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Gomes FP, Durbin KR, Schauer K, Nwachukwu JC, R Kobylski R, Njeri JW, Seath CP, Saviola AJ, McClatchy DB, Diedrich JK, Garrett PT, Papa AB, Ciolacu I, Kelleher NL, Nettles KW, Yates JR. Native top-down proteomics enables discovery in endocrine-resistant breast cancer. Nat Chem Biol 2025:10.1038/s41589-025-01866-8. [PMID: 40186031 DOI: 10.1038/s41589-025-01866-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 02/24/2025] [Indexed: 04/07/2025]
Abstract
Oligomerization of proteoforms produces functional protein complexes. Characterization of these assemblies within cells is critical to understanding the molecular mechanisms involved in disease and to designing effective drugs. Here we present a native top-down proteomics (nTDP) strategy to identify protein assemblies (≤70 kDa) in breast cancer cells and in cells that overexpress epidermal growth factor receptor (EGFR), which serves as a resistance model of estrogen receptor-alpha (ER)-targeted therapies. This nTDP approach identified ~104 complexoforms from 17 protein complexes, which revealed several molecular features of the breast cancer proteome, including EGFR-induced dissociation of nuclear transport factor 2 (NUTF2) assemblies that modulate ER activity. We found that the K4 and K55 post-translational modification sites discovered with nTDP differentially impact the effects of NUTF2 on the inhibition of the ER signaling pathway. The characterization of endogenous proteoform-proteoform/ligand interactions revealed the molecular diversity of complexoforms and their role in breast cancer growth.
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Affiliation(s)
| | | | | | - Jerome C Nwachukwu
- Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA
| | - Robin R Kobylski
- Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA
- The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA, USA
| | - Jacqline W Njeri
- Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA
- The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA, USA
| | - Ciaran P Seath
- Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA
| | | | | | | | | | - Alexandra B Papa
- Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA
- Florida Atlantic University, Jupiter, FL, USA
| | - Ianis Ciolacu
- Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA
- Florida Atlantic University, Jupiter, FL, USA
| | - Neil L Kelleher
- Proteinaceous, Evanston, IL, USA
- Northwestern University, National Resource for Translational and Developmental Proteomics, Evanston, IL, USA
| | - Kendall W Nettles
- Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA.
- The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA, USA.
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Chen XC, Gai MT, He CH, Zhao BH, Liu F, Ma X, Ma YT, Gao XM, Chen BD. Recombinant dsAAV9-mediated Endogenous Overexpression of Macrophage Migration Inhibitory Factor Alleviates Myocardial Ischemia-Reperfusion Injury via Activating AMPK and ERK1/2 Signaling Pathways. Cardiovasc Drugs Ther 2025:10.1007/s10557-024-07662-1. [PMID: 39747743 DOI: 10.1007/s10557-024-07662-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/12/2024] [Indexed: 01/04/2025]
Abstract
PURPOSE To investigate the protective effect and mechanism of enhanced expression of endogenous macrophage migration inhibitory factor (MIF) on cardiac ischemia-reperfusion (I/R) injury. METHODS A recombinant double-stranded adeno-associated virus serotype 9 with MIF or green fluorescent protein (GFP) genes (dsAAV9-MIF/GFP) was transduced into mice and neonatal rat ventricular myocytes (NRVMs). The models of cardiac 60 min ischemia and 24 h reperfusion and 12 h hypoxia/12 h reoxygenation (H/R) were established in mice and NRVMs, respectively. Infarct size, cardiac remodeling, and related signaling pathways were assessed. RESULTS The dsAAV9 vector demonstrated strong transduction efficacy and cardiac affinity. Cardiac overexpression of MIF led to a 35.3% reduction in infarct size and improved cardiac function following I/R injury. In the dsAAV9-MIF group, the AMP-activated protein kinase (AMPK) signaling pathway was activated, and autophagy was enhanced during the ischemic period. During reperfusion, the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway was upregulated, leading to reduced cardiac apoptosis. In vitro, transfection with MIF in NRVMs also upregulated AMPK and ERK1/2 signaling during hypoxia and reoxygenation, respectively. Furthermore, MIF overexpression significantly improved autophagy and mitochondrial function, evidenced by an increased LC3-II/I ratio and enhanced mitochondrial membrane potential (ΔΨm), with these effects reversed by the AMPK inhibitor compound C. Additionally, MIF overexpression led to a 60% reduction in the apoptosis rate of cardiomyocytes subjected to H/R and decreased the Bax/Bcl-2 ratio, partially through the ERK1/2 signaling pathway. CONCLUSION Enhanced endogenous MIF expression via the dsAAV9 vector provides significant cardioprotection against I/R injury by activating the AMPK and ERK1/2 signaling pathways. Our findings suggest that targeting MIF may represent a viable therapeutic strategy for severe and prolonged I/R injury.
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Affiliation(s)
- Xiao-Cui Chen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Clinical Medical Research Institute, Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, China
- College of Basic Medicine of Xinjiang Medical University, Urumqi, China
| | - Min-Tao Gai
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Clinical Medical Research Institute, Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, China
| | - Chun-Hui He
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Clinical Medical Research Institute, Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, China
| | - Bang-Hao Zhao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Clinical Medical Research Institute, Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, China
| | - Fen Liu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Clinical Medical Research Institute, Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, China
| | - Xiang Ma
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Clinical Medical Research Institute, Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, China
| | - Yi-Tong Ma
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Clinical Medical Research Institute, Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, China
| | - Xiao-Ming Gao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Clinical Medical Research Institute, Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, China.
- Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China.
| | - Bang-Dang Chen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Clinical Medical Research Institute, Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, China.
- College of Basic Medicine of Xinjiang Medical University, Urumqi, China.
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Zhao L, Zhao BH, Ruze A, Li QL, Deng AX, Gao XM. Distinct roles of MIF in the pathogenesis of ischemic heart disease. Cytokine Growth Factor Rev 2024; 80:121-137. [PMID: 39438226 DOI: 10.1016/j.cytogfr.2024.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/25/2024]
Abstract
The role of macrophage migration inhibitory factor (MIF) as a multifunctional cytokine in immunomodulation and inflammatory response is increasingly appreciated. Ischemic heart disease (IHD), the leading cause of global mortality, remains a focal point of research owing to its intricate pathophysiology. MIF has been identified as a critical player in IHD, where it exerts distinct roles. On one hand, MIF plays a protective role by enhancing energy metabolism through activation of AMPK, resisting oxidative stress, inhibiting activation of the JNK pathway, and maintaining intracellular calcium ion homeostasis. Additionally, MIF exerts protective effects through mesenchymal stem cells and exosomes. On the other hand, MIF can assume a pro-inflammatory role, which contributes to the exacerbation of IHD's development and progression. Furthermore, MIF levels significantly increase in IHD patients, and its genetic polymorphisms are positively correlated with prevalence and severity. These findings position MIF as a potential biomarker and therapeutic target in the management of IHD. This review summarizes the structure, source, signaling pathways and biological functions of MIF and focuses on its roles and clinical characteristics in IHD. The genetic variants of MIF associated with IHD is also discussed, providing more understandings of its complex interplay in the disease's pathology.
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Affiliation(s)
- Ling Zhao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Bang-Hao Zhao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Amanguli Ruze
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Qiu-Lin Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - An-Xia Deng
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Xiao-Ming Gao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China; Xinjiang Key Laboratory of Cardiovascular Disease, Urumqi, China.
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Sajko S, Skeens E, Schinagl A, Ferhat M, Mirkina I, Mayer J, Rossmueller G, Thiele M, Lisi GP. Redox-dependent plasticity of oxMIF facilitates its interaction with CD74 and therapeutic antibodies. Redox Biol 2024; 75:103264. [PMID: 38972295 PMCID: PMC11263951 DOI: 10.1016/j.redox.2024.103264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/01/2024] [Accepted: 07/03/2024] [Indexed: 07/09/2024] Open
Abstract
MIF is a ubiquitous protein involved in proinflammatory processes, which undergoes an oxidation-driven conformational change to oxidized (ox)MIF. We demonstrate that hypochlorous acid, produced by neutrophil-released myeloperoxidase (MPO) under inflammatory conditions, effectively oxidizes MIF into the oxMIF isoform, which is specifically recognized by the anti-oxMIF therapeutic antibody, ON104. NMR investigation of MIF oxidized by the MPO system revealed increased flexibility throughout the MIF structure, including at several catalytic and allosteric sites. Mass spectrometry of MPO-oxMIF revealed methionines as the primary site of oxidation, whereas Pro2 and Tyr99/100 remained almost unmodified. ELISA, SPR and cell-based assays demonstrated that structural changes caused by MPO-driven oxidation promoted binding of oxMIF to its receptor, CD74, which does not occur with native MIF. These data reveal the environment and modifications that facilitate interactions between MIF and its pro-inflammatory receptor, and a route for therapeutic intervention targeting the oxMIF isoform.
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Affiliation(s)
- Sara Sajko
- OncoOne Research and Development GmbH, Vienna, Austria
| | - Erin Skeens
- Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, USA
| | | | - Maroua Ferhat
- OncoOne Research and Development GmbH, Vienna, Austria
| | - Irina Mirkina
- OncoOne Research and Development GmbH, Vienna, Austria
| | - Julia Mayer
- OncoOne Research and Development GmbH, Vienna, Austria
| | | | | | - George P Lisi
- Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, USA
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Wang H, Rouhi N, Slotabec LA, Seale BC, Wen C, Filho F, Adenawoola MI, Li J. Myeloid Cells in Myocardial Ischemic Injury: The Role of the Macrophage Migration Inhibitory Factor. Life (Basel) 2024; 14:981. [PMID: 39202723 PMCID: PMC11355293 DOI: 10.3390/life14080981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 07/23/2024] [Accepted: 07/26/2024] [Indexed: 09/03/2024] Open
Abstract
Ischemic heart disease, manifesting as myocardial infarction (MI), remains the leading cause of death in the western world. Both ischemia and reperfusion (I/R) cause myocardial injury and result in cardiac inflammatory responses. This sterile inflammation in the myocardium consists of multiple phases, involving cell death, tissue remodeling, healing, and scar formation, modulated by various cytokines, including the macrophage migration inhibitory factor (MIF). Meanwhile, different immune cells participate in these phases, with myeloid cells acting as first responders. They migrate to the injured myocardium and regulate the initial phase of inflammation. The MIF modulates the acute inflammatory response by affecting the metabolic profile and activity of myeloid cells. This review summarizes the role of the MIF in regulating myeloid cell subsets in MI and I/R injury and discusses emerging evidence of metabolism-directed cellular inflammatory responses. Based on the multifaceted role of the MIF affecting myeloid cells in MI or I/R, the MIF can be a therapeutic target to achieve metabolic balance under pathology and alleviate inflammation in the heart.
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Affiliation(s)
- Hao Wang
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS 39216, USA; (H.W.); (N.R.); (L.A.S.); (B.C.S.); (C.W.); (F.F.); (M.I.A.)
| | - Nadiyeh Rouhi
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS 39216, USA; (H.W.); (N.R.); (L.A.S.); (B.C.S.); (C.W.); (F.F.); (M.I.A.)
| | - Lily A. Slotabec
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS 39216, USA; (H.W.); (N.R.); (L.A.S.); (B.C.S.); (C.W.); (F.F.); (M.I.A.)
- G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS 39216, USA
| | - Blaise C. Seale
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS 39216, USA; (H.W.); (N.R.); (L.A.S.); (B.C.S.); (C.W.); (F.F.); (M.I.A.)
| | - Changhong Wen
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS 39216, USA; (H.W.); (N.R.); (L.A.S.); (B.C.S.); (C.W.); (F.F.); (M.I.A.)
| | - Fernanda Filho
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS 39216, USA; (H.W.); (N.R.); (L.A.S.); (B.C.S.); (C.W.); (F.F.); (M.I.A.)
| | - Michael I. Adenawoola
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS 39216, USA; (H.W.); (N.R.); (L.A.S.); (B.C.S.); (C.W.); (F.F.); (M.I.A.)
| | - Ji Li
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS 39216, USA; (H.W.); (N.R.); (L.A.S.); (B.C.S.); (C.W.); (F.F.); (M.I.A.)
- G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS 39216, USA
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Wang H, Slotabec L, Didik S, Li Z, Leng L, Zhao B, Bucala R, Li J. A small molecule macrophage migration inhibitory factor agonist ameliorates age-related myocardial intolerance to ischemia-reperfusion insults via metabolic regulation. Metabolism 2024; 153:155792. [PMID: 38232801 PMCID: PMC10932879 DOI: 10.1016/j.metabol.2024.155792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/27/2023] [Accepted: 01/09/2024] [Indexed: 01/19/2024]
Abstract
Macrophage migration inhibitory factor (MIF) is an innate cytokine that regulates both inflammatory and homeostatic responses. MIF is expressed by cardiomyocytes, where it exerts a protective action against ischemia-reperfusion (I/R) injury by activating AMP-activated protein kinase (AMPK). This effect is attenuated in the senescent heart due to an intrinsic, age-related reduction in MIF expression. We hypothesized that treating the aged heart with the small molecule MIF agonist (MIF20) can reinforce protective MIF signaling in cardiomyocytes, leading to a beneficial effect against I/R stress. The administration of MIF20 at the onset of reperfusion was found to not only decrease myocardial infarct size but also preserves systolic function in the aged heart. Protection from I/R injury was reduced in mice with cardiomyocyte-specific Mif deletion, consistent with the mechanism of action of MIF20 to allosterically increase MIF affinity for its cognate receptor CD74. We further found MIF20 to contribute to the maintenance of mitochondrial fitness and to preserve the contractile properties of aged cardiomyocytes under hypoxia/reoxygenation. MIF20 augments protective metabolic responses by reducing the NADH/NAD ratio, leading to a decrease in the accumulation of reactive oxygen species (ROS) in the aged myocardium under I/R stress. We also identify alterations in the expression levels of the downstream effectors PDK4 and LCAD, which participate in the remodeling of the cardiac metabolic profile. Data from this study demonstrates that pharmacologic augmentation of MIF signaling provides beneficial homeostatic actions on senescent myocardium under I/R stress.
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Affiliation(s)
- Hao Wang
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States of America
| | - Lily Slotabec
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States of America
| | - Steven Didik
- Department of Surgery, University of South Florida, FL 33612, United States of America
| | - Zehui Li
- Department of Surgery, University of South Florida, FL 33612, United States of America
| | - Lin Leng
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, United States of America
| | - Bi Zhao
- Genomics Program, College of Public Health, University of South Florida, Tampa, FL 33612, United States of America.
| | - Richard Bucala
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, United States of America
| | - Ji Li
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States of America; G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS 39216, United States of America.
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Haj-Yehia E, Korste S, Jochem R, Lusha A, Roth A, Dietzel N, Niroomand J, Stock P, Westendorf AM, Buer J, Hendgen-Cotta UB, Rassaf T, Totzeck M. CD47 blockade enhances phagocytosis of cardiac cell debris by neutrophils. IJC HEART & VASCULATURE 2023; 48:101269. [PMID: 37731517 PMCID: PMC10507185 DOI: 10.1016/j.ijcha.2023.101269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/22/2023]
Abstract
CD47 is a cell surface protein controlling phagocytotic activity of innate immune cells. CD47 blockade was investigated as an immune checkpoint therapy in cancer treatment, enhancing phagocytosis of tumor cells by macrophages. Anti-CD47 treatment also reduced injury size during reperfused acute myocardial infarction (repAMI) by enhancing phagocytotic acitivity of macrophages. Little is known about the impact of CD47 blockade on neutrophils, representing the main portion of early infiltrating immune cells after repAMI. Therefore, we performed 45 min of cardiac ischemia followed by 24 h of reperfusion, observing a decreased cardiac injury size measured by triphenyl tetrazolium chloride (TTC) Evan's blue staining. We were able to detect this effect with an innovative three-dimensional method based on light sheet fluorescence microscopy (LSFM). This further allowed us a simultaneous analysis of neutrophil infiltration, showing an unaltered amount of injury-associated neutrophils with reduced cardiac injury volume from repAMI. This observation suggests modulated phagocytosis of cell debris by neutrophils. Therefore, we performed flow cytometry analysis, revealing an increased phagocytotic activity of neutrophils in vitro. These findings highlight that CD47 blockade also enhances phagocytosis of cardiac cell debris by neutrophils, which might be an additional protective effect of anti-CD47 treatment after repAMI.
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Affiliation(s)
- Elias Haj-Yehia
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, 45147 Essen, Germany
| | - Sebastian Korste
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, 45147 Essen, Germany
| | - Robert Jochem
- Department of Nephrology, University Hospital Essen, 45147 Essen, Germany
| | - Aldona Lusha
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, 45147 Essen, Germany
| | - Anna Roth
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, 45147 Essen, Germany
| | - Nina Dietzel
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, 45147 Essen, Germany
| | - Josefine Niroomand
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, 45147 Essen, Germany
| | - Pia Stock
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, 45147 Essen, Germany
| | - Astrid M. Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jan Buer
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ulrike B. Hendgen-Cotta
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, 45147 Essen, Germany
| | - Tienush Rassaf
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, 45147 Essen, Germany
| | - Matthias Totzeck
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, 45147 Essen, Germany
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Tang K, Zhang H, Deng J, Wang D, Liu S, Lu S, Cui Q, Chen C, Liu J, Yang Z, Li Y, Chen J, Lv J, Ma J, Huang B. Ammonia detoxification promotes CD8 + T cell memory development by urea and citrulline cycles. Nat Immunol 2023; 24:162-173. [PMID: 36471170 DOI: 10.1038/s41590-022-01365-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 10/17/2022] [Indexed: 12/12/2022]
Abstract
Amino acid metabolism is essential for cell survival, while the byproduct ammonia is toxic and can injure cellular longevity. Here we show that CD8+ memory T (TM) cells mobilize the carbamoyl phosphate (CP) metabolic pathway to clear ammonia, thus promoting memory development. CD8+ TM cells use β-hydroxybutyrylation to upregulate CP synthetase 1 and trigger the CP metabolic cascade to form arginine in the cytosol. This cytosolic arginine is then translocated into the mitochondria where it is split by arginase 2 to urea and ornithine. Cytosolic arginine is also converted to nitric oxide and citrulline by nitric oxide synthases. Thus, both the urea and citrulline cycles are employed by CD8+ T cells to clear ammonia and enable memory development. This ammonia clearance machinery might be targeted to improve T cell-based cancer immunotherapies.
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Affiliation(s)
- Ke Tang
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, China
| | - Huafeng Zhang
- Department of Pathology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinghui Deng
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dianheng Wang
- Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China
| | - Shichuan Liu
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuya Lu
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingfa Cui
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chen Chen
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jincheng Liu
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuoshun Yang
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yonggang Li
- Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Jie Chen
- Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China
| | - Jiadi Lv
- Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China
| | - Jingwei Ma
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Huang
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. .,Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China.
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9
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Zan C, Yang B, Brandhofer M, El Bounkari O, Bernhagen J. D-dopachrome tautomerase in cardiovascular and inflammatory diseases-A new kid on the block or just another MIF? FASEB J 2022; 36:e22601. [PMID: 36269019 DOI: 10.1096/fj.202201213r] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 11/11/2022]
Abstract
Macrophage migration inhibitory factor (MIF) as well as its more recently described structural homolog D-dopachrome tautomerase (D-DT), now also termed MIF-2, are atypical cytokines and chemokines with key roles in host immunity. They also have an important pathogenic role in acute and chronic inflammatory conditions, cardiovascular diseases, lung diseases, adipose tissue inflammation, and cancer. Although our mechanistic understanding of MIF-2 is relatively limited compared to the extensive body of evidence available for MIF, emerging data suggests that MIF-2 is not only a functional phenocopy of MIF, but may have differential or even oppositional activities, depending on the disease and context. In this review, we summarize and discuss the similarities and differences between MIF and MIF-2, with a focus on their structures, receptors, signaling pathways, and their roles in diseases. While mainly covering the roles of the MIF homologs in cardiovascular, inflammatory, autoimmune, and metabolic diseases, we also discuss their involvement in cancer, sepsis, and chronic obstructive lung disease (COPD). A particular emphasis is laid upon potential mechanistic explanations for synergistic or cooperative activities of the MIF homologs in cancer, myocardial diseases, and COPD as opposed to emerging disparate or antagonistic activities in adipose tissue inflammation, metabolic diseases, and atherosclerosis. Lastly, we discuss potential future opportunities of jointly targeting MIF and MIF-2 in certain diseases, whereas precision targeting of only one homolog might be preferable in other conditions. Together, this article provides an update of the mechanisms and future therapeutic avenues of human MIF proteins with a focus on their emerging, surprisingly disparate activities, suggesting that MIF-2 displays a variety of activities that are distinct from those of MIF.
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Affiliation(s)
- Chunfang Zan
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Bishan Yang
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Markus Brandhofer
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Omar El Bounkari
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Jürgen Bernhagen
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilian-University (LMU), Munich, Germany.,Deutsches Zentrum für Herz-Kreislauferkrankungen (DZHK), Munich Heart Alliance, Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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10
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Prediction of one-year adverse clinical outcomes by macrophage migration inhibitory factor in stemi patients. EUREKA: HEALTH SCIENCES 2022. [DOI: 10.21303/2504-5679.2022.002714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Biomarkers have taken one of the first places as diagnostic and prognostic tools in ST-segment elevation myocardial infarction (STEMI) and are consequently widely used as predictors of short-term and long-term prognosis. One of the promising biomarkers for early cardiovascular outcomes prediction is the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF).
The aim of the study was to elucidate a plausible predictive value of the MIF levels for one-year clinical outcomes in STEMI patients who underwent primary percutaneous coronary intervention (PCI).
Materials and methods. 134 STEMI patients were enrolled in the study after receiving voluntary informed consent. All patients underwent conventional investigations, and additionally, the MIF levels were determined at baseline, directly before and after PCI. During 1-year follow-up, 37 % of patients reached the endpoint, which was composite and included all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, heart failure decompensation, and urgent revascularization.
Results. We have found that pre-PCI MIF levels > 3934 pg/mL (AUC=0.7; 95 % CI 0.578 to 0.753; Youden index=0.31; p=0.008) might be an independent predictor of composite endpoints with sensitivity 54 % and specificity 82 %. A positive correlation between MIF and inflammatory biomarkers was revealed (WBC count r=0.33, p=0.0001; CRP r=0.19, p=0.032). Adverse outcomes associated with higher pre- and post-PCI MIF levels (OR 1.0, 95 % CI 1.0001–1.0008; p=0.013 and OR 1.0, 95 % CI 1.0001–1.0009; p=0.019) and CRP that determined during the first week after the event (OR 1.0, 95 % CI 1.005–1.2, p=0.03). Kaplan-Meier analysis has shown a substantially lower long-term survival rate in patients with a MIF level > 3493 pg/ml compared to a MIF level ≤ 3493 pg/ml (Log rank=0.00025).
Conclusions. The MIF levels exceeding 3934 ng/ml were associated with a higher risk of one-year adverse clinical outcomes in STEMI patients who underwent primary PCI.
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11
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Panstruga R, Donnelly SC, Bernhagen J. A Cross-Kingdom View on the Immunomodulatory Role of MIF/D-DT Proteins in Mammalian and Plant Pseudomonas Infections. Immunology 2022; 166:287-298. [PMID: 35416298 DOI: 10.1111/imm.13480] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/04/2022] [Accepted: 03/09/2022] [Indexed: 11/26/2022] Open
Abstract
Gram-negative Pseudomonas bacteria are largely harmless saprotrophs, but some species can be potent pathogens of both plants and mammals. Macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (D-DT, also referred to as MIF-2) are multifunctional proteins that in addition to their intracellular functions also serve as extracellular signaling molecules (cytokines) in orchestrating mammalian immune responses. It recently emerged that plants also possess MIF-like proteins, termed MIF/D-DT-like (MDL) proteins. We here provide a comparative cross-kingdom view on the immunomodulatory role of MIF and MDL proteins during Pseudomonas infections in mammals and plants. Although in both kingdoms the lack of MIF/MDL proteins is associated with a reduction in bacterial load and disease symptoms, the underlying molecular principles seem to be different. We provide a perspective for future research activities to unravel additional commonalities and differences in the MIF/MDL-mediated adjustment of antibacterial immune activities.
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Affiliation(s)
- Ralph Panstruga
- RWTH Aachen University, Institute for Biology I, Unit of Plant Molecular Cell Biology, Aachen, Germany
| | - Seamas C Donnelly
- Department of Medicine, Tallaght University Hospital & Trinity College Dublin, Dublin, Ireland
| | - Jürgen Bernhagen
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilian-University (LMU) Munich, Munich, Germany
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12
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Maslov LN, Popov SV, Mukhomedzyanov AV, Naryzhnaya NV, Voronkov NS, Ryabov VV, Boshchenko AA, Khaliulin I, Prasad NR, Fu F, Pei JM, Logvinov SV, Oeltgen PR. Reperfusion Cardiac Injury: Receptors and the Signaling Mechanisms. Curr Cardiol Rev 2022; 18:63-79. [PMID: 35422224 PMCID: PMC9896422 DOI: 10.2174/1573403x18666220413121730] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 01/01/2022] [Accepted: 01/10/2022] [Indexed: 11/22/2022] Open
Abstract
It has been documented that Ca2+ overload and increased production of reactive oxygen species play a significant role in reperfusion injury (RI) of cardiomyocytes. Ischemia/reperfusion induces cell death as a result of necrosis, necroptosis, apoptosis, and possibly autophagy, pyroptosis and ferroptosis. It has also been demonstrated that the NLRP3 inflammasome is involved in RI of the heart. An increase in adrenergic system activity during the restoration of coronary perfusion negatively affected cardiac resistance to RI. Toll-like receptors are involved in RI of the heart. Angiotensin II and endothelin-1 aggravated ischemic/reperfusion injury of the heart. Activation of neutrophils, monocytes, CD4+ T-cells and platelets contributes to cardiac ischemia/reperfusion injury. Our review outlines the role of these factors in reperfusion cardiac injury.
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Affiliation(s)
- Leonid N. Maslov
- Address correspondence to this author at the Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center of the Russian Academy of Science, Kyevskskaya 111A, 634012 Tomsk, Russia; Tel. +7 3822 262174; E-mail:
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13
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Sumaiya K, Langford D, Natarajaseenivasan K, Shanmughapriya S. Macrophage migration inhibitory factor (MIF): A multifaceted cytokine regulated by genetic and physiological strategies. Pharmacol Ther 2021; 233:108024. [PMID: 34673115 DOI: 10.1016/j.pharmthera.2021.108024] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 02/08/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine encoded within a functionally polymorphic genetic locus. MIF was initially recognized as a cytokine generated by activated T cells, but in recent days it has been identified as a multipotent key cytokine secreted by many other cell types involved in immune response and physiological processes. MIF is a highly conserved 12.5 kDa secretory protein that is involved in numerous biological processes. The expression and secretion profile of MIF suggests that MIF to be ubiquitously and constitutively expressed in almost all mammalian cells and is vital for numerous physiological processes. MIF is a critical upstream mediator of host innate and adaptive immunity and survival pathways resulting in the clearance of pathogens thus playing a protective role during infectious diseases. On the other hand, MIF being an immune modulator accelerates detrimental inflammation, promotes cancer metastasis and progression, thus worsening disease conditions. Several reports demonstrated that genetic and physiological factors, including MIF gene polymorphisms, posttranslational regulations, and receptor binding control the functional activities of MIF. Taking into consideration the multi-faceted role of MIF both in physiology and pathology, we thought it is timely to review and summarize the expressional and functional regulation of MIF, its functional mechanisms associated with its beneficial and pathological roles, and MIF-targeting therapies. Thus, our review will provide an overview on how MIF is regulated, its response, and the potency of the therapies that target MIF.
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Affiliation(s)
- Krishnamoorthi Sumaiya
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
| | - Dianne Langford
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Kalimuthusamy Natarajaseenivasan
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India; Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA..
| | - Santhanam Shanmughapriya
- Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University, College of Medicine, Hershey PA-17033, USA.
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14
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Macrophage migration inhibitory factor (MIF) enhances hypochlorous acid production in phagocytic neutrophils. Redox Biol 2021; 41:101946. [PMID: 33823474 PMCID: PMC8047225 DOI: 10.1016/j.redox.2021.101946] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/11/2021] [Accepted: 03/12/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Macrophage migration inhibitory factor (MIF) is an important immuno-regulatory cytokine and is elevated in inflammatory conditions. Neutrophils are the first immune cells to migrate to sites of infection and inflammation, where they generate, among other mediators, the potent oxidant hypochlorous acid (HOCl). Here, we investigated the impact of MIF on HOCl production in neutrophils in response to phagocytic stimuli. METHODS Production of HOCl during phagocytosis of zymosan was determined using the specific fluorescent probe R19-S in combination with flow cytometry and live cell microscopy. The rate of phagocytosis was monitored using fluorescently-labeled zymosan. Alternatively, HOCl production was assessed during phagocytosis of Pseudomonas aeruginosa by measuring the oxidation of bacterial glutathione to the HOCl-specific product glutathione sulfonamide. Formation of neutrophil extracellular traps (NETs), an oxidant-dependent process, was quantified using a SYTOX Green plate assay. RESULTS Exposure of human neutrophils to MIF doubled the proportion of neutrophils producing HOCl during early stages of zymosan phagocytosis, and the concentration of HOCl produced was greater. During phagocytosis of P. aeruginosa, a greater fraction of bacterial glutathione was oxidized to glutathione sulfonamide in MIF-treated compared to control neutrophils. The ability of MIF to increase neutrophil HOCl production was independent of the rate of phagocytosis and could be blocked by the MIF inhibitor 4-IPP. Neutrophils pre-treated with MIF produced more NETs than control cells in response to PMA. CONCLUSION Our results suggest a role for MIF in potentiating HOCl production in neutrophils in response to phagocytic stimuli. We propose that this newly discovered activity of MIF contributes to its role in mediating the inflammatory response and enhances host defence.
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15
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Erkens R, Totzeck M, Brum A, Duse D, Bøtker HE, Rassaf T, Kelm M. Endothelium-dependent remote signaling in ischemia and reperfusion: Alterations in the cardiometabolic continuum. Free Radic Biol Med 2021; 165:265-281. [PMID: 33497796 DOI: 10.1016/j.freeradbiomed.2021.01.040] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/15/2021] [Accepted: 01/19/2021] [Indexed: 02/07/2023]
Abstract
Intact endothelial function plays a fundamental role for the maintenance of cardiovascular (CV) health. The endothelium is also involved in remote signaling pathway-mediated protection against ischemia/reperfusion (I/R) injury. However, the transfer of these protective signals into clinical practice has been hampered by the complex metabolic alterations frequently observed in the cardiometabolic continuum, which affect redox balance and inflammatory pathways. Despite recent advances in determining the distinct roles of hyperglycemia, insulin resistance (InR), hyperinsulinemia, and ultimately diabetes mellitus (DM), which define the cardiometabolic continuum, our understanding of how these conditions modulate endothelial signaling remains challenging. It is widely accepted that endothelial cells (ECs) undergo functional changes within the cardiometabolic continuum. Beyond vascular tone and platelet-endothelium interaction, endothelial dysfunction may have profound negative effects on outcome during I/R. In this review, we summarize the current knowledge of the influence of hyperglycemia, InR, hyperinsulinemia, and DM on endothelial function and redox balance, their influence on remote protective signaling pathways, and their impact on potential therapeutic strategies to optimize protective heterocellular signaling.
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Affiliation(s)
- Ralf Erkens
- Department of Cardiology, Pulmonology and Angiology Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
| | - Matthias Totzeck
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Germany
| | - Amanda Brum
- Department of Cardiology, Pulmonology and Angiology Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
| | - Dragos Duse
- Department of Cardiology, Pulmonology and Angiology Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
| | - Hans Erik Bøtker
- Department of Cardiology, Institute of Clinical Medicine, Aarhus University Hospital, Denmark
| | - Tienush Rassaf
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Germany
| | - Malte Kelm
- Department of Cardiology, Pulmonology and Angiology Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
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16
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Li L, Xu M, Rowan SC, Howell K, Russell-Hallinan A, Donnelly SC, McLoughlin P, Baugh JA. The effects of genetic deletion of Macrophage migration inhibitory factor on the chronically hypoxic pulmonary circulation. Pulm Circ 2021; 10:2045894020941352. [PMID: 33447370 PMCID: PMC7780187 DOI: 10.1177/2045894020941352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 06/18/2020] [Indexed: 11/17/2022] Open
Abstract
While it is well established that the haemodynamic cause of hypoxic pulmonary hypertension is increased pulmonary vascular resistance, the molecular pathogenesis of the increased resistance remains incompletely understood. Macrophage migration inhibitory factor is a pleiotropic cytokine with endogenous tautomerase enzymatic activity as well as both intracellular and extracellular signalling functions. In several diseases, macrophage migration inhibitory factor has pro-inflammatory roles that are dependent upon signalling through the cell surface receptors CD74, CXCR2 and CXCR4. Macrophage migration inhibitory factor expression is increased in animal models of hypoxic pulmonary hypertension and macrophage migration inhibitory factor tautomerase inhibitors, which block some of the functions of macrophage migration inhibitory factor, and have been shown to attenuate hypoxic pulmonary hypertension in mice and monocrotaline-induced pulmonary hypertension in rats. However, because of the multiple pathways through which it acts, the integrated actions of macrophage migration inhibitory factor during the development of hypoxic pulmonary hypertension were unclear. We report here that isolated lungs from adult macrophage migration inhibitory factor knockout (MIF-/- ) mice maintained in normoxic conditions showed greater acute hypoxic vasoconstriction than the lungs of wild type mice (MIF+/+ ). Following exposure to hypoxia for three weeks, isolated lungs from MIF-/- mice had significantly higher pulmonary vascular resistance than those from MIF+/+ mice. The major mechanism underlying the greater increase in pulmonary vascular resistance in the hypoxic MIF-/- mice was reduction of the pulmonary vascular bed due to an impairment of the normal hypoxia-induced expansion of the alveolar capillary network. Taken together, these results demonstrate that macrophage migration inhibitory factor plays a central role in the development of the pulmonary vascular responses to chronic alveolar hypoxia.
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Affiliation(s)
- Lili Li
- UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Maojia Xu
- UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Simon C Rowan
- UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Katherine Howell
- UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Adam Russell-Hallinan
- UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Seamas C Donnelly
- Department of Medicine, Tallaght University Hospital & Trinity College Dublin, Dublin, Ireland
| | - Paul McLoughlin
- UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - John A Baugh
- UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
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17
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Illescas O, Pacheco-Fernández T, Laclette JP, Rodriguez T, Rodriguez-Sosa M. Immune modulation by the macrophage migration inhibitory factor (MIF) family: D-dopachrome tautomerase (DDT) is not (always) a backup system. Cytokine 2020; 133:155121. [PMID: 32417648 DOI: 10.1016/j.cyto.2020.155121] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 04/29/2020] [Accepted: 05/06/2020] [Indexed: 01/06/2023]
Abstract
Human macrophage migration inhibition factor (MIF) is a protein with cytokine and chemokine properties that regulates a diverse range of physiological functions related to innate immunity and inflammation. Most research has focused on the role of MIF in different inflammatory diseases. D-dopachrome tautomerase (DDT), a different molecule with structural similarities to MIF, which shares receptors and biological functions, has recently been reported, but little is known about its roles and mechanisms. In this review, we sought to understand the similarities and differences between these molecules by summarizing what is known about their different structures, receptors and mechanisms regulating their expression and biological activities with an emphasis on immunological aspects.
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Affiliation(s)
- Oscar Illescas
- Biomedicine Unit, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, MEX C.P. 54090, Mexico
| | - Thalia Pacheco-Fernández
- Biomedicine Unit, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, MEX C.P. 54090, Mexico
| | - Juan P Laclette
- Department of Immunology, Institute of Biomedical Research, Universidad Nacional Autónoma de México (UNAM), Mexico City C.P. 04510, Mexico
| | - Tonathiu Rodriguez
- Biomedicine Unit, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, MEX C.P. 54090, Mexico
| | - Miriam Rodriguez-Sosa
- Biomedicine Unit, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, MEX C.P. 54090, Mexico.
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18
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Nakahara K, Fujikawa K, Hiraoka H, Miyazaki I, Asanuma M, Ito A, Takasugi N, Uehara T. Attenuation of Macrophage Migration Inhibitory Factor-Stimulated Signaling via S-Nitrosylation. Biol Pharm Bull 2019; 42:1044-1047. [PMID: 31155581 DOI: 10.1248/bpb.b19-00025] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Nitric oxide (NO) is a key signaling molecule that has various effects via S-nitrosylation, a reversible post-translational modification that affects the enzymatic activity, localization, and metabolism of target proteins. As chronic nitrosative stress correlates with neurodegeneration, the targets have received focused attention. Macrophage migration inhibitory factor (MIF) plays a pivotal role in the induction of gene expression to control inflammatory responses. MIF acts as a ligand for CD74 receptor and activates the Src-p38 mitogen-activated protein kinase (MAPK) cascade. MIF also elevates the expression of brain-derived neurotrophic factor (BDNF), which contributes to the viability of neurons. Here, we show that MIF is S-nitrosylated by a physiological NO donor. Interestingly, the induction of S-nitrosylation resulted in a loss of MIF activity following stimulation of the Src and p38 MAPK signaling pathways and the induction of BDNF expression. Our results shed light on the pathogenic mechanisms of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.
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Affiliation(s)
- Kengo Nakahara
- Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
| | - Kana Fujikawa
- Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
| | - Hideki Hiraoka
- Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
| | - Ikuko Miyazaki
- Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
| | - Masato Asanuma
- Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
| | - Akihiro Ito
- School of Life Sciences, Tokyo University of Pharmacy and Life Sciences
| | - Nobumasa Takasugi
- Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
| | - Takashi Uehara
- Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
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19
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Meng F, Li D, Song B, Li L. Impaired Myocardial MIF/AMPK Activation Aggravates Myocardial Ischemia Reperfusion Injury in High-Fat Diet-Induced Obesity. Endocr Metab Immune Disord Drug Targets 2019; 19:1046-1054. [PMID: 30914037 DOI: 10.2174/1871530319666190326143254] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 02/28/2019] [Accepted: 03/02/2019] [Indexed: 11/22/2022]
Abstract
Background:
Obese patients are more sensitive to myocardial ischemia, which has been
linked with high mortality rates. The following study investigates the effects of impaired macrophage
Migration Inhibitory Factor (MIF)/AMP-Activated Protein Kinase (AMPK) activation on increased
susceptibility to myocardial ischemia/reperfusion (I/R) in high-fat diet-induced obesity.
Methods:
Male C57BL/6J mice were fed with a normal diet (10% kcal as fat, lean group) or a high-fat
diet (60kcal as fat, obese group) for 12 consecutive weeks. To detect the MIF expression and AMPK
activation in response to I/R in isolated hearts from lean and obese mice, myocardial samples were
collected from left ventricular areas at different time points. To determine whether MIF supplementation
is protective against I/R injury, recombined MIF (10 ng/mL) was applied before ischemia. Myocardial
infarct size was estimated by triphenyltetrazolium staining. Western blot was used to detect
myocardial MIF expression, AMPK activation and membrane glucose transporter 4 (Glut4) expression.
Results:
The expression of MIF was remarkably higher in obese group compared to lean group.
Ischemia increased myocardial MIF expression and phosphorylation of AMPK in lean mice, whereas it
had no significant effect on obese mice. Furthermore, administration of recombinant MIF increased
ischemic AMPK activation and membrane Glut4 expression in both lean and obese mice, while it reduced
the infarct size in lean mice only.
Conclusion:
An impaired MIF/AMPK activation response and consequent reduced membrane Glut4
expression may play an important role in increasing myocardial susceptibility to I/R in obesity.
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Affiliation(s)
- Fanqing Meng
- Department of Anesthesiology, Jinan Maternity and Childcare Hospital, Jinan City, Shandong Province, China
| | - Dongliang Li
- Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan City, Shandong Province, China
| | - Bingfeng Song
- Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan City, Shandong Province, China
| | - Liang Li
- Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan City, Shandong Province, China
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20
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Stoppe C, Averdunk L, Goetzenich A, Soppert J, Marlier A, Kraemer S, Vieten J, Coburn M, Kowark A, Kim BS, Marx G, Rex S, Ochi A, Leng L, Moeckel G, Linkermann A, El Bounkari O, Zarbock A, Bernhagen J, Djudjaj S, Bucala R, Boor P. The protective role of macrophage migration inhibitory factor in acute kidney injury after cardiac surgery. Sci Transl Med 2019; 10:10/441/eaan4886. [PMID: 29769287 DOI: 10.1126/scitranslmed.aan4886] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 12/22/2017] [Accepted: 04/13/2018] [Indexed: 12/20/2022]
Abstract
Acute kidney injury (AKI) represents the most frequent complication after cardiac surgery. Macrophage migration inhibitory factor (MIF) is a stress-regulating cytokine that was shown to protect the heart from myocardial ischemia-reperfusion injury, but its role in the pathogenesis of AKI remains unknown. In an observational study, serum and urinary MIF was quantified in 60 patients scheduled for elective conventional cardiac surgery with the use of cardiopulmonary bypass. Cardiac surgery triggered an increase in MIF serum concentrations, and patients with high circulating MIF (>median) 12 hours after surgery had a significantly reduced risk of developing AKI (relative risk reduction, 72.7%; 95% confidence interval, 12 to 91.5%; P = 0.03). Experimental AKI was induced in wild-type and Mif-/- mice by 30 min of ischemia followed by 6 or 24 hours of reperfusion, or by rhabdomyolysis. Mif-deficient mice exhibited increased tubular cell injury, increased regulated cell death (necroptosis and ferroptosis), and enhanced oxidative stress. Therapeutic administration of recombinant MIF after ischemia-reperfusion in mice ameliorated AKI. In vitro treatment of tubular epithelial cells with recombinant MIF reduced cell death and oxidative stress as measured by glutathione and thiobarbituric acid reactive substances in the setting of hypoxia. Our data provide evidence of a renoprotective role of MIF in experimental ischemia-reperfusion injury by protecting renal tubular epithelial cells, consistent with our observation that high MIF in cardiac surgery patients is associated with a reduced incidence of AKI.
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Affiliation(s)
- Christian Stoppe
- Department of Intensive Care Medicine, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.
| | - Luisa Averdunk
- Department of Intensive Care Medicine, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany
| | - Andreas Goetzenich
- Department of Thoracic, Cardiac and Vascular Surgery, University Hospital, RWTH Aachen, Aachen, Germany
| | - Josefin Soppert
- Department of Intensive Care Medicine, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.,Department of Thoracic, Cardiac and Vascular Surgery, University Hospital, RWTH Aachen, Aachen, Germany
| | - Arnaud Marlier
- Department of Nephrology, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Sandra Kraemer
- Department of Thoracic, Cardiac and Vascular Surgery, University Hospital, RWTH Aachen, Aachen, Germany
| | - Jil Vieten
- Department of Intensive Care Medicine, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany
| | - Mark Coburn
- Department of Anesthesiology, University Hospital, RWTH Aachen, Aachen, Germany
| | - Ana Kowark
- Department of Anesthesiology, University Hospital, RWTH Aachen, Aachen, Germany
| | - Bong-Song Kim
- Department of Plastic and Reconstructive Surgery, Hand Surgery, Burn Center, RWTH Aachen, Aachen, Germany
| | - Gernot Marx
- Department of Intensive Care Medicine, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany
| | - Steffen Rex
- Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium
| | - Akinobu Ochi
- Department of Nephropathology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Lin Leng
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Gilbert Moeckel
- Department of Nephropathology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Omar El Bounkari
- Department of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Alexander Zarbock
- Department of Anesthesiology, Critical Care Medicine and Pain Therapy, University Hospital Münster, Münster, Germany
| | - Jürgen Bernhagen
- Department of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany. .,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.,Munich Cluster for Systems Neurology (EXC 1010 SyNergy), Munich, Germany
| | - Sonja Djudjaj
- Institute of Pathology and Department of Nephrology, University Hospital, RWTH Aachen, Aachen, Germany
| | - Richard Bucala
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Peter Boor
- Institute of Pathology and Department of Nephrology, University Hospital, RWTH Aachen, Aachen, Germany. .,Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia
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21
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Zhang S, Zhao J, Zhang Y, Zhang Y, Cai F, Wang L, Song W. Upregulation of MIF as a defense mechanism and a biomarker of Alzheimer's disease. ALZHEIMERS RESEARCH & THERAPY 2019; 11:54. [PMID: 31174614 PMCID: PMC6555932 DOI: 10.1186/s13195-019-0508-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 05/21/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine. Chronic inflammation induced by amyloid β proteins (Aβ) is one prominent neuropathological feature in Alzheimer's disease (AD) brain. METHODS Elisa, Western blot, and immunohistochemical staining analysis were performed to examine the level of MIF protein in CSF and brain tissues. MTT and LDH assays were used to examine the neurotoxicity, and the Morris Water Maze test was performed to examine the cognitive function in the MIF+/-/APP23 transgenic mice. RESULTS MIF expression was upregulated in the brain of AD patients and AD model mice. Elevated MIF concentration was detected in the cerebrospinal fluid of AD patients but not in that of the patients suffering from mild cognitive impairment and vascular dementia. Reduced MIF expression impaired learning and memory in the AD model mice. MIF expression largely associates with Aβ deposits and microglia. The binding assay revealed a direct association between MIF and Aβ oligomers. Neurons instead of glial cells were responsible for the secretion of MIF upon stimulation by Aβ oligomers. In addition, overexpression of MIF significantly protected neuronal cells from Aβ-induced cytotoxicity. CONCLUSION Our study suggests that neuronal secretion of MIF may serve as a defense mechanism to compensate for declined cognitive function in AD, and increased MIF level could be a potential AD biomarker.
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Affiliation(s)
- Si Zhang
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Jiehao Zhao
- Department of Neurology, Guangdong Neuroscience Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Yuhu Zhang
- Department of Neurology, Guangdong Neuroscience Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Yun Zhang
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Fang Cai
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Lijuan Wang
- Department of Neurology, Guangdong Neuroscience Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
| | - Weihong Song
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
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22
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Andreadou I, Cabrera-Fuentes HA, Devaux Y, Frangogiannis NG, Frantz S, Guzik T, Liehn EA, Gomes CPC, Schulz R, Hausenloy DJ. Immune cells as targets for cardioprotection: new players and novel therapeutic opportunities. Cardiovasc Res 2019; 115:1117-1130. [PMID: 30825305 PMCID: PMC6529904 DOI: 10.1093/cvr/cvz050] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/18/2018] [Accepted: 02/24/2019] [Indexed: 12/22/2022] Open
Abstract
New therapies are required to reduce myocardial infarct (MI) size and prevent the onset of heart failure in patients presenting with acute myocardial infarction (AMI), one of the leading causes of death and disability globally. In this regard, the immune cell response to AMI, which comprises an initial pro-inflammatory reaction followed by an anti-inflammatory phase, contributes to final MI size and post-AMI remodelling [changes in left ventricular (LV) size and function]. The transition between these two phases is critical in this regard, with a persistent and severe pro-inflammatory reaction leading to adverse LV remodelling and increased propensity for developing heart failure. In this review article, we provide an overview of the immune cells involved in orchestrating the complex and dynamic inflammatory response to AMI-these include neutrophils, monocytes/macrophages, and emerging players such as dendritic cells, lymphocytes, pericardial lymphoid cells, endothelial cells, and cardiac fibroblasts. We discuss potential reasons for past failures of anti-inflammatory cardioprotective therapies, and highlight new treatment targets for modulating the immune cell response to AMI, as a potential therapeutic strategy to improve clinical outcomes in AMI patients. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
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Affiliation(s)
- Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, Athens, Greece
| | - Hector A Cabrera-Fuentes
- Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore
- National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, Singapore
- Institute of Biochemistry, Medical School, Justus-Liebig University, Ludwigstrasse 23, Giessen, Germany
- Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Av. Eugenio Garza Sada 2501 Sur, Nuevo Leon, Mexico
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Kremlyovskaya St, 18, Kazan, Respublika Tatarstan, Russia
| | - Yvan Devaux
- Cardiovascular Research Unit, Department of Population Health, Luxembourg Institute of Health, 1A-B rue Thomas Edison, Strassen, Luxembourg
| | - Nikolaos G Frangogiannis
- Wilf Family Cardiovascular Research Institute Department of Medicine (Cardiology) Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer G46B Bronx NY USA
| | - Stefan Frantz
- Department of Internal Medicine I, University Hospital Würzburg, Oberdürrbacher Str. 6, Würzburg, Germany
| | - Tomasz Guzik
- Department of Internal and Agricultural Medicine, Jagiellonian University Medical College, Świętej Anny 12, Kraków, Poland
- Institute of Cardiovascular and Medical Sciences, University ofGlasgow, University Avenue, Glasgow, UK
| | - Elisa A Liehn
- Institute for Molecular Cardiovascular Research, Rheinisch Westfälische Technische Hochschule Aachen University,Templergraben 55, Aachen, Germany
- Human Genomics Laboratory, University of Medicine and Pharmacy Craiova, Strada Petru Rareș 2, Craiova, Romania
- Department of Cardiology, Pulmonology, Angiology and Intensive Care, University Hospital, Rheinisch Westfälische Technische Hochschule,Templergraben 55, Aachen, Germany
| | - Clarissa P C Gomes
- Cardiovascular Research Unit, Department of Population Health, Luxembourg Institute of Health, 1A-B rue Thomas Edison, Strassen, Luxembourg
| | - Rainer Schulz
- Physiologisches Institut Fachbereich Medizin der Justus-Liebig-Universität, Aulweg 129, Giessen, Germany
| | - Derek J Hausenloy
- Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore
- National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, Singapore
- Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Av. Eugenio Garza Sada 2501 Sur, Nuevo Leon, Mexico
- Yong Loo Lin School of Medicine, National University Singapore, 1E Kent Ridge Road, Singapore
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, UK
- The National Institute of Health Research University College London Hospitals Biomedical Research Centre, Research & Development, Maple House 1st floor, 149 Tottenham Court Road, London, UK
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23
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Merz SF, Korste S, Bornemann L, Michel L, Stock P, Squire A, Soun C, Engel DR, Detzer J, Lörchner H, Hermann DM, Kamler M, Klode J, Hendgen-Cotta UB, Rassaf T, Gunzer M, Totzeck M. Contemporaneous 3D characterization of acute and chronic myocardial I/R injury and response. Nat Commun 2019; 10:2312. [PMID: 31127113 PMCID: PMC6534576 DOI: 10.1038/s41467-019-10338-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 05/07/2019] [Indexed: 12/11/2022] Open
Abstract
Cardioprotection by salvage of the infarct-affected myocardium is an unmet yet highly desired therapeutic goal. To develop new dedicated therapies, experimental myocardial ischemia/reperfusion (I/R) injury would require methods to simultaneously characterize extent and localization of the damage and the ensuing inflammatory responses in whole hearts over time. Here we present a three-dimensional (3D), simultaneous quantitative investigation of key I/R injury-components by combining bleaching-augmented solvent-based non-toxic clearing (BALANCE) using ethyl cinnamate (ECi) with light sheet fluorescence microscopy. This allows structural analyses of fluorescence-labeled I/R hearts with exceptional detail. We discover and 3D-quantify distinguishable acute and late vascular I/R damage zones. These contain highly localized and spatially structured neutrophil infiltrates that are modulated upon cardiac healing. Our model demonstrates that these characteristic I/R injury patterns can detect the extent of damage even days after the ischemic index event hence allowing the investigation of long-term recovery and remodeling processes.
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Affiliation(s)
- Simon F Merz
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, 45147, Essen, Germany
- Department of Dermatology, Venerology and Allergology, University Hospital Essen, 45147, Essen, Germany
| | - Sebastian Korste
- Department of Cardiology and Vascular Medicine, University Hospital Essen, 45147, Essen, Germany
| | - Lea Bornemann
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, 45147, Essen, Germany
| | - Lars Michel
- Department of Cardiology and Vascular Medicine, University Hospital Essen, 45147, Essen, Germany
| | - Pia Stock
- Department of Cardiology and Vascular Medicine, University Hospital Essen, 45147, Essen, Germany
| | - Anthony Squire
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, 45147, Essen, Germany
| | - Camille Soun
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, 45147, Essen, Germany
| | - Daniel R Engel
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, 45147, Essen, Germany
| | - Julia Detzer
- Dept. of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany
| | - Holger Lörchner
- Dept. of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner site Rhine-Main, Frankfurt am Main, Germany
| | - Dirk M Hermann
- Department of Neurology, University Hospital Essen, 45147, Essen, Germany
| | - Markus Kamler
- Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, 45147, Essen, Germany
| | - Joachim Klode
- Department of Dermatology, Venerology and Allergology, University Hospital Essen, 45147, Essen, Germany
| | - Ulrike B Hendgen-Cotta
- Department of Cardiology and Vascular Medicine, University Hospital Essen, 45147, Essen, Germany
| | - Tienush Rassaf
- Department of Cardiology and Vascular Medicine, University Hospital Essen, 45147, Essen, Germany
| | - Matthias Gunzer
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, 45147, Essen, Germany.
| | - Matthias Totzeck
- Department of Cardiology and Vascular Medicine, University Hospital Essen, 45147, Essen, Germany.
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24
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Jankauskas SS, Wong DW, Bucala R, Djudjaj S, Boor P. Evolving complexity of MIF signaling. Cell Signal 2019; 57:76-88. [DOI: 10.1016/j.cellsig.2019.01.006] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 01/17/2019] [Accepted: 01/18/2019] [Indexed: 01/27/2023]
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25
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Different adaptive NO-dependent Mechanisms in Normal and Hypertensive Conditions. Molecules 2019; 24:molecules24091682. [PMID: 31052164 PMCID: PMC6539476 DOI: 10.3390/molecules24091682] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/23/2019] [Accepted: 04/26/2019] [Indexed: 02/06/2023] Open
Abstract
Myocardial infarction (MI) remains the leading cause of death worldwide. We aimed to investigate the effect of NO deficiency on selective biochemical parameters within discreet myocardial zones after experimentally induced MI. To induce MI, the left descending coronary artery was ligated in two groups of 16-week-old WKY rats. In one group, NO production was inhibited by L-NAME (20 mg/kg/day) administration four weeks prior to ligation. Sham operations were performed on both groups as a control. Seven days after MI, we evaluated levels of nitric oxide synthase (NOS) activity, eNOS, iNOS, NFҡB/p65 and Nrf2 in ischemic, injured and non-ischemic zones of the heart. Levels of circulating TNF-α and IL-6 were evaluated in the plasma. MI led to increased NOS activity in all investigated zones of myocardium as well as circulating levels of TNF-α and IL-6. L-NAME treatment decreased NOS activity in the heart of sham operated animals. eNOS expression was increased in the injured zone and this could be a compensatory mechanism that improves the perfusion of the myocardium and cardiac dysfunction. Conversely, iNOS expression increased in the infarcted zone and may contribute to the inflammatory process and irreversible necrotic changes.
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26
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Protective cardiac conditioning by an atypical cytokine. Clin Sci (Lond) 2019; 133:933-937. [DOI: 10.1042/cs20190036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 04/06/2019] [Accepted: 04/08/2019] [Indexed: 11/17/2022]
Abstract
Abstract
Ischemic heart disease (IHD) represents the leading cause of morbidity and mortality worldwide. Therapy options generally aim at restoring the blood flow to the heart muscle and relieve the ischemic insult. Paradoxically, coronary artery reperfusion itself, both during emergency intervention in ST segment elevation myocardial infarction (STEMI) patients or in the setting of elective cardiac surgery, damages the heart muscle, a phenomenon known as myocardial ischemia-reperfusion (I/R) injury (IRI). Ischemic preconditioning (IPC) is defined by episodes of ‘sub-lethal’ ischemia and reperfusion prior to prolonged coronary artery occlusion. It has been extensively studied as a promising approach to attenuate IRI, but two recent multicenter clinical trials of remote IPC (RIPC) on clinical outcomes have been disappointing. Macrophage migration-inhibitory factor (MIF) is a structurally unique chemokine-like inflammatory cytokine. MIF is pro-atherogenic, but has a complex function in the ischemic heart with a surprising potential as a local cardioprotective factor in early myocardial ischemia. A recent paper published in Clinical Science by Ruze et al. [9], now suggests that MIF could be a key player mediating IPC in the ischemic heart. Employing a Mif gene knockout mouse model, the study indicates a role for endogenous MIF in IPC-mediated protection from myocardial IRI. It could assist in understanding how this atypical cytokine controls ischemic heart pathologies and may set the stage for novel MIF-based therapeutic strategies in IHD.
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27
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Macrophage migration inhibitory factor plays an essential role in ischemic preconditioning-mediated cardioprotection. Clin Sci (Lond) 2019; 133:665-680. [PMID: 30804219 DOI: 10.1042/cs20181013] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 01/26/2019] [Accepted: 02/22/2019] [Indexed: 12/23/2022]
Abstract
Ischemic preconditioning (IPC) is an endogenous protection strategy against myocardial ischemia-reperfusion (I/R) injury. Macrophage migration inhibitory factor (MIF) released from the myocardium subjected to brief periods of ischemia confers cardioprotection. We hypothesized that MIF plays an essential role in IPC-induced cardioprotection. I/R was induced either ex vivo or in vivo in male wild-type (WT) and MIF knockout (MIFKO) mice with or without proceeding IPC (three cycles of 5-min ischemia and 5-min reperfusion). Indices of myocardial injury, regional inflammation and cardiac function were determined to evaluate the extent of I/R injury. Activations of the reperfusion injury salvage kinase (RISK) pathway, AMP-activated protein kinase (AMPK) and their downstream components were investigated to explore the underlying mechanisms. IPC conferred prominent protection in WT hearts evidenced by reduced infarct size (by 33-35%), myocyte apoptosis and enzymatic markers of tissue injury, ROS production, inflammatory cell infiltration and MCP1/CCR2 expression (all P<0.05). IPC also ameliorated cardiac dysfunction both ex vivo and in vivo These protective effects were abolished in MIFKO hearts. Notably, IPC mediated further activations of RISK pathway, AMPK and the membrane translocation of GLUT4 in WT hearts. Deletion of MIF blunted these changes in response to IPC, which is the likely basis for the absence of protective effects of IPC against I/R injury. In conclusion, MIF plays a critical role in IPC-mediated cardioprotection under ischemic stress by activating RISK signaling pathway and AMPK. These results provide an insight for developing a novel therapeutic strategy that target MIF to protect ischemic hearts.
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28
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Kapurniotu A, Gokce O, Bernhagen J. The Multitasking Potential of Alarmins and Atypical Chemokines. Front Med (Lausanne) 2019; 6:3. [PMID: 30729111 PMCID: PMC6351468 DOI: 10.3389/fmed.2019.00003] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 01/04/2019] [Indexed: 12/19/2022] Open
Abstract
When the human genome was sequenced, it came as a surprise that it contains “only” 21,306 protein-coding genes. However, complexity and diversity are multiplied by alternative splicing, non-protein-coding transcripts, or post-translational modifications (PTMs) on proteome level. Here, we discuss how the multi-tasking potential of proteins can substantially enhance the complexity of the proteome further, while at the same time offering mechanisms for the fine-regulation of cell responses. Discoveries over the past two decades have led to the identification of “surprising” and previously unrecognized functionalities of long known cytokines, inflammatory mediators, and intracellular proteins that have established novel molecular networks in physiology, inflammation, and cardiovascular disease. In this mini-review, we focus on alarmins and atypical chemokines such as high-mobility group box protein-1 (HMGB-1) and macrophage migration-inhibitory factor (MIF)-type proteins that are prototypical examples of these classes, featuring a remarkable multitasking potential that allows for an elaborate fine-tuning of molecular networks in the extra- and intracellular space that may eventually give rise to novel “task”-based precision medicine intervention strategies.
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Affiliation(s)
- Aphrodite Kapurniotu
- Division of Peptide Biochemistry, Technische Universität München, Freising, Germany
| | - Ozgun Gokce
- System Neuroscience Laboratory, Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany
| | - Jürgen Bernhagen
- Department of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany.,Munich Heart Alliance, Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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29
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Nagasaka Y, Fernandez BO, Steinbicker AU, Spagnolli E, Malhotra R, Bloch DB, Bloch KD, Zapol WM, Feelisch M. Pharmacological preconditioning with inhaled nitric oxide (NO): Organ-specific differences in the lifetime of blood and tissue NO metabolites. Nitric Oxide 2018; 80:52-60. [PMID: 30114529 PMCID: PMC6198794 DOI: 10.1016/j.niox.2018.08.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 08/07/2018] [Accepted: 08/10/2018] [Indexed: 01/06/2023]
Abstract
BACKGROUND Endogenous nitric oxide (NO) may contribute to ischemic and anesthetic preconditioning while exogenous NO protects against ischemia-reperfusion (I/R) injury in the heart and other organs. Why those beneficial effects observed in animal models do not always translate into clinical effectiveness remains unclear. To mitigate reperfusion damage a source of NO is required. NO inhalation is known to increase tissue NO metabolites, but little information exists about the lifetime of these species. We therefore sought to investigate the fate of major NO metabolite classes following NO inhalation in mice in vivo. METHODS C57BL/6J mice were exposed to 80 ppm NO for 1 h. NO metabolites were measured in blood (plasma and erythrocytes) and tissues (heart, liver, lung, kidney and brain) immediately after NO exposure and up to 48 h thereafter. Concentrations of S-nitrosothiols, N-nitrosamines and NO-heme products as well as nitrite and nitrate were quantified by gas-phase chemiluminescence and ion chromatography. In separate experiments, mice breathed 80 ppm NO for 1 h prior to cardiac I/R injury (induced by coronary arterial ligation for 1 h, followed by recovery). After sacrifice, the size of the myocardial infarction (MI) and the area at risk (AAR) were measured. RESULTS After NO inhalation, elevated nitroso/nitrosyl levels returned to baseline over the next 24 h, with distinct multi-phasic decay profiles in each compartment. S/N-nitroso compounds and NO-hemoglobin in blood decreased exponentially, but remained above baseline for up to 30min, whereas nitrate was elevated for up to 3hrs after discontinuing NO breathing. Hepatic S/N-nitroso species concentrations remained steady for 30min before dropping exponentially. Nitrate only rose in blood, liver and kidney; nitrite tended to be lower in all organs immediately after NO inhalation but fluctuated considerably in concentration thereafter. NO inhalation before myocardial ischemia decreased the ratio of MI/AAR by 30% vs controls (p = 0.002); only cardiac S-nitrosothiols and NO-hemes were elevated at time of reperfusion onset. CONCLUSIONS Metabolites in blood do not reflect NO metabolite status of any organ. Although NO is rapidly inactivated by hemoglobin-mediated oxidation in the circulation, long-lived tissue metabolites may account for the myocardial preconditioning effects of inhaled NO. NO inhalation may afford similar protection in other organs.
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Affiliation(s)
- Yasuko Nagasaka
- Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Bernadette O Fernandez
- Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, UK; Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Andrea U Steinbicker
- Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, University of Münster, Münster, Germany
| | - Ester Spagnolli
- Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Rajeev Malhotra
- Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, UK
| | - Donald B Bloch
- Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Division of Rheumatology, Allergy and Clinical Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Kenneth D Bloch
- Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, UK
| | - Warren M Zapol
- Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Martin Feelisch
- Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, UK; Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
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30
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Deng F, Zhao Q, Deng Y, Wu Y, Zhou D, Liu W, Yuan Z, Zhou J. Prognostic significance and dynamic change of plasma macrophage migration inhibitory factor in patients with acute ST-elevation myocardial infarction. Medicine (Baltimore) 2018; 97:e12991. [PMID: 30412132 PMCID: PMC6221611 DOI: 10.1097/md.0000000000012991] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) has been reported as an inflammatory cytokine in many inflammatory diseases, including rheumatoid arthritis and ischemic diseases. However, dynamic changes of MIF within the first 24 hours on admission and potential prognostic significance following ST-elevation myocardial infarction (STEMI) have been little known. In this study, we examined the dynamic change of MIF level and its potential diagnostic and prognostic value after the onset of STEMI. Plasma MIF levels were evaluated in symptomatic subjects who received coronary angiogram with a median 27 months follow-up for the development of major adverse cardiovascular events (MACEs).Of all 993 subjects, patients with STEMI showed a significantly higher MIF levels than in patients with non-ST elevation acute coronary syndrome, stable angina, and normal coronary artery, respectively (P < .01). Plasma MIF levels elevated as early as 12 hours post-onset of STEMI and peaked rapidly within 24 hours, and remained elevated from about day 5 till day 9 during hospitalization. In multivariate analysis, MIF was associated with a decreased risk of MACEs occurrence in STEMI patients after adjustment for traditional cardiovascular risk factors [hazard ratio 0.81, (0.72-0.90), P < .001]. The ROC curve for MACEs was 0.72 (95% CI 0.62-0.80, P < .001) and 0.85 (95% CI 0.80-0.90, P < .001) using Framingham risk factors only and combined with MIF, individually.Measurement of MIF adds potential information for the early diagnosis of acute STEMI and significantly improves risk prediction of MACEs when added to a prognostic model with traditional Framingham risk factors.
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Affiliation(s)
- Fuxue Deng
- Department of Cardiovascular Medicine, the First Affiliated Hospital of Xi’an Jiaotong University College of Medicine
| | - Qiang Zhao
- Department of Cardiovascular Medicine, the First Affiliated Hospital of Xi’an Jiaotong University College of Medicine
| | - Yangyang Deng
- Department of Cardiovascular Medicine, the First Affiliated Hospital of Xi’an Jiaotong University College of Medicine
| | - Yue Wu
- Department of Cardiovascular Medicine, the First Affiliated Hospital of Xi’an Jiaotong University College of Medicine
| | - Dong Zhou
- Department of Cardiovascular Medicine, the First Affiliated Hospital of Xi’an Jiaotong University College of Medicine
| | - Weimin Liu
- Department of Cardiovascular Medicine, the First Affiliated Hospital of Xi’an Jiaotong University College of Medicine
| | - Zuyi Yuan
- Department of Cardiovascular Medicine, the First Affiliated Hospital of Xi’an Jiaotong University College of Medicine
- Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education, Xi’an, Shaanxi, P.R. China
| | - Juan Zhou
- Department of Cardiovascular Medicine, the First Affiliated Hospital of Xi’an Jiaotong University College of Medicine
- Key Laboratory of Molecular Cardiology
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Soppert J, Kraemer S, Beckers C, Averdunk L, Möllmann J, Denecke B, Goetzenich A, Marx G, Bernhagen J, Stoppe C. Soluble CD74 Reroutes MIF/CXCR4/AKT-Mediated Survival of Cardiac Myofibroblasts to Necroptosis. J Am Heart Assoc 2018; 7:e009384. [PMID: 30371153 PMCID: PMC6201423 DOI: 10.1161/jaha.118.009384] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 07/09/2018] [Indexed: 01/03/2023]
Abstract
Background Although macrophage migration inhibitory factor ( MIF ) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD 74, the function of the soluble CD 74 receptor ectodomain ( sCD 74) and its interaction with circulating MIF have not been explored in cardiac disease. Methods and Results Cardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co-treatment with recombinant MIF and sCD 74 induced cell death ( P<0.001), which was mediated by receptor-interacting serine/threonine-protein kinase ( RIP) 1/ RIP 3-dependent necroptosis ( P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT - qPCR technology revealed a 4-fold upregulation of several interferon-induced genes upon co-treatment of myofibroblasts with sCD 74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD 74 as a modulator of MIF signaling by diminishing MIF -mediated protein kinase B ( AKT) activation ( P=0.0197) and triggering p38 activation ( P=0.0641). We obtained evidence that sCD 74 inhibits MIF -mediated survival pathway through the C-X-C chemokine receptor 4/ AKT axis, enabling the induction of CD 74-dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD 74/ MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244). Conclusions These findings suggest that treatment of cardiac myofibroblasts with sCD 74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD 74/ MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.
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Affiliation(s)
- Josefin Soppert
- Department of Intensive Care MedicineUniversity HospitalRWTH AachenAachenGermany
- Department of Thoracic, Cardiac and Vascular SurgeryUniversity HospitalRWTH AachenAachenGermany
| | - Sandra Kraemer
- Department of Thoracic, Cardiac and Vascular SurgeryUniversity HospitalRWTH AachenAachenGermany
| | - Christian Beckers
- Department of Thoracic, Cardiac and Vascular SurgeryUniversity HospitalRWTH AachenAachenGermany
| | - Luisa Averdunk
- Department of Intensive Care MedicineUniversity HospitalRWTH AachenAachenGermany
| | - Julia Möllmann
- Department of Cardiology, Pneumology, Angiology and Internal Intensive CareUniversity HospitalRWTH AachenAachenGermany
| | - Bernd Denecke
- Interdisciplinary Center for Clinical Research (IZKF)University HospitalRWTH AachenAachenGermany
| | - Andreas Goetzenich
- Department of Thoracic, Cardiac and Vascular SurgeryUniversity HospitalRWTH AachenAachenGermany
| | - Gernot Marx
- Department of Intensive Care MedicineUniversity HospitalRWTH AachenAachenGermany
| | - Jürgen Bernhagen
- Department of Vascular BiologyInstitute for Stroke and Dementia Research (ISD)Ludwig‐Maximilians‐University (LMU) MunichMunichGermany
- German Center for Cardiovascular Research (DZHK)partner site Munich Heart AllianceMunichGermany
- Munich Cluster for Systems Neurology (EXC 1010 SyNergy)MunichGermany
| | - Christian Stoppe
- Department of Intensive Care MedicineUniversity HospitalRWTH AachenAachenGermany
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Circulating macrophage migration inhibitory factor (MIF) in patients with heart failure. Cytokine 2018; 110:104-109. [PMID: 29723777 DOI: 10.1016/j.cyto.2018.04.033] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/25/2018] [Accepted: 04/26/2018] [Indexed: 01/06/2023]
Abstract
BACKGROUND Heart failure (HF) is characterized by impaired systolic ejection capacity and/or diastolic filling of the heart, leading to a multisystem disorder. Remote organ failure, systemic inflammation or pulmonary hypertension (PH) are hallmarks of the pathophysiological changes in HF. The Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is involved in a variety of cardiovascular and inflammatory diseases. Circulating MIF levels and their potential role as a disease marker in the different subgroups of HF have not been investigated yet. We here aimed to unravel a potential role of MIF in HF. METHODS AND RESULTS MIF plasma levels were assessed in 249 consecutive patients with HF. MIF was detectable in all investigated subjects and showed no difference with regard to the nature of HF (preserved or reduced ejection fraction). Spearman correlation revealed an association with inflammatory biomarkers (white blood cell count r = 0.18, p = 0.005; c-reactive protein r = 0.20, p = 0.003). MIF was associated with higher pulmonary artery systolic pressure (PASP) as assessed by echocardiography (r = 0.23, p < 0.001). Log-transformed PASP was also independently associated with MIF in a multivariable linear regression model (p = 0.02). Follow-up (FU) data after 180 days revealed that patients with increased MIF values (in ng/ml) were more likely to reach the endpoint all-cause mortality (HR 1.01, 95% CI 1.004-1.02, p = 0.005, per unit change). CONCLUSION MIF is detectable in the circulation of patients with HF and might be associated with clinical endpoints in HF, markers of inflammation and PH. These promising results should stimulate further research to elucidate the role of MIF in the multisystem disorder of HF.
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Xia W, Zhuang L, Hou M. Role of lincRNA‑p21 in the protective effect of macrophage inhibition factor against hypoxia/serum deprivation‑induced apoptosis in mesenchymal stem cells. Int J Mol Med 2018; 42:2175-2184. [PMID: 30015822 DOI: 10.3892/ijmm.2018.3767] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 06/28/2018] [Indexed: 01/09/2023] Open
Abstract
Stem cell transplantation is a promising clinical strategy for curing ischemic cardiomyopathy. However, its efficacy is impaired by low cell survival following transplantation, partly caused by insufficient resistance of the transplanted stem cells to severe oxidative stress at the injury site. In the current study, it was demonstrated that the small‑molecule macrophage migration inhibitory factor (MIF) enhanced the defense of bone marrow‑derived mesenchymal stem cells (MSCs) against hypoxia/serum deprivation (SD)‑induced apoptosis in vitro. MIF significantly suppressed apoptosis and caspase family activities through inhibition of long intergenic noncoding (linc) RNA‑p21 to maintain activation of the Wnt/β‑catenin signaling pathway. The regulatory loop between MIF and the lincRNA‑p21‑Wnt/β‑catenin signaling pathway was identified to be associated with the inhibition of oxidative stress. The involvement of the lincRNA‑p21‑Wnt/β‑catenin signaling pathway in the effects of MIF in MSCs by overexpression of lincRNA‑p21and silencing β‑catenin using small interfering RNA was also demonstrated, both of which abolished the anti‑apoptotic and anti‑oxidative effects of MIF in MSCs under hypoxia/SD conditions. In conclusion, MIF protected MSCs from hypoxia/SD‑induced apoptosis by interacting with lincRNA‑p21, leading to activation of the downstream Wnt/β‑catenin signaling pathway and decreased oxidative stress. Thus, treatment with MIF may have important therapeutic implications in improving MSC survival and therapeutic efficiency.
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Affiliation(s)
- Wenzheng Xia
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Lei Zhuang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Meng Hou
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Luedike P, Alatzides G, Papathanasiou M, Heisler M, Pohl J, Lehmann N, Rassaf T. Predictive potential of macrophage migration inhibitory factor (MIF) in patients with heart failure with preserved ejection fraction (HFpEF). Eur J Med Res 2018; 23:22. [PMID: 29728137 PMCID: PMC5935947 DOI: 10.1186/s40001-018-0321-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 04/28/2018] [Indexed: 12/12/2022] Open
Abstract
Background Prognostication in heart failure with preserved ejection fraction (HFpEF) is challenging and novel biomarkers are urgently needed. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays a crucial role in cardiovascular and various inflammatory diseases. Whether MIF is involved in HFpEF is unknown. Methods and results Sixty-two patients with HFpEF were enrolled and followed up for 180 days. MIF plasma levels as well as natriuretic peptide (NP) levels were assessed. High MIF levels significantly predicted the combined end-point of all-cause death or hospitalization at 180 days in the univariate analysis (HR 2.41, 95% CI 1.12–5.19, p = 0.025) and after adjustment for relevant covariates in a Cox proportional hazard regression model (HR 2.35, 95% CI 1.05–5.27, p = 0.0374). Furthermore, MIF levels above the median were associated with higher pulmonary artery systolic pressure (PASP) as assessed by echocardiography (PASP 31 mmHg vs 48 mmHg in the low- and high-MIF group, respectively, p = 0.017). NPs significantly correlated with MIF in HFpEF patients (BNP p = 0.011; r = 0.32; NT-proBNP p = 0.027; r = 0.28). Conclusion MIF was associated with clinical outcomes and might be involved in the pathophysiology of pulmonary hypertension in patients with HFpEF. These first data on MIF in HFpEF should stimulate further research to elucidate the role of this cytokine in heart failure. Trial registration NCT03232671
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Affiliation(s)
- Peter Luedike
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany.
| | - Georgios Alatzides
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Maria Papathanasiou
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Martin Heisler
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Julia Pohl
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Nils Lehmann
- Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany
| | - Tienush Rassaf
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany
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35
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Mattugini N, Merl-Pham J, Petrozziello E, Schindler L, Bernhagen J, Hauck SM, Götz M. Influence of white matter injury on gray matter reactive gliosis upon stab wound in the adult murine cerebral cortex. Glia 2018; 66:1644-1662. [PMID: 29573353 DOI: 10.1002/glia.23329] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 02/13/2018] [Accepted: 03/02/2018] [Indexed: 01/01/2023]
Abstract
Traumatic brain injury frequently affects the cerebral cortex, yet little is known about the differential effects that occur if only the gray matter (GM) is damaged or if the injury also involves the white matter (WM). To tackle this important question and directly compare similarities and differences in reactive gliosis, we performed stab wound injury affecting GM and WM (GM+) and one restricted to the GM (GM-) in the adult murine cerebral cortex. First, we examined glial reactivity in the regions affected (WM and GM) and determined the influence of WM injury on reactive gliosis in the GM comparing the same area in the two injury paradigms. In the GM+ injury microglia proliferation is increased in the WM compared with GM, while proliferating astrocytes are more abundant in the GM than in the WM. Interestingly, WM lesion exerted a strong influence on the proliferation of the GM glial cells that was most pronounced at early stages, 3 days post lesion. While astrocyte proliferation was increased, NG2 glia proliferation was decreased in the GM+ compared with GM- lesion condition. Importantly, these differences were not observed when a lesion of the same size affected only the GM. Unbiased proteomic analyses further corroborate our findings in support of a profound difference in GM reactivity when WM is also injured and revealed MIF as a key regulator of NG2 glia proliferation.
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Affiliation(s)
- Nicola Mattugini
- Physiological Genomics, Biomedical center (BMC), Ludwig-Maximilians-University (LMU), Großhaderner Str. 9, Planegg/Martinsried, 82152, Germany.,Institute of Stem Cell Research, Helmholtz Center Munich, Biomedical Center (BMC), Department of Physiological Genomics, Ludwig-Maximilians-University (LMU), Großhaderner Str. 9, Planegg/Martinsried, 82152, Germany.,Graduate School of Systemic Neurosciences Ludwig-Maximilians University (LMU), Großhaderner Str. 2, Planegg/Martinsried, 82152, Germany
| | - Juliane Merl-Pham
- Research Unit Protein Science, Helmholtz Center Munich, Ingolstädter Landstrasse 1, Neuherberg, 85764, Germany
| | - Elisabetta Petrozziello
- Institute for Immunology, Biomedical Center (BMC), Ludwig-Maximilians-University (LMU), Großhadernerstr. 9, Planegg/Martinsried, 82152, Germany
| | - Lisa Schindler
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-University (LMU) Munich, Munich, 81377, Germany
| | - Jürgen Bernhagen
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-University (LMU) Munich, Munich, 81377, Germany.,SyNergy Excellence Cluster, Munich, 81377, Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Center Munich, Ingolstädter Landstrasse 1, Neuherberg, 85764, Germany
| | - Magdalena Götz
- Physiological Genomics, Biomedical center (BMC), Ludwig-Maximilians-University (LMU), Großhaderner Str. 9, Planegg/Martinsried, 82152, Germany.,Institute of Stem Cell Research, Helmholtz Center Munich, Biomedical Center (BMC), Department of Physiological Genomics, Ludwig-Maximilians-University (LMU), Großhaderner Str. 9, Planegg/Martinsried, 82152, Germany.,SyNergy Excellence Cluster, Munich, 81377, Germany
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Schindler L, Dickerhof N, Hampton MB, Bernhagen J. Post-translational regulation of macrophage migration inhibitory factor: Basis for functional fine-tuning. Redox Biol 2017; 15:135-142. [PMID: 29247897 PMCID: PMC5975065 DOI: 10.1016/j.redox.2017.11.028] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 11/27/2017] [Accepted: 11/30/2017] [Indexed: 11/29/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a chemokine-like protein and an important mediator in the inflammatory response. Unlike most other pro-inflammatory cytokines, a number of cell types constitutively express MIF and secretion occurs from preformed stores. MIF is an evolutionarily conserved protein that shows a remarkable functional diversity, including specific binding to surface CD74 and chemokine receptors and the presence of two intrinsic tautomerase and oxidoreductase activities. Several studies have shown that MIF is subject to post-translational modification, particularly redox-dependent modification of the catalytic proline and cysteine residues. In this review, we summarize and discuss MIF post-translational modifications and their effects on the biological properties of this protein. We propose that the redox-sensitive residues in MIF will be modified at sites of inflammation and that this will add further depth to the functional diversity of this intriguing cytokine.
MIF is a pro-inflammatory cytokine with tautomerase and oxidoreductase activity. MIF is susceptible to post-translational modifications, including redox modification. Oxidants and electrophiles generated at inflammatory sites can modify MIF. The biological consequences of redox modification need detailed characterization.
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Affiliation(s)
- Lisa Schindler
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Nina Dickerhof
- Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand
| | - Mark B Hampton
- Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand
| | - Jürgen Bernhagen
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-University (LMU), Munich, Germany; Munich Cluster for System Neurology (EXC 1010 SyNergy), Munich, Germany.
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Myocardial Expression of Macrophage Migration Inhibitory Factor in Patients with Heart Failure. J Clin Med 2017; 6:jcm6100095. [PMID: 29027966 PMCID: PMC5664010 DOI: 10.3390/jcm6100095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 09/26/2017] [Accepted: 10/10/2017] [Indexed: 12/28/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory protein and contributes to several different inflammatory and ischemic/hypoxic diseases. MIF was shown to be cardioprotective in experimental myocardial ischemia/reperfusion injury and its expression is regulated by the transcription factor hypoxia-inducible factor (HIF)-1α. We here report on MIF expression in the failing human heart and assess myocardial MIF in different types of cardiomyopathy. Myocardial tissue samples from n = 30 patients were analyzed by quantitative Real-Time PCR. MIF and HIF-1α mRNA expression was analyzed in myocardial samples from patients with ischemic (ICM) and non-ischemic cardiomyopathy (NICM) and from patients after heart transplantation (HTX). MIF expression was elevated in myocardial samples from patients with ICM compared to NICM. Transplanted hearts showed lower MIF levels compared to hearts from patients with ICM. Expression of HIF-1α was analyzed and was shown to be significantly increased in ICM patients compared to patients with NICM. MIF and HIF-1α mRNA is expressed in the human heart. MIF and HIF-1α expression depends on the underlying type of cardiomyopathy. Patients with ICM show increased myocardial MIF and HIF-1α expression.
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Gao Y, Hou R, Liu F, Liu H, Fei Q, Han Y, Cai R, Peng C, Qi Y. Obacunone causes sustained expression of MKP-1 thus inactivating p38 MAPK to suppress pro-inflammatory mediators through intracellular MIF. J Cell Biochem 2017; 119:837-849. [PMID: 28657665 DOI: 10.1002/jcb.26248] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 06/26/2017] [Indexed: 12/11/2022]
Abstract
Obacunone (OBA) is a highly oxygenated triterpenoid with various pharmacological activities. In this study, we explored its anti-inflammatory effect and underlying mechanisms in LPS-activated macrophages. Our data showed that OBA potently decreased pro-inflammatory mediators (eg, NO, IL-6, IL-1β, and MCP-1) at the transcriptional and translational levels without cytotoxicity. A mechanism study showed that OBA significantly suppressed p38-mediated AP-1 signaling by stabilizing the mRNA of mitogen-activated protein kinase phosphatase 1 (MKP-1), thus prolonging the expression time of the MKP-1 protein. Next, we used computational target-fishing technology to predict the possible target of OBA. Only one potential target, macrophage migration inhibitory factor (MIF), was presented. Experimentally, the interaction between OBA and MIF was also confirmed. By using an anti-mouse MIF antibody, extracellular MIF (exMIF) was neutralized. Our results showed that autocrine MIF had slight influence on the pro-inflammatory mediator production. Correspondingly, the anti-inflammatory activity of OBA was also not affected. Accordingly, we knocked down the MIF gene in RAW 264.7 cells and obtained stable MIF deficient cells MIF(-), in which the effects of OBA on p38 phosphorylation, AP-1 activation, and pro-inflammatory mediator production in response to LPS nearly disappeared. In contrast to MIF(+) cells, the MKP-1 protein expression time of the MIF(-) cells was markedly prolonged. We conclude that OBA exerts its anti-inflammatory effect by targeting intracellular MIF (inMIF) inhibition to regulate the MKP-1/p38/AP-1 pathway. Our findings also provide a chain of evidence that the inhibition of inMIF, rather than exMIF, may become a novel target for inflammation.
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Affiliation(s)
- Yuan Gao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China.,Chegndu University of Traditional Chinese Medicine, Chengdu, P.R. China
| | - Rui Hou
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Fen Liu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Haibo Liu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Qiaoling Fei
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Yixin Han
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Runlan Cai
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Cheng Peng
- Chegndu University of Traditional Chinese Medicine, Chengdu, P.R. China
| | - Yun Qi
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
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Totzeck M, Korste S, Miinalainen I, Hendgen-Cotta UB, Rassaf T. S -nitrosation of calpains is associated with cardioprotection in myocardial I/R injury. Nitric Oxide 2017; 67:68-74. [DOI: 10.1016/j.niox.2017.04.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 03/03/2017] [Accepted: 04/05/2017] [Indexed: 01/23/2023]
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Tilstam PV, Qi D, Leng L, Young L, Bucala R. MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics. Expert Opin Ther Targets 2017; 21:671-683. [PMID: 28562118 DOI: 10.1080/14728222.2017.1336227] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with chemokine-like functions that increasingly is being studied in different aspects of cardiovascular disease. MIF was first identified as a proinflammatory and pro-survival mediator within the immune system, and a second structurally related MIF family member, D-dopachrome tautomerase (a.k.a. MIF-2), was reported recently. Both MIF family members are released by myocardium and modulate the manifestations of cardiovascular disease, specifically in myocardial ischemia. Areas covered: A scientific overview is provided for the involvement of MIF family cytokines in the inflammatory pathogenesis of atherosclerosis, myocardial infarction, and ischemia-reperfusion injury. We summarize findings of experimental, human genetic and clinical studies, and suggest therapeutic opportunities for modulating the activity of MIF family proteins that potentially may be applied in a MIF allele specific manner. Expert opinion: Knowledge of MIF, MIF-2 and their receptor pathways are under active investigation in different types of cardiovascular diseases, and novel therapeutic opportunities are being identified. Clinical translation may be accelerated by accruing experience with MIF-directed therapies currently in human testing in cancer and autoimmunity.
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Affiliation(s)
- Pathricia V Tilstam
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| | - Dake Qi
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA.,b Department of Biomedical Sciences , Memorial University of Newfoundland , St. John's , Canada
| | - Lin Leng
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| | - Lawrence Young
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| | - Richard Bucala
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
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Nitrite-Nitric Oxide Signaling and Cardioprotection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 982:335-346. [DOI: 10.1007/978-3-319-55330-6_18] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Nederlof R, Weber NC, Juffermans NP, de Mol BAMJ, Hollmann MW, Preckel B, Zuurbier CJ. A randomized trial of remote ischemic preconditioning and control treatment for cardioprotection in sevoflurane-anesthetized CABG patients. BMC Anesthesiol 2017; 17:51. [PMID: 28356068 PMCID: PMC5372281 DOI: 10.1186/s12871-017-0330-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 02/24/2017] [Indexed: 01/29/2023] Open
Abstract
Background Remote ischemic preconditioning (RIPC) efficacy is debated. Possibly, because propofol, which has a RIPC-inhibiting action, is used in most RIPC trials. It has been suggested that clinical efficacy is, however, present with volatile anesthesia in the absence of propofol, although this is based on one phase 1 trial only. Therefore, in the present study we further explore the relation between RIPC and cardioprotection with perioperative anesthesia restricted to sevoflurane and fentanyl, in CABG patients without concomitant procedures. Methods In a single-center study, we aimed to randomize 46 patients to either RIPC (3x5 min inflation of a blood pressure cuff around the arm) or control treatment (deflated cuff around the arm). Blood samples were obtained before and after RIPC to evaluate potential RIPC-induced mediators (Interleukin (IL)-6, IL-10, Tumor Necrosis Factor-α, Macrophage Inhibitory Factor). An atrial tissue sample was obtained at cannulation of the appendix of the right atrium for determination of mitochondrial bound hexokinase II (mtHKII) and other survival proteins (Akt and AMP-activated protein kinase α). In blood samples taken before and 6, 12 and 24 h after surgery cardiac troponin T (cTnT) and C-reactive protein (CRP) were determined. Surgery was strictly performed under sevoflurane anesthesia (no propofol). Results We actually randomized 16 patients to control treatment and 13 patients to RIPC. The mean 24 h area under the curve (AUC) cTnT was 11.44 (standard deviation 4.66) in the control group and 10.90 (standard deviation 4.73) in the RIPC group (mean difference 0.54, 95% CI −3.06 to 4.13; p = 0.76). The mean 24 h AUC CRP was 1319 (standard deviation 92) in the control group and 1273 (standard deviation 141) in the RIPC group (mean difference 46.2, 95% CI −288 to 380; p = 0.78). RIPC was without effect on survival proteins in atrial tissue samples obtained before surgery (mitochondrial hexokinase, Akt and AMPK) and inflammatory mediators obtained before and immediately after RIPC (IL-6, IL-10, TNF-α, macrophage migration inhibitory factor). Conclusion Many factors can interfere with the outcome of RIPC. Trying to correct for this led to strict inclusion criteria, which, in combination with a decreased institutional frequency of CABG without concomitant procedures and a change in institutional anesthetic regimen away from volatile anesthetics towards total intravenous anesthesia, caused slow inclusion and halting of this trial after 3 years, before target inclusion could be reached. Therefore this study is underpowered to prove its primary goal that RIPC reduced AUC cTnT by < 25%. Nevertheless, we have shown that the effect of RIPC on 24 h AUC cTnT, in cardiac surgery with anesthesia during surgery restricted to sevoflurane/fentanyl (no propofol), was between a decrease of 27% and an increase of 36%. These findings are not in line with previous studies in this field. Trial registration The Netherlands Trial Register: NTR2915; Registered 25 Mei 2011.
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Affiliation(s)
- Rianne Nederlof
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands
| | - Nina C Weber
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands
| | - Nicole P Juffermans
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Intensive Care Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - Bas A M J de Mol
- Department of Cardiothoracic Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - Markus W Hollmann
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands
| | - Benedikt Preckel
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands
| | - Coert J Zuurbier
- Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands. .,Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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Cytosolic BNIP3 Dimer Interacts with Mitochondrial BAX Forming Heterodimers in the Mitochondrial Outer Membrane under Basal Conditions. Int J Mol Sci 2017; 18:ijms18040687. [PMID: 28333095 PMCID: PMC5412273 DOI: 10.3390/ijms18040687] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 03/14/2017] [Accepted: 03/20/2017] [Indexed: 02/03/2023] Open
Abstract
The primary function of mitochondria is energy production, a task of particular importance especially for cells with a high energy demand like cardiomyocytes. The B-cell lymphoma (BCL-2) family member BCL-2 adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) is linked to mitochondrial targeting after homodimerization, where it functions in inner membrane depolarization and permeabilization of the mitochondrial outer membrane (MOM) mediating cell death. We investigated the basal distribution of cardiac BNIP3 in vivo and its physical interaction with the pro-death protein BCL2 associated X, apoptosis regulator (BAX) and with mitochondria using immunoblot analysis, co-immunoprecipitation, and continuous wave and pulsed electron paramagnetic resonance spectroscopy techniques. We found that BNIP3 is present as a dimer in the cytosol and in the outer membrane of cardiac mitochondria under basal conditions. It forms disulfide-bridged, but mainly non-covalent dimers in the cytosol. Heterodimers with BAX are formed exclusively in the MOM. Furthermore, our results suggest that BNIP3 interacts with the MOM directly via mitochondrial BAX. However, the physical interactions with BAX and the MOM did not affect the membrane potential and cell viability. These findings suggest that another stimulus other than the mere existence of the BNIP3/BAX dimer in the MOM is required to promote BNIP3 cell-death activity; this could be a potential disturbance of the BNIP3 distribution homeostasis, namely in the direction of the mitochondria.
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Pohl J, Hendgen-Cotta UB, Stock P, Luedike P, Rassaf T. Elevated MIF-2 levels predict mortality in critically ill patients. J Crit Care 2017; 40:52-57. [PMID: 28329734 DOI: 10.1016/j.jcrc.2017.03.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 02/05/2017] [Accepted: 03/12/2017] [Indexed: 12/11/2022]
Abstract
PURPOSE D-dopachrome tautomerase (MIF-2 or DDT) is a member of the macrophage migration inhibitory factor (MIF) superfamily and a close structural homolog to MIF. Circulating MIF-2 has been described to be elevated in patients suffering from sepsis, severe burn injury and after surgery. We sought to evaluate the prognostic value of MIF-2 in critically ill patients. METHODS A total of 72 patients were studied upon admission to the medical intensive care unit (ICU). MIF and MIF-2 levels were assessed and compared to healthy controls. Clinical data, various laboratory parameters and mortality were assessed. RESULTS We found significantly elevated levels of MIF-2 and MIF at admission to the ICU in critically ill patients compared to healthy controls. MIF-2 levels were associated with disease severity as measured by APACHE II scores. MIF-2 levels in ICU patients correlated with biomarkers reflecting organ damage, but were not influenced by acute or chronic kidney disease. Kaplan-Meier analysis revealed distinctly elevated mortality in patients with high plasma MIF-2 levels. CONCLUSIONS MIF-2 levels are elevated in critically ill patients and linked to parameters of organ damage, supporting its value as a potential tool for the assessment of prognosis in critical illness.
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Affiliation(s)
- Julia Pohl
- University Hospital Essen, West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, Hufelandstr. 55, 45147 Essen, Germany.
| | - Ulrike B Hendgen-Cotta
- University Hospital Essen, West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, Hufelandstr. 55, 45147 Essen, Germany
| | - Pia Stock
- University Hospital Essen, West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, Hufelandstr. 55, 45147 Essen, Germany
| | - Peter Luedike
- University Hospital Essen, West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, Hufelandstr. 55, 45147 Essen, Germany
| | - Tienush Rassaf
- University Hospital Essen, West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, Hufelandstr. 55, 45147 Essen, Germany
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Hendgen-Cotta UB, Messiha D, Esfeld S, Deenen R, Rassaf T, Totzeck M. Inorganic nitrite modulates miRNA signatures in acute myocardial in vivo ischemia/reperfusion. Free Radic Res 2017; 51:91-102. [PMID: 28090786 DOI: 10.1080/10715762.2017.1282158] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Acute myocardial infarction is the leading cause of mortality in the industrialized world. While it is essential to attempt an early reperfusion of ischemic myocardial territories, reperfusion itself adds damage to the heart, the ischemia-reperfusion (I/R) injury. Particularly the injury resulting from the very first minutes of reperfusion remains incompletely understood. MicroRNAs (miRNAs) are dynamic regulators in I/R injury. Nitric oxide (•NO) signaling, in turn, interacts with miRNA signaling. Our previous investigations showed that •NO signaling in I/R could be modulated by nitrite. We therefore sought to investigate the role of miRNAs in nitrite cardioprotection with focus on the first few minutes of reperfusion. The study was conducted in mice in vivo with 30 min of ischemia and 5 min of reperfusion. Mice received a single-dose of nitrite or saline intracardially 5 min prior to reperfusion. We identified nine miRNAs to be up-regulated after 5 min of reperfusion. The up-regulation of almost half of those miRNAs (miR-125a-5p, miR-146b, miR-339-3p, miR-433) was inhibited by nitrite treatment, perpetuating baseline values. In silico analysis revealed the Irak-M gene to be a target of miR-146b and miR-339-3p. Correspondingly, a rise in Irak-M transcript and protein levels occurred by nitrite treatment within the early phase of reperfusion. The results demonstrate that already a very short phase of reperfusion is sufficient for significant dysregulation in cardiac miRNAs expression and that nitrite preserves baseline values of miRNAs in the scale of only a few minutes. These findings hint at a potential novel cardioprotective mechanism of nitrite signaling.
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Affiliation(s)
- Ulrike B Hendgen-Cotta
- a Department of Cardiology and Angiology, Medical Faculty , West German Heart and Vascular Center Essen, University Hospital Essen , Essen , Germany
| | - Daniel Messiha
- a Department of Cardiology and Angiology, Medical Faculty , West German Heart and Vascular Center Essen, University Hospital Essen , Essen , Germany
| | - Sonja Esfeld
- a Department of Cardiology and Angiology, Medical Faculty , West German Heart and Vascular Center Essen, University Hospital Essen , Essen , Germany
| | - René Deenen
- b Biological and Medical Research Center (BMFZ), Heinrich-Heine-University , Düsseldorf , Germany
| | - Tienush Rassaf
- a Department of Cardiology and Angiology, Medical Faculty , West German Heart and Vascular Center Essen, University Hospital Essen , Essen , Germany
| | - Matthias Totzeck
- a Department of Cardiology and Angiology, Medical Faculty , West German Heart and Vascular Center Essen, University Hospital Essen , Essen , Germany
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Hendgen-Cotta UB, Esfeld S, Coman C, Ahrends R, Klein-Hitpass L, Flögel U, Rassaf T, Totzeck M. A novel physiological role for cardiac myoglobin in lipid metabolism. Sci Rep 2017; 7:43219. [PMID: 28230173 PMCID: PMC5322402 DOI: 10.1038/srep43219] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 01/20/2017] [Indexed: 02/06/2023] Open
Abstract
Continuous contractile activity of the heart is essential and the required energy is mostly provided by fatty acid (FA) oxidation. Myocardial lipid accumulation can lead to pathological responses, however the underlying mechanisms remain elusive. The role of myoglobin in dioxygen binding in cardiomyocytes and oxidative skeletal muscle has widely been appreciated. Our recent work established myoglobin as a protector of cardiac function in hypoxia and disease states. We here unravel a novel role of cardiac myoglobin in governing FA metabolism to ensure the physiological energy production through β-oxidation, preventing myocardial lipid accumulation and preserving cardiac functions. In vivo1H magnetic resonance spectroscopy unveils a 3-fold higher deposition of lipids in mouse hearts lacking myoglobin, which was associated with depressed cardiac function compared to wild-type hearts as assessed by echocardiography. Mass spectrometry reveals a marked increase in tissue triglycerides with preferential incorporation of palmitic and oleic acids. Phospholipid levels as well as the metabolome, transcriptome and proteome related to FA metabolism tend to be unaffected by myoglobin ablation. Our results reveal a physiological role of myoglobin in FA metabolism with the lipid accumulation-suppressing effects of myoglobin preventing cardiac lipotoxicity.
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Affiliation(s)
- Ulrike B Hendgen-Cotta
- University Hospital Essen, Medical Faculty, West German Heart and Vascular Center, Department of Cardiology and Department of Angiology, Hufelandstr. 55, 45147 Essen, Germany
| | - Sonja Esfeld
- University Hospital Essen, Medical Faculty, West German Heart and Vascular Center, Department of Cardiology and Department of Angiology, Hufelandstr. 55, 45147 Essen, Germany
| | - Cristina Coman
- Leibniz-Institut für Analytische Wissenschaften-ISAS e.V. Otto-Hahn-Str. 6b, 44227 Dortmund, Germany
| | - Robert Ahrends
- Leibniz-Institut für Analytische Wissenschaften-ISAS e.V. Otto-Hahn-Str. 6b, 44227 Dortmund, Germany
| | - Ludger Klein-Hitpass
- University Hospital Essen, Institute of Cell Biology, Medical Faculty, Virchowstr. 173, 45122 Essen, Germany
| | - Ulrich Flögel
- University Hospital Düsseldorf, Department of Molecular Cardiology, Universitätsstr. 1, 40225 Düsseldorf, Germany
| | - Tienush Rassaf
- University Hospital Essen, Medical Faculty, West German Heart and Vascular Center, Department of Cardiology and Department of Angiology, Hufelandstr. 55, 45147 Essen, Germany
| | - Matthias Totzeck
- University Hospital Essen, Medical Faculty, West German Heart and Vascular Center, Department of Cardiology and Department of Angiology, Hufelandstr. 55, 45147 Essen, Germany
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Exogenous Administration of Recombinant MIF at Physiological Concentrations Failed to Attenuate Infarct Size in a Langendorff Perfused Isolated Mouse Heart Model. Cardiovasc Drugs Ther 2017; 30:445-453. [PMID: 27335054 PMCID: PMC5055564 DOI: 10.1007/s10557-016-6673-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Purpose Evidence suggests a two-pronged role of endogenous macrophage migration inhibitory factor (MIF) release in ischemia/reperfusion injury. We aimed to assess whether its exogenous administration confers cardioprotection. Methods Male C57/BL6 mice were randomly allocated to receive recombinant mouse MIF (rMIF) at physiological (ng/mL) concentrations in a dose–response fashion before or after a protocol of 35 min of ischemia and 2 h of reperfusion in an isolated Langendorff-perfused model with infarct size as endpoint. Isolated primary cardiomyocytes were also used for cell survival studies using rMIF at a supra-physiological concentration of 1 μg/mL. Pro-survival kinase activation was also studied using Western blot analyses. Results Exogenous MIF did not elicit a cardioprotective effect either when administered before the ischemic insult or when applied at reperfusion. rMIF did not confer protection when it was applied immediately before or after a hypoxia/reoxygenation insult in primary isolated cardiomyocytes. Consistently, hearts treated with MIF did not show a significant increase in phosphorylated Akt and ERK1/2. Conclusion The exogenous administration of rMIF in a physiological concentration range both before ischemia and at reperfusion did not show cardioprotective effects. Although these results do not address the role of endogenous MIF after an ischemic insult followed by reperfusion, they may limit the potential translational value of rMIF.
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Totzeck M, Hendgen-Cotta UB, French BA, Rassaf T. A practical approach to remote ischemic preconditioning and ischemic preconditioning against myocardial ischemia/reperfusion injury. J Biol Methods 2016; 3. [PMID: 28066791 PMCID: PMC5218813 DOI: 10.14440/jbm.2016.149] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Although urgently needed in clinical practice, a cardioprotective therapeutic approach against myocardial ischemia/ reperfusion injury remains to be established. Remote ischemic preconditioning (rIPC) and ischemic preconditioning (IPC) represent promising tools comprising three entities: the generation of a protective signal, the transfer of the signal to the target organ, and the response to the transferred signal resulting in cardioprotection. However, in light of recent scientific advances, many controversies arise regarding the efficacy of the underlying signaling. We here show methods for the generation of the signaling cascade by rIPC as well as IPC in a mouse model for in vivo myocardial ischemia/ reperfusion injury using highly reproducible approaches. This is accomplished by taking advantage of easily applicable preconditioning strategies compatible with the clinical setting. We describe methods for using laser Doppler perfusion imaging to monitor the cessation and recovery of perfusion in real time. The effects of preconditioning on cardiac function can also be assessed using ultrasound or magnetic resonance imaging approaches. On a cellular level, we confirm how tissue injury can be monitored using histological assessment of infarct size in conjunction with immunohistochemistry to assess both aspects in a single specimen. Finally, we outline, how the rIPC-associated signaling can be transferred to the target cell via conservation of the signal in the humoral (blood) compartment. This compilation of experimental protocols including a conditioning regimen comparable to the clinical setting should proof useful to both beginners and experts in the field of myocardial infarction, supplying information for the detailed procedures as well as troubleshooting guides.
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Affiliation(s)
- Matthias Totzeck
- Department of Cardiology and Department of Angiology, West German Heart and Vascular Center, Medical Faculty, University Hospital Essen, Essen 45147, Germany
| | - Ulrike B Hendgen-Cotta
- Department of Cardiology and Department of Angiology, West German Heart and Vascular Center, Medical Faculty, University Hospital Essen, Essen 45147, Germany
| | - Brent A French
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22903, USA
| | - Tienush Rassaf
- Department of Cardiology and Department of Angiology, West German Heart and Vascular Center, Medical Faculty, University Hospital Essen, Essen 45147, Germany
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Pohl J, Papathanasiou M, Heisler M, Stock P, Kelm M, Hendgen-Cotta UB, Rassaf T, Luedike P. Renal replacement therapy neutralizes elevated MIF levels in septic shock. J Intensive Care 2016; 4:39. [PMID: 27313864 PMCID: PMC4910205 DOI: 10.1186/s40560-016-0163-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 06/08/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Macrophage migration inhibitory factor (MIF) is known to amplify the immune response in septic animal models. Few clinical data support this pro-inflammatory role in septic patients. Renal replacement therapy (RRT) as adjuvants in the complex therapy of sepsis has been proposed as a possible approach to eliminate elevated circulating cytokines. Since recent data suggest that MIF can be effectively removed from the circulating blood pool in patients with chronic kidney disease, we here aimed to investigate whether RRT in septic shock can lower plasma levels of this pro-inflammatory cytokine in septic shock patients. METHODS An observational single-center study on an internist intensive care unit (ICU) was conducted. MIF plasma levels and mortality of n = 25 patients with septic shock were assessed with a previously validated method for reliable MIF values. The effect of continuous renal replacement therapy (CRRT) on daily MIF levels and mortality was assessed by comparing patients with and without need for CRRT due to acute kidney injury (AKI). RESULTS MIF plasma levels in patients undergoing CRRT due to septic AKI were steadily decreased compared to those from patients without CRRT hinting at a MIF removal by hemodialysis. MIF release during ICU stay as assessed by MIFAUC was lower in patients undergoing CRRT, and Kaplan-Meier analysis revealed a distinctly lower mortality in patients undergoing CRRT. Analysis of daily MIF levels showed that patients who did not survive septic shock exhibited steadily higher MIF plasma levels and higher MIFAUC compared to those surviving sepsis. Low MIF levels were closely associated with improved survival. CONCLUSIONS This is the first study investigating the effect of efficient MIF removal from the plasma pool of patients with septic shock. Reduction of high circulating MIF by CRRT therapy was accompanied by improved survival. Thus, targeted removal of MIF from the circulating blood pool might be a promising approach to reduce mortality in severe sepsis.
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Affiliation(s)
- Julia Pohl
- West-German Heart and Vascular Center Essen, Department of Cardiology and Department ofVascular Medicine, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Maria Papathanasiou
- West-German Heart and Vascular Center Essen, Department of Cardiology and Department ofVascular Medicine, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Martin Heisler
- West-German Heart and Vascular Center Essen, Department of Cardiology and Department ofVascular Medicine, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Pia Stock
- West-German Heart and Vascular Center Essen, Department of Cardiology and Department ofVascular Medicine, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Malte Kelm
- Medical Faculty, Division of Cardiology, Pulmonology and Vascular Medicine, University Hospital Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Ulrike B Hendgen-Cotta
- West-German Heart and Vascular Center Essen, Department of Cardiology and Department ofVascular Medicine, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Tienush Rassaf
- West-German Heart and Vascular Center Essen, Department of Cardiology and Department ofVascular Medicine, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Peter Luedike
- West-German Heart and Vascular Center Essen, Department of Cardiology and Department ofVascular Medicine, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany
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Cui J, Zhang F, Wang Y, Liu J, Ming X, Hou J, Lv B, Fang S, Yu B. Macrophage migration inhibitory factor promotes cardiac stem cell proliferation and endothelial differentiation through the activation of the PI3K/Akt/mTOR and AMPK pathways. Int J Mol Med 2016; 37:1299-309. [PMID: 27035848 PMCID: PMC4829139 DOI: 10.3892/ijmm.2016.2542] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 03/16/2016] [Indexed: 01/05/2023] Open
Abstract
Macrophage migration inhibitory factor (MIF) has pleiotropic immune functions in a number of inflammatory diseases. Recent evidence from expression and functional studies has indicated that MIF is involved in various aspects of cardiovascular disease. In this study, we aimed to determine whether MIF supports in vitro c-kit+CD45− cardiac stem cell (CSC) survival, proliferation and differentiation into endothelial cells, as well as the possible mechanisms involved. We observed MIF receptor (CD74) expression in mouse CSCs (mCSCs) using PCR and immunofluorescence staining, and MIF secretion by mCSCs using PCR and ELISA in vitro. Increasing amounts of exogenous MIF did not affect CD74 expression, but promoted mCSC survival, proliferation and endothelial differentiation. By contrast, treatment with an MIF inhibitor (ISO-1) or siRNA targeting CD74 (CD74-siRNA) suppressed the biological changes induced by MIF in the mCSCs. Increasing amounts of MIF increased the phosphorylation of Akt and mammalian target of rapamycin (mTOR), which are known to support cell survival, proliferation and differentiation. These effects of MIF on the mCSCs were abolished by LY294002 [a phosphoinositide 3-kinase (PI3K) inhibitor] and MK-2206 (an Akt inhibitor). Moreover, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation increased following treatment with MIF. The AMPK inhibitor, compound C, partly blocked the pro-proliferative effects of MIF on the mCSCs. In conclusion, our results suggest that MIF promotes mCSC survival, proliferation and endothelial differentiation through the activation of the PI3K/Akt/mTOR and AMPK signaling pathways. Thus, MIF may prove to be a potential therapeutic factor in the treatment of heart failure and myocardial infarction by activating CSCs.
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Affiliation(s)
- Jinjin Cui
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Fengyun Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Yongshun Wang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Jingjin Liu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Xing Ming
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Jingbo Hou
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Bo Lv
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Shaohong Fang
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, Heilongjiang 150081, P.R. China
| | - Bo Yu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
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