.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2010] [Revised: 08/02/2010] [Accepted: 08/03/2010] [Indexed: 05/29/2023]
Abstract
Oxytetracycline (OTC) is a kind of widely used veterinary drugs. The residue of OTC in the environment is potentially harmful. In the present work, the non-covalent toxic interaction of OTC with catalase was investigated by the fluorescence spectroscopy, UV-vis absorption and circular dichroism (CD) spectroscopy at physiological pH 7.4. OTC can interact with catalase to form a complex mainly by van der Waals' interactions and hydrogen bonds with one binding site. The association constants K were determined to be K(293K)=7.09×10(4)Lmol(-1) and K(311K)=3.31×10(4)Lmol(-1). The thermodynamic parameters (ΔH°, ΔG° and ΔS°) of the interaction were calculated. Based on the Förster theory of non-radiative energy transfer, the distance between bound OTC and the tryptophan residues of catalase was determined to be 6.48nm. The binding of OTC can result in change of the micro-environment of the tryptophan residues and the secondary structure of catalase. The activity of catalase was also inhibited for the bound OTC. This work establishes a new strategy to probe the enzyme toxicity of veterinary drug residues and is helpful for clarifying the molecular toxic mechanism of OTC in vivo. The established strategy can be used to investigate the potential enzyme toxicity of other small organic pollutants and drugs.
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Affiliation(s)
- Zhenxing Chi
- School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, Shandong Province, 27# Shanda South Road,Jinan 250100, PR China
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38
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Wondergem R, Graves BM, Ozment-Skelton TR, Li C, Williams DL. Lipopolysaccharides directly decrease Ca2+ oscillations and the hyperpolarization-activated nonselective cation current If in immortalized HL-1 cardiomyocytes. Am J Physiol Cell Physiol 2010; 299:C665-71. [PMID: 20573997 DOI: 10.1152/ajpcell.00129.2010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Lipopolysaccharide (LPS) has been implicated in sepsis-mediated heart failure and chronic cardiac myopathies. We determined that LPS directly and reversibly affects cardiac myocyte function by altering regulation of intracellular Ca2+ concentration ([Ca2+]i) in immortalized cardiomyocytes, HL-1 cells. [Ca2+]i oscillated (<0.4 Hz), displaying slow and transient components. LPS (1 microg/ml), derived either from Escherichia coli or from Salmonella enteritidis, reversibly abolished Ca2+ oscillations and decreased basal [Ca2+]i by 30-40 nM. HL-1 cells expressed Toll-like receptors, i.e., TLR-2 and TLR-4. Thus, we differentiated effects of LPS on [Ca2+]i and Ca2+ oscillations by addition of utlrapure LPS, a TLR-4 ligand. Ultrapure LPS had no effect on basal [Ca2+]i, but it reduced the rate of Ca2+ oscillations. Interestingly, Pam3CSK4, a TLR-2 ligand, affected neither Ca2+ parameter, and the effect of ultrapure LPS and Pam3CSK4 combined was similar to that of utlrapure LPS alone. Thus, unpurified LPS directly inhibits HL-1 calcium metabolism via TLR-4 and non-TLR-4-dependent mechanisms. Since others have shown that endotoxin impairs the hyperpolarization-activated, nonselective cationic pacemaker current (I(f)), which is expressed in HL-1 cells, we utilized whole cell voltage-clamp techniques to demonstrate that LPS (1 microg/ml) reduced I(f) in HL-1 cells. This inhibition was marginal at physiologic membrane potentials and significant at very negative potentials (P < 0.05 at -140, -150, and -160 mV). So, we also evaluated effects of LPS on tail currents of fully activated I(f). LPS reduced the slope conductance of the tail currents from 498 +/- 140 pS/pF to 223 +/- 65 pS/pF (P < 0.05) without affecting reversal potential of -11 mV. Ultrapure LPS had similar effect on I(f), whereas Pam3CSK4 had no effect on I(f). We conclude that LPS inhibits activation of I(f), enhances its deactivation, and impairs regulation of [Ca2+]i in HL-1 cardiomyocytes via TLR-4 and other mechanisms.
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Affiliation(s)
- Robert Wondergem
- Dept. of Physiology, James H. Quillen College of Medicine, East Tennessee State Univ., P. O. Box 70576, Johnson City, TN 37614-1708, USA.
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Draisma A, de Goeij M, Wouters CW, Riksen NP, Oyen WJG, Rongen GA, Boerman OC, van Deuren M, van der Hoeven JG, Pickkers P. Endotoxin tolerance does not limit mild ischemia-reperfusion injury in humans in vivo. Innate Immun 2010; 15:360-7. [PMID: 19710089 DOI: 10.1177/1753425909105548] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Animal studies have shown that previous exposure to lipopolysaccharide (LPS) can limit ischemia-reperfusion injury. We tested whether pretreatment with LPS also protects against ischemia-reperfusion injury in humans in vivo. Fourteen volunteers received bolus injections of incremental dosages of LPS on 5 consecutive days (LPS group). Before the first and 1 day after the last LPS administration, the forearm circulation of the non-dominant arm was occluded for 10 min, with concomitant intermittent handgripping to induce transient ischemia. After reperfusion, 0.1 mg of ( 99m)Tc-labeled annexin A5 (400 MBq) was injected intravenously to detect phosphatidylserine expression as an early marker of ischemia-reperfusion injury. Similarly, the control group (n = 10) underwent the ischemic exercise twice, but without pretreatment with LPS. Annexin A5 targeting was expressed as the percentage difference in radioactivity in the thenar muscle between both hands. Endotoxin tolerance developed during 5 consecutive days of LPS administration. Annexin A5 targeting was 12.1 +/- 2.2% and 10.4 +/- 2.1% before LPS treatment at 1 h and 4 h after reperfusion, compared to 12.2 +/- 2.4% and 8.9 +/- 2.1% at 1 h and 4 h after reperfusion on day 5 (P = 1.0 and 0.6, respectively). Also, no significant changes in annexin A5 targeting were found in the control group. So, in this model, LPS-tolerance does not protect against ischemia-reperfusion injury in humans in vivo.
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Affiliation(s)
- Annelies Draisma
- Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, The Netherlands
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40
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Preconditioning by toll-like receptor 2 agonist Pam3CSK4 reduces CXCL1-dependent leukocyte recruitment in murine myocardial ischemia/reperfusion injury. Crit Care Med 2010; 38:903-9. [PMID: 20081527 DOI: 10.1097/ccm.0b013e3181ce50e6] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To test whether preconditioning with a toll-like receptor (TLR) 2 agonist protects against myocardial ischemia and reperfusion by interfering with chemokine CXCL1 release from cardiomyocytes. DESIGN C3H mice were challenged with vehicle or synthetic TLR2 agonist Pam3Cys-Ser-Lys4 (Pam3CSK4; 1 mg/kg) 24 hrs before myocardial ischemia (20 mins) and reperfusion (2 hrs or 24 hrs). Infarct size, troponin T release, and leukocyte recruitment were quantified. In murine cardiomyocytes (HL-1), we studied the expression/activation profile of TLR2 in response to stimulation with Pam3CSK4 (0.01-1 mg/mL). Furthermore, we studied the chemokine ligand 1 (CXCL1) response to Pam3CSK4 and ischemia/reperfusion in vivo and in vitro. SETTING University hospital research laboratory. SUBJECTS Anesthetized male mice and murine cardiomyocytes. MEASUREMENTS AND MAIN RESULTS Preconditioning by Pam3CSK4 reduced infarct size and troponin T release. This was accompanied by a decreased recruitment of leukocytes into the ischemic area and an improved cardiac function. In HL-1 cells, TLR2 activation amplified the expression of the receptor in a time-dependent manner and led to CXCL1 release in a concentration-dependent manner. Preconditioning by Pam3CSK4 impaired CXCL1 release in response to a second inflammatory stimulus in vivo and in vitro. CONCLUSIONS Preconditioning by TLR2 agonist Pam3CSK4 reduces myocardial infarct size after myocardial ischemia/reperfusion. One of the mechanisms involved is a diminished chemokine release from cardiomyocytes, which subsequently limits leukocyte infiltration.
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Fan MHM, Wong KL, Wu S, Leung WK, Yam WC, Wong TM. Preconditioning withPorphyromonas gingivalislipopolysaccharide may confer cardioprotection and improve recovery of the electrically induced intracellular calcium transient during ischemia and reperfusion. J Periodontal Res 2010; 45:100-8. [DOI: 10.1111/j.1600-0765.2009.01206.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Mann DL, Topkara VK, Evans S, Barger PM. Innate immunity in the adult mammalian heart: for whom the cell tolls. TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION 2010; 121:34-51. [PMID: 20697548 PMCID: PMC2917144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Recent studies suggest that the heart possesses an intrinsic system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses within the heart. The extant literature suggests that this intrinsic stress response is mediated, at least in part, by a family of pattern recognition receptors that belong to the innate immune system, including CD14, the soluble pattern recognition receptor for lipopolysaccharide, and Toll like receptors-2, 3, 4, and 6. Although this intrinsic stress response system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if myocardial expression of these molecules either becomes sustained and/or excessive, in which case the salutary effects of activation of these pathways may be contravened by the known deleterious effects of inflammatory signaling. Herein we present new information with regard to activation of innate immune gene expression in the failing human heart. Taken together, these new observations provide provisional evidence that the innate immune system is activated in human heart failure, raising the interesting possibility that this pathway may represent a target for the development of novel heart failure therapeutics.
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Affiliation(s)
- Douglas L Mann
- Division of Cardiology, 660 S. Euclid Ave, Campus Box 8086, St. Louis, MO 63110, USA.
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Draisma A, Pickkers P, Bouw MP, van der Hoeven JG. Development of endotoxin tolerance in humans in vivo. Crit Care Med 2009; 37:1261-7. [DOI: 10.1097/ccm.0b013e31819c3c67] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Leung PY, Packard AE, Stenzel-Poore MP. It's all in the family: multiple Toll-like receptors offer promise as novel therapeutic targets for stroke neuroprotection. FUTURE NEUROLOGY 2009; 4:201-208. [PMID: 19885374 DOI: 10.2217/14796708.4.2.201] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ischemic tolerance is a biological process that can be utilized to unlock the brain's own endogenous protection mechanisms and, as such, holds true promise for patients at risk of ischemic injury. Experimentally, preconditioning with various Toll-like receptor (TLR) agonists has now been demonstrated to successfully attenuate ischemic damage, partly through genomic reprogramming of the body's response to stroke. This treatment diminishes the inflammatory response to stroke and at the same time enhances the production of anti-inflammatory cytokines and neuroprotective mediators. This review discusses recent discoveries about the role of TLRs in preconditioning and ischemic tolerance.
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Affiliation(s)
- Philberta Y Leung
- Department of Molecular Microbiology & Immunology L220, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Tel.: +1 503 494 5312,
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Sicard P, Jacquet S, Kobayashi KS, Flavell RA, Marber MS. Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1. Cardiovasc Res 2009; 83:277-84. [PMID: 19213760 DOI: 10.1093/cvr/cvp055] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
AIMS Despite their ability to cause septic shock and myocardial dysfunction, components of Gram-negative bacterial cell walls, like lipopolysaccharide, have been shown in numerous studies to induce myocardial protection during ischaemia-reperfusion injury. Muramyl dipeptide (MDP) is another such component recognized by an intracellular receptor, nucleotide-binding oligomerization domain 2. Receptor activation leads to intracellular signals through receptor interacting protein-2 (RIP2) and tumour growth factor-beta-activated kinase-1 (TAK1). However, little is known about the RIP2/TAK1 pathway in the heart. The aim of this study was to determine whether the RIP2/TAK1 pathway has a cardioprotective role in a mouse model of myocardial infarction. METHODS AND RESULTS We isolated and subjected wild-type (WT) and RIP2(-/-) mouse hearts to 30 min of global ischaemia and 120 min of reperfusion with or without perfusion of MDP (10 microg/mL) before or after the ischaemic period and determined the infarct size. We examined activation of the TAK1/nuclear factor kappaB (NFkappaB) signalling pathway. The effect of TAK1 inhibition on MDP-induced cardioprotection was also evaluated. Exposure to MDP during reperfusion significantly reduced infarct size in WT hearts (from 51.7 +/- 5.6% in control to 38.1 +/- 6.7%, P < 0.05), but not in RIP2(-/-) hearts or in WT hearts with coincident pharmacological inhibition of TAK1. MDP treatment significantly increased the levels of p-TAK1 and p-JNK (Jun N-terminal kinase) and led to NFkappaB activation via phosphorylation and degradation of IkappaB in the WT, but not in the RIP2(-/-), myocardium. CONCLUSION These results indicate that MDP at reperfusion induced cardioprotection through an RIP2/TAK1-dependent mechanism.
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Affiliation(s)
- Pierre Sicard
- King's College London British Heart Foundation Centre of Research Excellence, The Cardiovascular Division, The Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK
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Chao W. Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart. Am J Physiol Heart Circ Physiol 2008; 296:H1-12. [PMID: 19011041 DOI: 10.1152/ajpheart.00995.2008] [Citation(s) in RCA: 183] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Toll-like receptors (TLRs) represent the first line of host defense against microbial infection and play a pivotal role in both innate and adaptive immunity. TLRs recognize invading pathogens through molecular pattern recognition, transduce signals via distinct intracellular pathways involving a unique set of adaptor proteins and kinases, and ultimately lead to the activation of transcription factors and inflammatory responses. Among 10 TLRs identified in humans, at least two exist in the heart, i.e., TLR2 and TLR4. In addition to the critical role of these in mediating cardiac dysfunction in septic conditions, emerging evidence suggests that the TLRs can also recognize endogenous ligands and may play an important role in modulating cardiomyocyte survival and in ischemic myocardial injury. In animal models of ischemia-reperfusion injury or in hypoxic cardiomyocytes in vitro, the administration of a sublethal dose of lipopolysaccharide, which signals through TLR4, reduces subsequent myocardial infarction, improves cardiac functions, and attenuates cardiomyocyte apoptosis. By contrast, a systemic deficiency of TLR2, TLR4, or myeloid differentiation primary-response gene 88, an adaptor critical for all TLR signaling, except TLR3, leads to an attenuated myocardial inflammation, a smaller infarction size, a better preserved ventricular function, and a reduced ventricular remodeling after ischemic injury. These loss-of-function studies suggest that both TLRs contribute to myocardial inflammation and ischemic injury in the heart although the exact contribution of cardiac (vs. circulatory cell) TLRs remains to be defined. These recent studies demonstrate an emerging role for TLRs as a critical modulator in both cell survival and tissue injury in the heart.
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Affiliation(s)
- Wei Chao
- Dept. of Anesthesia & Critical Care, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, USA.
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Schober P, Oprea G, Mersmann J, Nebert A, Zacharowski K, Zacharowski PA. Lipoteichoic acid induces delayed myocardial protection in isolated rat hearts: A comparison with endotoxin. Resuscitation 2008; 79:311-5. [DOI: 10.1016/j.resuscitation.2008.06.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2008] [Accepted: 06/04/2008] [Indexed: 10/21/2022]
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Valeur HS, Valen G. Innate immunity and myocardial adaptation to ischemia. Basic Res Cardiol 2008; 104:22-32. [DOI: 10.1007/s00395-008-0756-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Accepted: 09/19/2008] [Indexed: 12/27/2022]
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49
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Feng Y, Zhao H, Xu X, Buys ES, Raher MJ, Bopassa JC, Thibault H, Scherrer-Crosbie M, Schmidt U, Chao W. Innate immune adaptor MyD88 mediates neutrophil recruitment and myocardial injury after ischemia-reperfusion in mice. Am J Physiol Heart Circ Physiol 2008; 295:H1311-H1318. [PMID: 18660455 DOI: 10.1152/ajpheart.00119.2008] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
MyD88 is an adaptor protein critical for innate immune response against microbial infection and in certain noninfectious tissue injury. The present study examined the role of MyD88 in myocardial inflammation and injury after ischemia-reperfusion (I/R). I/R was produced by coronary artery ligation for 30 min followed by reperfusion. The ratios of area at risk to left ventricle (LV) were similar between wild-type (WT) and MyD88-deficient (MyD88-/-) mice. However, 24 h after I/R, the ratios of myocardial infarction to area at risk were 58% less in MyD88(-/-) than in WT mice (14 +/- 2% vs. 33 +/- 6%, P = 0.01). Serial echocardiographic studies demonstrated that there was no difference in baseline LV contractile function between the two groups. Twenty-four hours after I/R, LV ejection fraction (EF) and fractional shortening (FS) in WT mice were reduced by 44% and 62% (EF, 51 +/- 2%, and FS, 22 +/- 1%, P < 0.001), respectively, and remained depressed on the seventh day after I/R. In comparison, EF and FS in MyD88(-/-) mice were 67 +/- 3% and 33 +/- 2%, respectively, after I/R (P < 0.001 vs. WT). Similarly, LV function, as demonstrated by invasive hemodynamic measurements, was better preserved in MyD88(-/-) compared with WT mice after I/R. Furthermore, when compared with WT mice, MyD88(-/-) mice subjected to I/R had a marked decrease in myocardial inflammation as demonstrated by attenuated neutrophil recruitment and decreased expression of the proinflammatory mediators keratinocyte chemoattractant, monocyte chemoattractant protein-1, and ICAM-1. Taken together, these data suggest that MyD88 modulates myocardial inflammatory injury and contributes to myocardial infarction and LV dysfunction during I/R.
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Affiliation(s)
- Yan Feng
- Anesthesia Center for Critical Care Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
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Hansen HR, Wolfs JL, Bruggemann L, Sommeijer DW, Bevers E, Hauer AD, Kuiper J, Spek CA, Spronk HMH, Reitsma PH, ten Cate H. Hyperglycemia accelerates arterial thrombus formation and attenuates the antithrombotic response to endotoxin in mice. Blood Coagul Fibrinolysis 2007; 18:627-36. [PMID: 17890950 DOI: 10.1097/mbc.0b013e3282891ebd] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Recent human studies reveal that hyperglycemia induces procoagulant and antifibrinolytic effects in blood that may contribute to a greater risk of arterial thrombosis, but the direct relationship between high blood glucose levels and thrombosis has not yet been investigated. We performed a number of experiments to clarify whether hyperglycemia was causally related to arterial thrombosis and whether the combined stimulus of hyperglycemia and inflammation would enhance the thrombotic effect. In a model of ferric-chloride-induced carotid artery thrombosis, hyperglycemia did not influence the time to occlusion in mice pretreated with streptozotocin, but the rate of thrombus formation was accelerated. This effect was associated with increased thrombin generation and could not be explained by changes in vessel-wall tissue factor activity. The prothrombotic effect of hyperglycemia was assessed in a separate experiment, showing that collagen/thrombin-induced platelet procoagulant activity was increased in hyperglycemic mice. The effect of inflammation was studied by injecting a low dose of endotoxin that caused a systemic inflammatory state after 24 h (increased plasma levels of tumor necrosis factor alpha, interleukin-6 and monocyte chemotactic protein 1 in diabetic and nondiabetic mice) associated with a mild delay in thrombus formation. This reduced rate of thrombus formation was attenuated by hyperglycemia. Together, these data establish a discrete but clear contribution of hyperglycemia in experimental arterial thrombosis.
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Affiliation(s)
- Hjalmar R Hansen
- Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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