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Kim K, Abramishvili D, Du S, Papadopoulos Z, Cao J, Herz J, Smirnov I, Thomas JL, Colonna M, Kipnis J. Meningeal lymphatics-microglia axis regulates synaptic physiology. Cell 2025:S0092-8674(25)00210-7. [PMID: 40120575 DOI: 10.1016/j.cell.2025.02.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 12/30/2024] [Accepted: 02/21/2025] [Indexed: 03/25/2025]
Abstract
Meningeal lymphatics serve as an outlet for cerebrospinal fluid, and their dysfunction is associated with various neurodegenerative conditions. Previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral changes, but the neural mechanisms underlying these changes have remained elusive. Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs, accompanied by deficits in memory tasks. These synaptic and behavioral alterations induced by lymphatic dysfunction are mediated by microglia, leading to increased expression of the interleukin 6 gene (Il6). IL-6 drives inhibitory synapse phenotypes via a combination of trans- and classical IL-6 signaling. Restoring meningeal lymphatic function in aged mice reverses age-associated synaptic and behavioral alterations. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through an IL-6-dependent mechanism and identify a potential target for treating aging-associated cognitive decline.
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Affiliation(s)
- Kyungdeok Kim
- Brain Immunology and Glia (BIG) Center, Washington University in St Louis, St Louis, MO, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, USA.
| | - Daviti Abramishvili
- Brain Immunology and Glia (BIG) Center, Washington University in St Louis, St Louis, MO, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, USA
| | - Siling Du
- Brain Immunology and Glia (BIG) Center, Washington University in St Louis, St Louis, MO, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, USA
| | - Zachary Papadopoulos
- Brain Immunology and Glia (BIG) Center, Washington University in St Louis, St Louis, MO, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, USA; Neuroscience Graduate Program, School of Medicine, Washington University in St Louis, St Louis, MO, USA
| | - Jay Cao
- Brain Immunology and Glia (BIG) Center, Washington University in St Louis, St Louis, MO, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, USA
| | - Jasmin Herz
- Brain Immunology and Glia (BIG) Center, Washington University in St Louis, St Louis, MO, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, USA
| | - Igor Smirnov
- Brain Immunology and Glia (BIG) Center, Washington University in St Louis, St Louis, MO, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, USA
| | - Jean-Leon Thomas
- Department of Neurology, Yale University School of Medicine, New Haven, CT, USA; Paris Brain Institute, Université Pierre et Marie Curie Paris 06, UMRS1127, Sorbonne Université, Paris, France
| | - Marco Colonna
- Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, USA
| | - Jonathan Kipnis
- Brain Immunology and Glia (BIG) Center, Washington University in St Louis, St Louis, MO, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, USA.
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Zhou Y, Dou L, Wang L, Chen J, Mao R, Zhu L, Liu D, Zheng K. Growth and differentiation factor 15: An emerging therapeutic target for brain diseases. Biosci Trends 2025; 19:72-86. [PMID: 39864834 DOI: 10.5582/bst.2024.01305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Growth and differentiation factor 15 (GDF15), a member of the transforming growth factor-βsuperfamily, is considered a stress response factor and has garnered increasing attention in recent years due to its roles in neurological diseases. Although many studies have suggested that GDF15 expression is elevated in patients with neurodegenerative diseases (NDDs), glioma, and ischemic stroke, the effects of increased GDF15 expression and the potential underlying mechanisms remain unclear. Notably, many experimental studies have shown the multidimensional beneficial effects of GDF15 on NDDs, and GDF15 overexpression is able to rescue NDD-associated pathological changes and phenotypes. In glioma, GDF15 exerts opposite effects, it is both protumorigenic and antitumorigenic. The causes of these conflicting findings are not comprehensively clear, but inhibiting GDF15 is helpful for suppressing tumor progression. GDF15 is also regarded as a biomarker of poor clinical outcomes in ischemic stroke patients, and targeting GDF15 may help prevent this disease. Thus, we systematically reviewed the synthesis, transcriptional regulation, and biological functions of GDF15 and its related signaling pathways within the brain. Furthermore, we explored the potential of GDF15 as a therapeutic target and assessed its clinical applicability in interventions for brain diseases. By integrating the latest research findings, this study provides new insights into the future treatment of neurological diseases.
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Affiliation(s)
- Yingying Zhou
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lei Dou
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Luyao Wang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiajie Chen
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ruxue Mao
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lingqiang Zhu
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Dan Liu
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kai Zheng
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Chen L, Luo S, Liu T, Shuai Z, Song Y, Yang Q, Wang Y, Huang H, Luo Y. Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis. J Neuroinflammation 2025; 22:44. [PMID: 39985040 PMCID: PMC11846340 DOI: 10.1186/s12974-025-03369-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 02/05/2025] [Indexed: 02/23/2025] Open
Abstract
BACKGROUND Sepsis-associated encephalopathy (SAE) is a severe neurological condition caused by sepsis, and presents with symptoms ranging from delirium and coma to long-term cognitive dysfunction. SAE is acknowledged as a widespread brain impairment characterized by the activation of microglia. However, the specific pathological mechanisms that drive this activation are still not clearly understood. Growth differentiation factor 15 (GDF15) levels have been noted to be considerably increased in patients with sepsis, where they are linked to disease severity and can independently predict short- and long-term mortality risk. Serum levels of GDF15 have also been negatively associated with gray matter volume and predict cognitive impairment in older individuals. However, the impact of GDF15 on sepsis-induced cognitive and memory impairments, as well as the mechanisms behind these effects, are poorly understood. METHODS To examine the role of GDF15 in SAE, a sepsis model was created in adult C57BL/6J mice using intraperitoneal administration of lipopolysaccharide (LPS). GDF15 levels in plasma and cerebrospinal fluid were measured by ELISA. The anti-GDF15 monoclonal antibody ponsegromab was injected intracerebroventricularly before modeling, and cognitive and memory functions of the septic mice were assessed using fear-conditioning and novel object recognition tests. Microglial activation and phagocytosis were evaluated using immunofluorescence and Golgi staining. Additionally, an in vitro investigation of LPS-stimulated microglia was conducted to evaluate the impacts of GDF15 on inflammatory cytokine productions and microglial phagocytic activity. Mechanisms were explored using RNA sequencing, qPCR, western blotting, flow cytometry, and immunofluorescence assays. RESULTS In the cerebrospinal fluid of septic mice, levels of GDF15 were notably elevated after intraperitoneal injection of LPS. Lateral ventricular injection of the anti-GDF15 antibody alleviated both cognitive and memory impairment in the septic mice, together with microglial activation and phagocytosis in the hippocampus, thereby protecting against synaptic loss. CONCLUSION The levels of GDF15 were elevated in the brains of septic mice. Targeting GDF15 with an anti-GDF15 antibody was found to improve sepsis-induced cognitive and memory impairment by reducing the microglial inflammatory response and phagocytosis. These results indicate that GDF15 could serve as an important therapeutic target for treating SAE.
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Affiliation(s)
- Lijiao Chen
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Shiyuan Luo
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ting Liu
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhewei Shuai
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yifan Song
- School of Anesthesiology, Shandong Second Medical University, Weifang, 261053, China
| | - Qianzi Yang
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ying Wang
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Hongjun Huang
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Yan Luo
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Hes C, Gui LT, Bay A, Alvarez F, Katz P, Paul T, Bozadjieva-Kramer N, Seeley RJ, Piccirillo CA, Sabatini PV. GDNF family receptor alpha-like (GFRAL) expression is restricted to the caudal brainstem. Mol Metab 2025; 91:102070. [PMID: 39608751 PMCID: PMC11650321 DOI: 10.1016/j.molmet.2024.102070] [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: 09/20/2024] [Revised: 11/12/2024] [Accepted: 11/18/2024] [Indexed: 11/30/2024] Open
Abstract
OBJECTIVE Growth differentiation factor 15 (GDF15) acts on the receptor dimer of GDNF family receptor alpha-like (GFRAL) and Rearranged during transfection (RET). While Gfral-expressing cells are known to be present in the area postrema and nucleus of the solitary tract (AP/NTS) located in the brainstem, the presence of Gfral-expressing cells in other sites within the central nervous system and peripheral tissues is not been fully addressed. Our objective was to thoroughly investigate whether GFRAL is expressed in peripheral tissues and in brain sites different from the brainstem. METHODS From Gfral:eGFP mice we collected tissue from 12 different tissues, including brain, and used single molecule in-situ hybridizations to identify cells within those tissues expressing Gfral. We then contrasted the results with human Gfral-expression by analyzing publicly available single-cell RNA sequencing data. RESULTS In mice we found readably detectable Gfral mRNA within the AP/NTS but not within other brain sites. Within peripheral tissues, we failed to detect any Gfral-labelled cells in the vast majority of examined tissues and when present, were extremely rare. Single cell sequencing of human tissues confirmed GFRAL-expressing cells are detectable in some sites outside the AP/NTS in an extremely sparse manner. Importantly, across the utilized methodologies, smFISH, genetic Gfral reporter mice and scRNA-Seq, we failed to detect Gfral-labelled cells with all three. CONCLUSIONS Through highly sensitive and selective technologies we show Gfral expression is overwhelmingly restricted to the brainstem and expect that GDF15 and GFRAL-based therapies in development for cancer cachexia will specifically target AP/NTS cells.
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Affiliation(s)
- Cecilia Hes
- Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada
| | - Lu Ting Gui
- Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Integrated Program in Neuroscience, Department of Medicine, McGill University, Room 302 Irving Ludmer Building, 1033 Pine Ave. W. Montreal, QC, H3A 1A1, Canada
| | - Alexandre Bay
- Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada
| | - Fernando Alvarez
- Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada
| | - Pierce Katz
- Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Integrated Program in Neuroscience, Department of Medicine, McGill University, Room 302 Irving Ludmer Building, 1033 Pine Ave. W. Montreal, QC, H3A 1A1, Canada
| | - Tanushree Paul
- Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada
| | - Nadejda Bozadjieva-Kramer
- Department of Surgery, University of Michigan, 2800 Plymouth Rd, Ann Arbor, MI, 48109, USA; Veterans Affairs Ann Arbor Healthcare System, Research Service, 2215 Fuller Rd, Ann Arbor, MI, 48105, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, 2800 Plymouth Rd, Ann Arbor, MI, 48109, USA
| | - Ciriaco A Piccirillo
- Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Department of Microbiology and Immunology, Department of Medicine, McGill University, 3775 University Street, Montreal, QC, H3A 2B4, Canada; Centre of Excellence in Translational Immunology (CETI), Research Institute of the McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Program in Infectious Diseases and Immunology in Global Health, Research Institute of the McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada
| | - Paul V Sabatini
- Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Integrated Program in Neuroscience, Department of Medicine, McGill University, Room 302 Irving Ludmer Building, 1033 Pine Ave. W. Montreal, QC, H3A 1A1, Canada.
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Skau E, Wagner P, Leppert J, Ärnlöv J, Hedberg P. Determinants of growth differentiation factor 15 plasma levels in outpatients with peripheral arterial disease. Ups J Med Sci 2024; 129:11001. [PMID: 39780955 PMCID: PMC11708457 DOI: 10.48101/ujms.v129.11001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/27/2024] [Accepted: 08/27/2024] [Indexed: 01/11/2025] Open
Abstract
Background Growth differentiation factor 15 (GDF-15) is a robust prognostic biomarker in patients with cardiovascular (CV) disease, and a better understanding of its clinical determinants is desirable. We aimed to study the associations between GDF-15 levels and traditional CV risk factors, indicators of atherosclerotic burden, and cardiac geometry and dysfunction in outpatients with peripheral arterial disease (PAD). Methods An explorative cross-sectional study (Study of Atherosclerosis in Vastmanland, Västerås, Sweden) included 439 outpatients with carotid or lower extremity PAD. The mean age was 70 years (standard deviation [SD] 7), and 59% of the patients were men. Plasma levels of GDF-15 were obtained along with potential determinants, including medical history, biochemical data, echocardiographic measures of cardiac geometry and function, ankle-brachial index (ABI), and carotid ultrasonographic data on intima-media thickness (IMT) and occurrence of carotid stenosis. The relations between GDF-15 concentrations (transformed with the natural logarithm) and the different determinants were evaluated using uni- and multivariable linear regression models. All pre-specified variables were included in the multivariable models. Results The multivariable analysis identified independent relations of GDF-15 with several of the included variables (adjusted R 2 = 0.48). Diabetes (beta coefficient [β] of 0.37, 95% confidence interval [95% CI] 0.25 to 0.50), low-density lipoprotein (LDL) cholesterol (β = -0.22, 95% confidence interval [CI]: -0.34 to -0.09), and physical activity (β = -0.16, 95% CI: -0.25 to -0.06) had the strongest associations. In contrast, no significant independent associations with GDF-15 level were observed for cardiac geometry and function, ABI, IMT, or carotid stenosis. Conclusions Circulating GDF-15 is more strongly associated with traditional CV risk factors, especially diabetes, LDL cholesterol, and physical activity than with specific indicators of atherosclerotic burden or cardiac dysfunction. To better understand the pathophysiological role of GDF-15 and its link to clinical outcomes in patients with PAD, future studies should focus on the metabolic processes involved in atherosclerotic disease.
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Affiliation(s)
- Emma Skau
- Centre for Clinical Research, Uppsala University, Västmanland County Hospital, Västerås, Sweden
- Department of Cardiology, Danderyd University Hospital, Stockholm, Sweden
| | - Philippe Wagner
- Centre for Clinical Research, Uppsala University, Västmanland County Hospital, Västerås, Sweden
| | - Jerzy Leppert
- Centre for Clinical Research, Uppsala University, Västmanland County Hospital, Västerås, Sweden
| | - Johan Ärnlöv
- School of Health and Social Studies, Dalarna University, Falun, Sweden
- Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Huddinge, Sweden
| | - Pär Hedberg
- Centre for Clinical Research, Uppsala University, Västmanland County Hospital, Västerås, Sweden
- Department of Clinical Physiology, Västmanland County Hospital, Västerås, Sweden
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Isik FI, Thomson S, Cueto JF, Spathos J, Breit SN, Tsai VWW, Brown DA, Finney CA. A systematic review of the neuroprotective role and biomarker potential of GDF15 in neurodegeneration. Front Immunol 2024; 15:1514518. [PMID: 39737171 PMCID: PMC11682991 DOI: 10.3389/fimmu.2024.1514518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 11/25/2024] [Indexed: 01/01/2025] Open
Abstract
Neurodegeneration is characteristically multifaceted, with limited therapeutic options. One of the chief pathophysiological mechanisms driving these conditions is neuroinflammation, prompting increasing clinical interest in immunomodulatory agents. Growth differentiation factor 15 (GDF15; previously also called macrophage inhibitory cytokine-1 or MIC-1), an anti-inflammatory cytokine with established neurotrophic properties, has emerged as a promising therapeutic agent in recent decades. However, methodological challenges and the delayed identification of its specific receptor GFRAL have hindered research progress. This review systematically examines literature about GDF15 in neurodegenerative diseases and neurotrauma. The evidence collated in this review indicates that GDF15 expression is upregulated in response to neurodegenerative pathophysiology and increasing its levels in preclinical models typically improves outcomes. Key knowledge gaps are addressed for future investigations to foster a more comprehensive understanding of the neuroprotective effects elicited by GDF15.
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Affiliation(s)
- Finula I. Isik
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Shannon Thomson
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - John F. Cueto
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Jessica Spathos
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Samuel N. Breit
- St. Vincent’s Centre for Applied Medical Research, St. Vincent’s Hospital and Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Vicky W. W. Tsai
- St. Vincent’s Centre for Applied Medical Research, St. Vincent’s Hospital and Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - David A. Brown
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
- Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Western Sydney Local Health District, Institute for Clinical Pathology and Medical Research, NSW Health Pathology, Sydney, NSW, Australia
| | - Caitlin A. Finney
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
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Vaja R, Ferreira P, Portas L, Ahmetaj-Shala B, Cypaite N, Gashaw H, Quint J, Khamis R, Hartley A, MacDonald TM, Mackenzie IS, Kirkby NS, Mitchell JA. Vascular and inflammatory biomarkers of cardiovascular events in non-steroidal anti-inflammatory drug users. EUROPEAN HEART JOURNAL OPEN 2024; 4:oeae088. [PMID: 39660078 PMCID: PMC11630077 DOI: 10.1093/ehjopen/oeae088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/29/2024] [Accepted: 09/12/2024] [Indexed: 12/12/2024]
Abstract
Aims The Standard care vs. Celecoxib Outcome Trial (SCOT) found similar risk of cardiovascular events with traditional non-steroidal anti-inflammatory drugs (NSAIDs) and the cyclooxygenase-2-selective drug celecoxib. While pre-clinical work has suggested roles for vascular and renal dysfunction in NSAID cardiovascular toxicity, our understanding of these mechanisms remains incomplete. A post hoc analysis of the SCOT cohort was performed to identify clinical risk factors and circulating biomarkers of cardiovascular events in NSAID users. Methods and results Within SCOT (7295 NSAID users with osteoarthritis or rheumatoid arthritis), clinical risk factors associated with cardiovascular events were identified using least absolute shrinkage and selection operator regression. A nested case-control study of serum biomarkers including targeted proteomics was performed in individuals who experienced a cardiovascular event within 1 year (n = 49), matched 2:1 with controls who did not (n = 97). Risk factors significantly associated with cardiovascular events included increasing age, male sex, smoking, total cholesterol:HDL ratio ≥5, and aspirin use. Statin use was cardioprotective [odds ratio (OR) 0.68; 95% confidence interval (CI) 0.46-0.98]. There was significantly higher immunoglobulin (Ig)G anti-malondialdehyde-modified LDL (MDA-LDL), asymmetric dimethylarginine (ADMA), and lower arginine/ADMA. Targeted proteomic analysis identified serum growth differentiation factor 15 (GDF-15) as a candidate biomarker [area under the curve of 0.715 (95% CI 0.63-0.81)]. Conclusion Growth differentiation factor 15 has been identified as a candidate biomarker and should be explored for its mechanistic contribution to NSAID cardiovascular toxicity, particularly given the remarkable providence that GDF-15 was originally described as NSAID-activated gene-1.
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Affiliation(s)
- Ricky Vaja
- The National Heart and Lung Institute, Imperial College LondonSW7 2AZ, UK
- The Royal Brompton Hospital, London SW3 6NP, UK
| | - Plinio Ferreira
- The National Heart and Lung Institute, Imperial College LondonSW7 2AZ, UK
| | - Laura Portas
- The National Heart and Lung Institute, Imperial College LondonSW7 2AZ, UK
| | | | - Neringa Cypaite
- The National Heart and Lung Institute, Imperial College LondonSW7 2AZ, UK
| | - Hime Gashaw
- The National Heart and Lung Institute, Imperial College LondonSW7 2AZ, UK
| | - Jennifer Quint
- The National Heart and Lung Institute, Imperial College LondonSW7 2AZ, UK
| | - Ramzi Khamis
- The National Heart and Lung Institute, Imperial College LondonSW7 2AZ, UK
| | - Adam Hartley
- The National Heart and Lung Institute, Imperial College LondonSW7 2AZ, UK
| | - Thomas M MacDonald
- Ninewells Hospital and Medical School, University of Dundee, Dundee DD2 1SG, UK
| | - Isla S Mackenzie
- Ninewells Hospital and Medical School, University of Dundee, Dundee DD2 1SG, UK
| | - Nicholas S Kirkby
- The National Heart and Lung Institute, Imperial College LondonSW7 2AZ, UK
| | - Jane A Mitchell
- The National Heart and Lung Institute, Imperial College LondonSW7 2AZ, UK
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Turkistani A, Al‐Kuraishy HM, Al‐Gareeb AI, Alexiou A, Papadakis M, Bahaa MM, Al‐Windy S, Batiha GE. Pharmacological characterization of the antidiabetic drug metformin in atherosclerosis inhibition: A comprehensive insight. Immun Inflamm Dis 2024; 12:e1346. [PMID: 39092773 PMCID: PMC11295104 DOI: 10.1002/iid3.1346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 05/05/2024] [Accepted: 07/06/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Atherosclerosis (AS) is a progressive disease that interferes with blood flow, leading to cardiovascular complications such as hypertension, ischemic heart disease, ischemic stroke, and vascular ischemia. The progression of AS is correlated with inflammation, oxidative stress, and endothelial dysfunction. Various signaling pathways, like nuclear erythroid-related factor 2 (Nrf2) and Kruppel-like factor 2 (KLF2), are involved in the pathogenesis of AS. Nrf2 and KLF2 have anti-inflammatory and antioxidant properties. Thus, activation of these pathways may reduce the development of AS. Metformin, an insulin-sensitizing drug used in the management of type 2 diabetes mellitus (T2DM), increases the expression of Nrf2 and KLF2. AS is a common long-term macrovascular complication of T2DM. Thus, metformin, through its pleiotropic anti-inflammatory effect, may attenuate the development and progression of AS. AIMS Therefore, this review aims to investigate the possible role of metformin in AS concerning its effect on Nrf2 and KLF2 and inhibition of reactive oxygen species (ROS) formation. In addition to its antidiabetic effect, metformin can reduce cardiovascular morbidities and mortalities compared to other antidiabetic agents, even with similar blood glucose control by the Nrf2/KLF2 pathway activation. CONCLUSION In conclusion, metformin is an effective therapeutic strategy against the development and progression of AS, mainly through activation of the KLF2/Nrf2 axis.
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Affiliation(s)
- Areej Turkistani
- Department of Pharmacology and Toxicology, College of MedicineTaif UniversityTaifSaudi Arabia
| | - Haydar M. Al‐Kuraishy
- Department of Clinical Pharmacology and Medicine, College of MedicineMustansiriyah UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Clinical Pharmacology and Medicine, College of MedicineMustansiriyah UniversityBaghdadIraq
- Department of Clinical Pharmacology and MedicineJabir ibn Hayyan Medical UniversityKufaIraq
| | - Athanasios Alexiou
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamNew South WalesAustralia
- AFNP MedWienAustria
- Department of Research & DevelopmentFunogenAthensGreece
- University Centre for Research & DevelopmentChandigarh UniversityPunjabIndia
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten‐HerdeckeUniversity of Witten‐HerdeckeWuppertalGermany
| | - Mostafa M. Bahaa
- Pharmacy Practice Department, Faculty of PharmacyHorus UniversityNew DamiettaEgypt
| | - Salah Al‐Windy
- Department of Biology, College of ScienceBaghdad UniversityBaghdadIraq
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhour UniversityDamanhourEgypt
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Shimizu Y, Kawashiri SY, Noguchi Y, Sasaki N, Matsuyama M, Nakamichi S, Arima K, Nagata Y, Maeda T, Hayashida N. Association between eating speed and atherosclerosis in relation to growth differentiation factor-15 levels in older individuals in a cross-sectional study. Sci Rep 2024; 14:16492. [PMID: 39019981 PMCID: PMC11255208 DOI: 10.1038/s41598-024-67187-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 07/09/2024] [Indexed: 07/19/2024] Open
Abstract
Although fast eating speed has been associated with cardiovascular risk factors, no studies have reported an association between fast eating speed and atherosclerosis as evaluated by carotid intima-media thickness (CIMT). Rapid glucose ingestion is known to cause glucose spikes, which may accelerate atherogenesis and increase levels of growth differentiation factor 15 (GDF-15). Therefore, GDF-15 levels may influence the association between fast eating speed and atherosclerosis. To evaluate the association between eating speed and atherosclerosis in relation to GDF-15, this cross-sectional study analyzed 742 Japanese aged 60-69 years. They were required to have normal thyroid hormone levels, because both GDF-15 levels and atherosclerosis (CIMT ≥ 1.1 mm) can be influenced by thyroid dysfunction. Participants were stratified by the median GDF-15 level. A significant positive association was observed between fast eating speed and atherosclerosis, but only among participants with a high GDF-15 level: the sex- and age-adjusted odds ratios (95% confidence intervals) were 1.95 (1.09, 3.48) in participants with a high GDF-15 level, and 0.83 (0.37, 1.88) in those with a low GDF-15 level. This association remained even after further adjustment for thyroid function and metabolic factors. Serum concentrations of GDF-15 may mediate the association between fast eating speed and atherosclerosis.
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Affiliation(s)
- Yuji Shimizu
- Epidemiology Section, Division of Public Health, Osaka Institute of Public Health, Osaka, 537-0025, Japan.
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan.
| | - Shin-Ya Kawashiri
- Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
| | - Yuko Noguchi
- Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
| | - Nagisa Sasaki
- Epidemiology Section, Division of Public Health, Osaka Institute of Public Health, Osaka, 537-0025, Japan
| | - Mutsumi Matsuyama
- Division of Strategic Collaborative Research, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, 852-8523, Japan
| | - Seiko Nakamichi
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
- Nagasaki University Health Center, Nagasaki, 852-8523, Japan
| | - Kazuhiko Arima
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
- Department of Public Health, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
| | - Yasuhiro Nagata
- Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
| | - Takahiro Maeda
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
- Department of Island and Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 853-0031, Japan
| | - Naomi Hayashida
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
- Division of Strategic Collaborative Research, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, 852-8523, Japan
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10
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Shikama T, Otaki Y, Watanabe T, Tamura H, Kato S, Nishiyama S, Takahashi H, Arimoto T, Watanabe M. Growth Differentiation Factor-15 and Clinical Outcomes in Lower Extremity Artery Disease. J Atheroscler Thromb 2024; 31:964-978. [PMID: 38296521 PMCID: PMC11150723 DOI: 10.5551/jat.64515] [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: 08/01/2023] [Accepted: 11/28/2023] [Indexed: 06/04/2024] Open
Abstract
AIM Lower extremity artery disease (LEAD) is an increasingly common health problem that is associated with high mortality due to thrombotic and bleeding events. Growth differentiation factor-15 (GDF15), a stress-response cytokine belonging to the transforming growth factor-beta superfamily, is associated with cardiovascular disease and its outcomes. The aim of the present study was to examine the effect of serum GDF15 levels on clinical outcomes in patients with LEAD. METHODS We measured serum GDF15 levels in 200 patients with LEAD before their initial endovascular therapy. The primary endpoint was the all-cause mortality rate. The secondary endpoints, on the other hand, were thrombotic and bleeding events, such as cerebral infarction, acute coronary syndrome, acute limb ischemia, and Bleeding Academic Research Consortium types 3 and 5. RESULTS The serum GDF15 levels increased with advancing Fontaine class. Kaplan-Meier analysis revealed that the high-GDF15 group (≥ 2,275 pg/mL) had higher rates of all-cause deaths and thrombotic and bleeding events than the low-GDF15 group (＜2,275 pg/mL). Multivariate Cox proportional-hazards regression analysis revealed that GDF15 was an independent predictor of all-cause mortality and thrombotic and bleeding events after adjusting for confounding risk factors. When the ABC-AF-bleeding score was substituted for GDF15, similar results were obtained. CONCLUSION Serum GDF15 levels were associated with all-cause mortality and thrombotic and bleeding events in patients with LEAD. Serum GDF15 is a potentially useful marker of clinical outcomes, specifically for tracking thrombotic and bleeding events in patients with LEAD.
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Affiliation(s)
- Taku Shikama
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Yoichiro Otaki
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Tetsu Watanabe
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Harutoshi Tamura
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Shigehiko Kato
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Satoshi Nishiyama
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Hiroki Takahashi
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Takanori Arimoto
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Masafumi Watanabe
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
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11
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Chen R, Zhang H, Tang B, Luo Y, Yang Y, Zhong X, Chen S, Xu X, Huang S, Liu C. Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:130. [PMID: 38816371 PMCID: PMC11139930 DOI: 10.1038/s41392-024-01840-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 04/02/2024] [Accepted: 04/21/2024] [Indexed: 06/01/2024] Open
Abstract
The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate immune system, macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and severity of cardiovascular diseases, including coronary heart disease, valvular disease, myocarditis, cardiomyopathy, heart failure, atherosclerosis and aneurysm, which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific diseases. Besides, recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity, cell-cell interactions, and downstream mechanisms of therapeutic targets at a higher resolution, which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular diseases. Remarkably, myocardial fibrosis, a prevalent characteristic in most cardiac diseases, remains a formidable clinical challenge, necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac diseases. In this review, we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by single-cell sequencing technologies, with a focus on different causes and characteristics of diseases, especially the relationship between inflammation and fibrosis in cardiac diseases (myocardial infarction, pressure overload, myocarditis, dilated cardiomyopathy, diabetic cardiomyopathy and cardiac aging) and the relationship between inflammation and vascular injury in vascular diseases (atherosclerosis and aneurysm). Finally, we also highlight the preclinical/clinical macrophage targeting strategies and translational implications.
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Affiliation(s)
- Runkai Chen
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Hongrui Zhang
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Botao Tang
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Yukun Luo
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Yufei Yang
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Xin Zhong
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Sifei Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Xinjie Xu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
| | - Shengkang Huang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
| | - Canzhao Liu
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China.
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12
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Yeyeodu S, Hanafi D, Webb K, Laurie NA, Kimbro KS. Population-enriched innate immune variants may identify candidate gene targets at the intersection of cancer and cardio-metabolic disease. Front Endocrinol (Lausanne) 2024; 14:1286979. [PMID: 38577257 PMCID: PMC10991756 DOI: 10.3389/fendo.2023.1286979] [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: 09/01/2023] [Accepted: 12/07/2023] [Indexed: 04/06/2024] Open
Abstract
Both cancer and cardio-metabolic disease disparities exist among specific populations in the US. For example, African Americans experience the highest rates of breast and prostate cancer mortality and the highest incidence of obesity. Native and Hispanic Americans experience the highest rates of liver cancer mortality. At the same time, Pacific Islanders have the highest death rate attributed to type 2 diabetes (T2D), and Asian Americans experience the highest incidence of non-alcoholic fatty liver disease (NAFLD) and cancers induced by infectious agents. Notably, the pathologic progression of both cancer and cardio-metabolic diseases involves innate immunity and mechanisms of inflammation. Innate immunity in individuals is established through genetic inheritance and external stimuli to respond to environmental threats and stresses such as pathogen exposure. Further, individual genomes contain characteristic genetic markers associated with one or more geographic ancestries (ethnic groups), including protective innate immune genetic programming optimized for survival in their corresponding ancestral environment(s). This perspective explores evidence related to our working hypothesis that genetic variations in innate immune genes, particularly those that are commonly found but unevenly distributed between populations, are associated with disparities between populations in both cancer and cardio-metabolic diseases. Identifying conventional and unconventional innate immune genes that fit this profile may provide critical insights into the underlying mechanisms that connect these two families of complex diseases and offer novel targets for precision-based treatment of cancer and/or cardio-metabolic disease.
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Affiliation(s)
- Susan Yeyeodu
- Julius L Chambers Biomedical/Biotechnology Institute (JLC-BBRI), North Carolina Central University, Durham, NC, United States
- Charles River Discovery Services, Morrisville, NC, United States
| | - Donia Hanafi
- Julius L Chambers Biomedical/Biotechnology Institute (JLC-BBRI), North Carolina Central University, Durham, NC, United States
| | - Kenisha Webb
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Nikia A. Laurie
- Julius L Chambers Biomedical/Biotechnology Institute (JLC-BBRI), North Carolina Central University, Durham, NC, United States
| | - K. Sean Kimbro
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
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13
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Li B, Shaikh F, Zamzam A, Syed MH, Abdin R, Qadura M. A machine learning algorithm for peripheral artery disease prognosis using biomarker data. iScience 2024; 27:109081. [PMID: 38361633 PMCID: PMC10867451 DOI: 10.1016/j.isci.2024.109081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 01/11/2024] [Accepted: 01/26/2024] [Indexed: 02/17/2024] Open
Abstract
Peripheral artery disease (PAD) biomarkers have been studied in isolation; however, an algorithm that considers a protein panel to inform PAD prognosis may improve predictive accuracy. Biomarker-based prediction models were developed and evaluated using a model development (n = 270) and prospective validation cohort (n = 277). Plasma concentrations of 37 proteins were measured at baseline and the patients were followed for 2 years. The primary outcome was 2-year major adverse limb event (MALE; composite of vascular intervention or major amputation). Of the 37 proteins tested, 6 were differentially expressed in patients with vs. without PAD (ADAMTS13, ICAM-1, ANGPTL3, Alpha 1-microglobulin, GDF15, and endostatin). Using 10-fold cross-validation, we developed a random forest machine learning model that accurately predicts 2-year MALE in a prospective validation cohort of PAD patients using a 6-protein panel (AUROC 0.84). This algorithm can support PAD risk stratification, informing clinical decisions on further vascular evaluation and management.
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Affiliation(s)
- Ben Li
- Department of Surgery, University of Toronto, Toronto, ON, Canada
- Division of Vascular Surgery, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Temerty Centre for Artificial Intelligence Research and Education in Medicine (T-CAIREM), University of Toronto, Toronto, ON, Canada
| | - Farah Shaikh
- Division of Vascular Surgery, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
| | - Abdelrahman Zamzam
- Division of Vascular Surgery, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
| | - Muzammil H. Syed
- Division of Vascular Surgery, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
| | - Rawand Abdin
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Mohammad Qadura
- Department of Surgery, University of Toronto, Toronto, ON, Canada
- Division of Vascular Surgery, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
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14
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Vázquez-Carrera M. Is Helicobacter pylori a new kid on the block? CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ARTERIOSCLEROSIS 2024; 36:78-79. [PMID: 38402024 DOI: 10.1016/j.arteri.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/26/2024]
Affiliation(s)
- Manuel Vázquez-Carrera
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
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15
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Kiss LZ, Nyárády BB, Pállinger É, Lux Á, Jermendy ÁL, Csobay-Novák C, Soós P, Szelid Z, Láng O, Kőhidai L, Dinya E, Dósa E, Merkely B, Bagyura Z. Association of growth and differentiation factor-15 with coronary artery calcium score and ankle-brachial index in a middle-aged and elderly Caucasian population sample free of manifest cardiovascular disease. GeroScience 2024; 46:1343-1350. [PMID: 37548881 PMCID: PMC10828406 DOI: 10.1007/s11357-023-00899-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 07/30/2023] [Indexed: 08/08/2023] Open
Abstract
Growth and differentiation factor-15 (GDF-15) is a stress-associated cytokine of the transforming growth factor-β superfamily. The inflammatory and angiogenic effects of GDF-15 in atherosclerosis are controversial, and its correlation with the long asymptomatic phase of the disease is not well understood. Coronary artery calcium score (CACS) and ankle-brachial index (ABI) are sensitive markers of subclinical atherosclerosis. To date, only a few studies have examined the impact of GDF-15 on coronary artery calcification, and the association between GDF-15 and ABI has not been evaluated. Therefore, we aimed to investigate the possible relationship between serum GDF-15 concentrations and CACS and ABI in a Caucasian population sample of middle-aged (35-65 years) and elderly (> 65 years) people. In addition to recording demographic and anthropometric characteristics, atherosclerotic risk factors, and laboratory tests including serum HDL-cholesterol, LDL-cholesterol, hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein, and N-terminal pro-B-type natriuretic peptide (NT-proBNP); GDF-15 level, cardiac computed tomography, and ABI measurements were also performed. A total of 269 asymptomatic individuals (men, n = 125; median age, 61.5 [IQR, 12.7] years) formed the basis of this study. Participants were divided into two groups according to their age (middle-aged, n = 175 and elderly, n = 94). Hypertension and diabetes mellitus were significantly more prevalent and CACS values and HbA1c, NT-proBNP, and GDF-15 levels were significantly higher (all p < 0.001) in the elderly group compared to the middle-aged group. Multivariate ridge regression analysis revealed a significant positive association between GDF-15 and CACS (middle-aged group: β = 0.072, p = 0.333; elderly group: β = 0.148, p = 0.003), and between GDF-15 and ABI (middle-aged group: β = 0.062, p = 0.393; elderly group: β = 0.088, p = 0.041) only in the elderly group. Our results show that GDF-15 is not only a useful biomarker of inflammation but can also predict early signs of asymptomatic atherosclerosis, especially in elderly people with chronic systemic inflammation associated with aging (inflammaging).
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Affiliation(s)
- Loretta Zsuzsa Kiss
- Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, 1122, Budapest, Hungary.
| | - Balázs Bence Nyárády
- Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, 1122, Budapest, Hungary
| | - Éva Pállinger
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, 4 Nagyvárad Square, 1089, Budapest, Hungary
| | - Árpád Lux
- Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, 1122, Budapest, Hungary
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
| | - Ádám Levente Jermendy
- Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, 1122, Budapest, Hungary
| | - Csaba Csobay-Novák
- Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, 1122, Budapest, Hungary
| | - Pál Soós
- Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, 1122, Budapest, Hungary
| | - Zsolt Szelid
- Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, 1122, Budapest, Hungary
| | - Orsolya Láng
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, 4 Nagyvárad Square, 1089, Budapest, Hungary
| | - László Kőhidai
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, 4 Nagyvárad Square, 1089, Budapest, Hungary
| | - Elek Dinya
- Institute of Digital Health Sciences, Semmelweis University, 15 Ferenc Square, 1094, Budapest, Hungary
| | - Edit Dósa
- Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, 1122, Budapest, Hungary
| | - Béla Merkely
- Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, 1122, Budapest, Hungary
| | - Zsolt Bagyura
- Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, 1122, Budapest, Hungary
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16
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He Z, Luo J, Lv M, Li Q, Ke W, Niu X, Zhang Z. Characteristics and evaluation of atherosclerotic plaques: an overview of state-of-the-art techniques. Front Neurol 2023; 14:1159288. [PMID: 37900593 PMCID: PMC10603250 DOI: 10.3389/fneur.2023.1159288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 09/28/2023] [Indexed: 10/31/2023] Open
Abstract
Atherosclerosis is an important cause of cerebrovascular and cardiovascular disease (CVD). Lipid infiltration, inflammation, and altered vascular stress are the critical mechanisms that cause atherosclerotic plaque formation. The hallmarks of the progression of atherosclerosis include plaque ulceration, rupture, neovascularization, and intraplaque hemorrhage, all of which are closely associated with the occurrence of CVD. Assessing the severity of atherosclerosis and plaque vulnerability is crucial for the prevention and treatment of CVD. Integrating imaging techniques for evaluating the characteristics of atherosclerotic plaques with computer simulations yields insights into plaque inflammation levels, spatial morphology, and intravascular stress distribution, resulting in a more realistic and accurate estimation of plaque state. Here, we review the characteristics and advancing techniques used to analyze intracranial and extracranial atherosclerotic plaques to provide a comprehensive understanding of atheroma.
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Affiliation(s)
- Zhiwei He
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jiaying Luo
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mengna Lv
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qingwen Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Ke
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xuan Niu
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhaohui Zhang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
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17
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Luo J, He Z, Li Q, Lv M, Cai Y, Ke W, Niu X, Zhang Z. Adipokines in atherosclerosis: unraveling complex roles. Front Cardiovasc Med 2023; 10:1235953. [PMID: 37645520 PMCID: PMC10461402 DOI: 10.3389/fcvm.2023.1235953] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023] Open
Abstract
Adipokines are biologically active factors secreted by adipose tissue that act on local and distant tissues through autocrine, paracrine, and endocrine mechanisms. However, adipokines are believed to be involved in an increased risk of atherosclerosis. Classical adipokines include leptin, adiponectin, and ceramide, while newly identified adipokines include visceral adipose tissue-derived serpin, omentin, and asprosin. New evidence suggests that adipokines can play an essential role in atherosclerosis progression and regression. Here, we summarize the complex roles of various adipokines in atherosclerosis lesions. Representative protective adipokines include adiponectin and neuregulin 4; deteriorating adipokines include leptin, resistin, thrombospondin-1, and C1q/tumor necrosis factor-related protein 5; and adipokines with dual protective and deteriorating effects include C1q/tumor necrosis factor-related protein 1 and C1q/tumor necrosis factor-related protein 3; and adipose tissue-derived bioactive materials include sphingosine-1-phosphate, ceramide, and adipose tissue-derived exosomes. However, the role of a newly discovered adipokine, asprosin, in atherosclerosis remains unclear. This article reviews progress in the research on the effects of adipokines in atherosclerosis and how they may be regulated to halt its progression.
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Affiliation(s)
- Jiaying Luo
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhiwei He
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qingwen Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mengna Lv
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuli Cai
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Ke
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xuan Niu
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhaohui Zhang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
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18
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Ray N, Park SJ, Jung H, Kim J, Korcsmaros T, Moon Y. Stress-responsive Gdf15 counteracts renointestinal toxicity via autophagic and microbiota reprogramming. Commun Biol 2023; 6:602. [PMID: 37270567 DOI: 10.1038/s42003-023-04965-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 05/22/2023] [Indexed: 06/05/2023] Open
Abstract
The integrated stress response (ISR) plays a pivotal role in the cellular stress response, primarily through global translational arrest and the upregulation of cellular adaptation-linked molecules. Growth differentiation factor 15 (Gdf15) is a potent stress-responsive biomarker of clinical inflammatory and metabolic distress in various types of diseases. Herein, we assess whether ISR-driven cellular stress contributes to pathophysiological outcomes by modulating Gdf15. Clinical transcriptome analysis demonstrates that PKR is positively associated with Gdf15 expression in patients with renal injury. Gdf15 expression is dependent on protein kinase R (PKR)-linked ISR during acute renointestinal distress in mice and genetic ablation of Gdf15 aggravates chemical-induced lesions in renal tissues and the gut barrier. An in-depth evaluation of the gut microbiota indicates that Gdf15 is associated with the abundance of mucin metabolism-linked bacteria and their enzymes. Moreover, stress-responsive Gdf15 facilitates mucin production and cellular survival via the reorganization of the autophagy regulatory network. Collectively, ISR-activated Gdf15 counteracts pathological processes via the protective reprogramming of the autophagic network and microbial community, thereby providing robust predictive biomarkers and interventions against renointestinal distress.
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Affiliation(s)
- Navin Ray
- Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical Sciences, Pusan National University, Yangsan, Korea
| | - Seung Jun Park
- Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical Sciences, Pusan National University, Yangsan, Korea
| | - Hoyung Jung
- Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical Sciences, Pusan National University, Yangsan, Korea
| | - Juil Kim
- Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical Sciences, Pusan National University, Yangsan, Korea
| | - Tamas Korcsmaros
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, UK
- Earlham Institute, Norwich Research Park, Norwich, UK
- Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
| | - Yuseok Moon
- Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical Sciences, Pusan National University, Yangsan, Korea.
- Earlham Institute, Norwich Research Park, Norwich, UK.
- Graduate Program of Genomic Data Sciences, Pusan National University, Yangsan, Korea.
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19
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Shimizu Y, Hayashida N, Yamanashi H, Noguchi Y, Kawashiri SY, Takada M, Arima K, Nakamichi S, Nagata Y, Maeda T. Serum Concentration of Growth Differentiation Factor 15 and Atherosclerosis among General Older Japanese Individuals with Normal Weight. Biomedicines 2023; 11:1572. [PMID: 37371667 DOI: 10.3390/biomedicines11061572] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/24/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Growth differentiation factor 15 (GDF-15), which modulates cellular energy balance, is reported to be positively associated with cardiovascular disease. However, there have been no reports about the association between serum GDF-15 concentration and atherosclerosis as evaluated by carotid intima-media thickness (CIMT) among the general population. A cross-sectional study of 536 Japanese individuals aged 60 to 69 years was conducted. To avoid the influence of abnormal cellular energy balance, this study only included participants who had a normal body mass index (BMI) and normal thyroid hormone (free thyroxine and free triiodothyronine) levels. A significant positive association between serum GDF-15 concentration and atherosclerosis was observed. In the sex- and age-adjusted model (Model 1), the odds ratio (OR) (95% confidence interval (CI)) for the logarithmic value of GDF-15 and atherosclerosis was 2.62 (1.67, 5.87). This association remained after adjusting for thyroid function and renal function (Model 2) and further adjusting for known cardiovascular risk factors (Model 3). The corresponding values were 2.61 (1.15, 5.93) for Model 2 and 2.49 (1.08, 5.71) for Model 3, respectively. Serum GDF-15 concentrations could help us to estimate the risk of atherosclerosis by indicating the status of cellular energy balance, which is related to mitochondrial activity among comparative healthy older individuals.
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Affiliation(s)
- Yuji Shimizu
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
- Epidemiology Section, Division of Public Health, Osaka Institute of Public Health, Osaka 537-0025, Japan
| | - Naomi Hayashida
- Division of Strategic Collaborative Research, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 853-8523, Japan
| | - Hirotomo Yamanashi
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 853-8523, Japan
| | - Yuko Noguchi
- Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
| | - Shin-Ya Kawashiri
- Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
| | - Midori Takada
- Epidemiology Section, Division of Public Health, Osaka Institute of Public Health, Osaka 537-0025, Japan
| | - Kazuhiko Arima
- Department of Public Health, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
| | | | - Yasuhiro Nagata
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 853-8523, Japan
- Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
| | - Takahiro Maeda
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 853-8523, Japan
- Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
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20
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Cheng J, Lyu Y, Mei Y, Chen Q, Liu H, Li Y. Serum growth differentiation factor-15 and non-esterified fatty acid levels in patients with coronary artery disease and hyperuricemia. Lipids Health Dis 2023; 22:31. [PMID: 36864452 PMCID: PMC9979416 DOI: 10.1186/s12944-023-01792-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/20/2023] [Indexed: 03/04/2023] Open
Abstract
BACKGROUND High serum NEFA and GDF-15 are risk factors for CAD and have been linked to detrimental cardiovascular events. It has been hypothesized that hyperuricemia causes CAD via the oxidative metabolism and inflammation. The current study sought to clarify the relationship between serum GDF-15/NEFA and CAD in individuals with hyperuricemia. METHODS Blood samples collected from 350 male patients with hyperuricemia(191 patients without CAD and 159 patients with CAD, serum UA > 420 μmol/L) to measure serum GDF-15 and NEFA concentrations with baseline parameters. RESULTS Serum circulating GDF-15 concentrations(pg/dL) [8.48(6.67,12.73)] and NEFA levels(mmol/L) [0.45(0.32,0.60)] were higher in hyperuricemia patients with CAD. Logistic regression analysis revealed that the OR (95% CI) for CAD were 10.476 (4.158, 26.391) and 11.244 (4.740, 26.669) in quartile 4 (highest) respectively. The AUC of the combined serum GDF-15 and NEFA was 0.813 (0.767,0.858) as a predictor of whether CAD occurred in male with hyperuricemia. CONCLUSIONS Circulating GDF-15 and NEFA levels correlated positively with CAD in male patients with hyperuricemia and measurements may be a useful clinical adjunct.
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Affiliation(s)
- Jingru Cheng
- grid.412632.00000 0004 1758 2270Department of Clinical Laboratory,institute of translational medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yongnan Lyu
- grid.412632.00000 0004 1758 2270Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yufeng Mei
- grid.412632.00000 0004 1758 2270Department of Clinical Laboratory,institute of translational medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qian Chen
- grid.412632.00000 0004 1758 2270Department of Clinical Laboratory,institute of translational medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hang Liu
- grid.412632.00000 0004 1758 2270Department of Clinical Laboratory,institute of translational medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yan Li
- Department of Clinical Laboratory,institute of translational medicine, Renmin Hospital of Wuhan University, Wuhan, China.
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21
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Schwarz A, Kinscherf R, Bonaterra GA. Role of the Stress- and Inflammation-Induced Cytokine GDF-15 in Cardiovascular Diseases: From Basic Research to Clinical Relevance. Rev Cardiovasc Med 2023; 24:81. [PMID: 39077481 PMCID: PMC11264000 DOI: 10.31083/j.rcm2403081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/16/2023] [Accepted: 02/10/2023] [Indexed: 07/31/2024] Open
Abstract
Stress- and inflammation-induced growth differentiation factor-15 (GDF-15) is proposed as a biomarker for mortality and disease progression in patients with atherosclerosis and/or cardiovascular disease (CVD). The development of atherosclerotic lesions depends, among other factors, on inflammatory processes, oxidative stress, and impaired lipid homeostasis. As a consequence, activation and dysfunction of endothelial cells, release of chemokines, growth factors and lipid mediators occur. GDF-15 is suggested as an acute-phase modifier of transforming growth factor (TGF)-ßRII-dependent pro-inflammatory responses leading to rupture of atherosclerotic plaques, although the exact biological function is poorly understood to date. GDF-15 is upregulated in many disease processes, and its effects may be highly context-dependent. To date, it is unclear whether the upregulation of GDF-15 leads to disease progression or provides protection against disease. Concerning CVD, cardiomyocytes are already known to produce and release GDF-15 in response to angiotensin II stimulation, ischemia, and mechanical stretch. Cardiomyocytes, macrophages, vascular smooth muscle cells, endothelial cells, and adipocytes also release GDF-15 in response to oxidative as well as metabolic stress or stimulation with pro-inflammatory cytokines. Given the critically discussed pathophysiological and cellular functions and the important clinical significance of GDF-15 as a biomarker in CVD, we have summarized here the basic research findings on different cell types. In the context of cellular stress and inflammation, we further elucidated the signaling pathway of GDF-15 in coronary artery disease (CAD), the most common CVD in developing and industrial nations.
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Affiliation(s)
- Anja Schwarz
- Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Philipps-University of Marburg, 35037 Marburg, Germany
| | - Ralf Kinscherf
- Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Philipps-University of Marburg, 35037 Marburg, Germany
| | - Gabriel A. Bonaterra
- Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Philipps-University of Marburg, 35037 Marburg, Germany
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22
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Zhang J, He L, Wang Z, Shao S, Qiao P, Zhang J, Zhang K, Li C, Zhang Y, Wang G, Li M. Decreasing GDF15 Promotes Inflammatory Signals and Neutrophil Infiltration in Psoriasis Models. J Invest Dermatol 2023; 143:419-430.e8. [PMID: 36049542 DOI: 10.1016/j.jid.2022.07.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 11/26/2022]
Abstract
Psoriasis is driven by the interplay between hyperproliferative keratinocytes and infiltrating inflammatory cells. GDF15, a member of the TGF-β superfamily, has been implicated in cachexia, metabolic control, and cancer invasion. However, the expression and immunomodulatory role of GDF15 in inflammatory diseases has not been clarified. In this study, we report that GDF15 is decreased in the epidermis of patients with psoriasis and in an imiquimod-induced psoriasis-like mouse model. TNF-α suppresses GDF15 expression in keratinocytes by inhibiting the protein level of the transcription factor GATA2. GDF15 deficiency aggravates the development of psoriatic lesions, as evidenced by more severe skin inflammation in imiquimod-treated Gdf15-knockout (Gdf15‒/‒) mice compared with that in wild-type mice. Importantly, GDF15 limited the synthesis of a panel of keratinocyte cytokines and chemokines by inhibiting TAK1/NF-κB activation and directly inhibited neutrophil adhesion and migration by inhibiting the activation of the small GTPase Rap1. Epidermal hyperplasia, infiltration of neutrophils, and transcripts of psoriasis-related markers in imiquimod-induced psoriasiform dermatitis were significantly alleviated by a topical supplement of recombinant murine GDF15. In summary, our study revealed an unexpected role of GDF15 in keratinocyte and neutrophil function in the skin of psoriasis, implying its therapeutic potential in treating psoriasis.
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Affiliation(s)
- Jieyu Zhang
- The State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China; Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Lei He
- The State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Zhaowei Wang
- The State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Shuai Shao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Pei Qiao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jine Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Kuo Zhang
- The State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Caixia Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yingqi Zhang
- The State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China
| | - Gang Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Meng Li
- The State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
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23
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Liu H, Hallauer Hastings M, Kitchen R, Xiao C, Baldovino Guerra JR, Kuznetsov A, Rosenzweig A. Beneficial Effects of Moderate Hepatic Activin A Expression on Metabolic Pathways, Inflammation, and Atherosclerosis. Arterioscler Thromb Vasc Biol 2023; 43:330-349. [PMID: 36453275 DOI: 10.1161/atvbaha.122.318138] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
BACKGROUND Atherosclerosis is an inflammatory vascular disease marked by hyperlipidemia and hematopoietic stem cell expansion. Activin A, a member of the Activin/GDF/TGFβ/BMP (growth/differentiation factor/transforming growth factor beta/bone morphogenetic protein) family is broadly expressed and increases in human atherosclerosis, but its functional effects in vivo in this context remain unclear. METHODS We studied LDLR-/- mice on a Western diet for 12 weeks and used adeno-associated viral vectors with a liver-specific TBG (thyroxine-binding globulin) promoter to express Activin A or GFP (control). Atherosclerotic lesions were analyzed by oil red staining. Blood lipid profiling was performed by high-performance liquid chromatography, and immune cells were evaluated by flow cytometry. Liver RNA-sequencing was performed to explore the underlying mechanisms. RESULTS Activin A expression decreased in both livers and aortae from LDLR-/- mice fed a Western diet compared with standard laboratory diet. Adenoassociated virus-TBG-Activin A increased Activin A hepatic expression ≈10-fold at 12 weeks; P<0.001) and circulating Activin A levels ≈2000 pg/ml versus ≈50 pg/ml; P<0.001, compared with controls). Hepatic Activin A expression decreased plasma total and LDL (low-density lipoprotein) cholesterol ≈60% and ≈40%, respectively), reduced inflammatory cells in aortae and proliferating hematopoietic stem cells in bone marrow, and reduced atherosclerotic lesion and necrotic core area in aortae. Activin A also attenuated liver steatosis and expression of the lipogenesis genes, Srebp1 and Srebp2. RNA sequencing revealed Activin A not only blocked expression of genes involved in hepatic de novo lipogenesis but also fatty acid uptake and liver inflammation. In addition, Activin A expressed in the liver also reduced white fat tissue accumulation, decreased adipocyte size, and improved glucose tolerance. CONCLUSIONS Our studies reveal hepatic Activin A expression reduces inflammation, hematopoietic stem cell expansion, liver steatosis, circulating cholesterol, and fat accumulation, which likely all contribute to the observed protection against atherosclerosis. The reduced Activin A observed in LDLR-/- mice on a Western diet seems maladaptive and deleterious for atherogenesis.
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Affiliation(s)
- Huan Liu
- Cardiovascular Research Center, Massachusetts General Hospital, and Harvard Medical School, Boston
| | | | - Robert Kitchen
- Cardiovascular Research Center, Massachusetts General Hospital, and Harvard Medical School, Boston
| | - Chunyang Xiao
- Cardiovascular Research Center, Massachusetts General Hospital, and Harvard Medical School, Boston
| | | | - Alexandra Kuznetsov
- Cardiovascular Research Center, Massachusetts General Hospital, and Harvard Medical School, Boston
| | - Anthony Rosenzweig
- Cardiovascular Research Center, Massachusetts General Hospital, and Harvard Medical School, Boston
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24
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Reyes J, Yap GS. Emerging Roles of Growth Differentiation Factor 15 in Immunoregulation and Pathogenesis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:5-11. [PMID: 36542831 PMCID: PMC9779231 DOI: 10.4049/jimmunol.2200641] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 09/08/2022] [Indexed: 12/24/2022]
Abstract
Growth differentiation factor 15 (GDF-15) is a cytokine that is widely used as a biomarker for the severity of diverse disease states. It also has been shown to play a protective role after tissue injury and to promote a negative energy balance during obesity and diabetes. In addition to its metabolic effects, GDF-15 also regulates the host's immune responses to infectious and noninfectious diseases. GDF-15 can suppress a type 1 and, in contrast, promote a type 2 inflammatory response. In this brief review, we discuss how GDF-15 affects the effector function and recruitment of immune cells, the pathways that induce its expression, and the diverse mechanisms by which it is regulated during inflammation and infection. We further highlight outstanding questions that should be the focus of future investigations in this emerging field.
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Affiliation(s)
- Jojo Reyes
- Department of Medicine and Center for Immunity and Inflammation, New Jersey Medical School, Rutgers University, Newark, NJ 07101
| | - George S. Yap
- Department of Medicine and Center for Immunity and Inflammation, New Jersey Medical School, Rutgers University, Newark, NJ 07101
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25
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Al‐kuraishy HM, Al‐Gareeb AI, Alexiou A, Papadakis M, Nadwa EH, Albogami SM, Alorabi M, Saad HM, Batiha GE. Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure. J Diabetes 2022; 14:806-814. [PMID: 36444166 PMCID: PMC9789395 DOI: 10.1111/1753-0407.13334] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/03/2022] [Accepted: 11/03/2022] [Indexed: 11/30/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic endocrine disorder due to the reduction of insulin sensitivity and relative deficiency of insulin secretion. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor beta (TGF-β) superfamily and was initially identified as macrophage inhibitory cytokine-1 (MIC-1). GDF15 is considered a cytokine with an anti-inflammatory effect and increases insulin sensitivity, reduces body weight, and improves clinical outcomes in diabetic patients. GDF15 acts through stimulation of glial-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), which is highly expressed in the brain stem to induce taste aversion. Metformin belongs to the group of biguanides that are derived from the plant Galega officinalis. It is interesting to note that metformin is an insulin-sensitizing agent used as a first-line therapy for T2DM that has been shown to increase the circulating level of GDF15. Thus, the present review aims to determine the critical association of the GDF15 biomarker in T2DM and how metformin agents affect it. This review illustrates that metformin activates GDF15 expression, which reduces appetite and leads to weight loss in both diabetic and nondiabetic patients. However, the present review cannot give a conclusion in this regard. Therefore, experimental, preclinical, and clinical studies are warranted to confirm the potential role of GDF15 in T2DM patients.
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Affiliation(s)
- Hayder M. Al‐kuraishy
- Department of Clinical Pharmacology and Medicine, College of MedicineAL‐Mustansiriyah UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Clinical Pharmacology and Medicine, College of MedicineAL‐Mustansiriyah UniversityBaghdadIraq
| | - Athanasios Alexiou
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamAustralia
- AFNP MedWienAustria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten‐Herdecke, Heusnerstrasse 40WuppertalGermany
| | - Eman Hassan Nadwa
- Department of Pharmacology and TherapeuticsCollege of Medicine, Jouf UniversitySakakahSaudi Arabia
- Department of Medical Pharmacology, Faculty of MedicineCairo UniversityGizaEgypt
| | - Sarah M. Albogami
- Department of BiotechnologyCollege of Science, Taif UniversityTaifSaudi Arabia
| | - Mohammed Alorabi
- Department of BiotechnologyCollege of Science, Taif UniversityTaifSaudi Arabia
| | - Hebatallah M. Saad
- Department of Pathology, Faculty of Veterinary MedicineMatrouh UniversityMarsa MatruhEgypt
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhour UniversityDamanhourEgypt
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26
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Pazzaglia S, Eidemüller M, Lumniczky K, Mancuso M, Ramadan R, Stolarczyk L, Moertl S. Out-of-field effects: lessons learned from partial body exposure. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2022; 61:485-504. [PMID: 36001144 PMCID: PMC9722818 DOI: 10.1007/s00411-022-00988-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 08/03/2022] [Indexed: 05/27/2023]
Abstract
Partial body exposure and inhomogeneous dose delivery are features of the majority of medical and occupational exposure situations. However, mounting evidence indicates that the effects of partial body exposure are not limited to the irradiated area but also have systemic effects that are propagated outside the irradiated field. It was the aim of the "Partial body exposure" session within the MELODI workshop 2020 to discuss recent developments and insights into this field by covering clinical, epidemiological, dosimetric as well as mechanistic aspects. Especially the impact of out-of-field effects on dysfunctions of immune cells, cardiovascular diseases and effects on the brain were debated. The presentations at the workshop acknowledged the relevance of out-of-field effects as components of the cellular and organismal radiation response. Furthermore, their importance for the understanding of radiation-induced pathologies, for the discovery of early disease biomarkers and for the identification of high-risk organs after inhomogeneous exposure was emphasized. With the rapid advancement of clinical treatment modalities, including new dose rates and distributions a better understanding of individual health risk is urgently needed. To achieve this, a deeper mechanistic understanding of out-of-field effects in close connection to improved modelling was suggested as priorities for future research. This will support the amelioration of risk models and the personalization of risk assessments for cancer and non-cancer effects after partial body irradiation.
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Affiliation(s)
- S. Pazzaglia
- Laboratory of Biomedical Technologies, ENEA CR-Casaccia, Via Anguillarese 301, 00123 Rome, Italy
| | - M. Eidemüller
- Institute of Radiation Medicine, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - K. Lumniczky
- Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, National Public Health Centre, Albert Florian u. 2-6, 1097 Budapest, Hungary
| | - M. Mancuso
- Laboratory of Biomedical Technologies, ENEA CR-Casaccia, Via Anguillarese 301, 00123 Rome, Italy
| | - R. Ramadan
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - L. Stolarczyk
- Danish Centre for Particle Therapy, Palle Juul-Jensens Boulevard 25, 8200 Aarhus N, Denmark
| | - S. Moertl
- Federal Office for Radiation Protection, Ingolstädter Landstr. 1, 85764 Oberschleißheim, Germany
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27
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Mei Y, Lyu Y, Le J, Li D, Liu H, Zhao Z, Li Y. Raised circulating soluble growth differentiation factor 15 is negatively associated with testosterone level in hypogonadic men with type 2 diabetes. Diabetes Metab Res Rev 2022; 38:e3564. [PMID: 35801986 DOI: 10.1002/dmrr.3564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 04/11/2022] [Accepted: 07/01/2022] [Indexed: 11/10/2022]
Abstract
AIMS Epidemiological studies consistently show that decreases in serum testosterone level are observed more frequently in men with type 2 diabetes mellitus (T2DM), while clinical investigations have demonstrated that an increased level of circulating growth differentiation factor-15 (GDF-15) are also related closely to T2DM. The aim of this study was to examine the potential relationship between serum GDF-15 levels and hypogonadism in Chinese male patients with T2DM. MATERIALS AND METHODS A total of 305 T2DM men were recruited between July 2020 and August 2021. GDF-15 and total testosterone concentrations were quantified by an enzyme-linked immunosorbent assay and LC/MS mass spectrometry, respectively. Multiple linear regression analysis, logistic regression, and restricted cubic splined models were used to examine the correlation between GDF-15 levels and hypogonadism in these patients. RESULTS When compared with T2DM patients without hypogonadism circulating GDF-15 levels were significantly higher in the hypogonadism group [1081.83 (746.79,1539.94) versus 779.49 (548.46,1001.27), p < 0.001] and were associated positively with hypogonadism in unadjusted and fully adjusted multivariate regression models (p < 0.01). The fully adjusted regression coefficients with 95% confidence intervals for circulating GDF-15 and testosterone deficiency were -1.795 (-2.929, -0.661). Serum GDF-15 levels were also associated positively with testosterone deficiency in each logistic regression model (p < 0.05), while after adjustment for all risk factors, the same findings were obtained in the restricted cubic splined models (p < 0.01). CONCLUSIONS In hypogonadal men with T2DM, an elevated serum GDF-15 level is associated negatively with serum testosterone concentration. GDF-15 may be a novel cytokine related to T2DM men with hypogonadism.
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Affiliation(s)
- Yufeng Mei
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yongnan Lyu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Juan Le
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Di Li
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hang Liu
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhiming Zhao
- Department of Geratology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yan Li
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
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28
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Fiorucci S, Urbani G. GDF15 in Vascular and Liver Metabolic Disorders: A Novel Therapeutic Target. RECENT ADVANCES IN INFLAMMATION & ALLERGY DRUG DISCOVERY 2022; 16:55-59. [PMID: 36578252 DOI: 10.2174/277227081602221221113442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 11/30/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy
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29
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Radwanska A, Cottage CT, Piras A, Overed-Sayer C, Sihlbom C, Budida R, Wrench C, Connor J, Monkley S, Hazon P, Schluter H, Thomas MJ, Hogaboam CM, Murray LA. Increased expression and accumulation of GDF15 in IPF extracellular matrix contribute to fibrosis. JCI Insight 2022; 7:153058. [PMID: 35993367 PMCID: PMC9462497 DOI: 10.1172/jci.insight.153058] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 07/15/2022] [Indexed: 11/17/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unmet medical need. It is characterized by formation of scar tissue leading to a progressive and irreversible decline in lung function. IPF is associated with repeated injury, which may alter the composition of the extracellular matrix (ECM). Here, we demonstrate that IPF patient–derived pulmonary ECM drives profibrotic response in normal human lung fibroblasts (NHLF) in a 3D spheroid assay. Next, we reveal distinct alterations in composition of the diseased ECM, identifying potentially novel associations with IPF. Growth differentiation factor 15 (GDF15) was identified among the most significantly upregulated proteins in the IPF lung–derived ECM. In vivo, GDF15 neutralization in a bleomycin-induced lung fibrosis model led to significantly less fibrosis. In vitro, recombinant GDF15 (rGDF15) stimulated α smooth muscle actin (αSMA) expression in NHLF, and this was mediated by the activin receptor-like kinase 5 (ALK5) receptor. Furthermore, in the presence of rGDF15, the migration of NHLF in collagen gel was reduced. In addition, we observed a cell type–dependent effect of GDF15 on the expression of cell senescence markers. Our data suggest that GDF15 mediates lung fibrosis through fibroblast activation and differentiation, implicating a potential direct role of this matrix-associated cytokine in promoting aberrant cell responses in disease.
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Affiliation(s)
- Agata Radwanska
- Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Christopher Travis Cottage
- Bioscience COPD/IPF, Research and Early Development, R&I, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Antonio Piras
- Bioscience In Vivo, Research and Early Development, R&I, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Catherine Overed-Sayer
- Bioscience COPD/IPF, Research and Early Development, R&I, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Carina Sihlbom
- Proteomics Core Facility of Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Ramachandramouli Budida
- Translational Science and Experimental Medicine, Research and Early Development, R&I, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Catherine Wrench
- Bioscience COPD/IPF, Research and Early Development, R&I, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Jane Connor
- Bioscience COPD/IPF, Research and Early Development, R&I, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Susan Monkley
- Translational Science and Experimental Medicine, Research and Early Development, R&I, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Petra Hazon
- Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Holger Schluter
- Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Matthew J. Thomas
- Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | | | - Lynne A. Murray
- Bioscience COPD/IPF, Research and Early Development, R&I, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
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Cao M, Gu L, Guo L, Liu M, Wang T, Zhang J, Zhang H, Zhang Y, Shi Y, Zhao Y, Qiu X, Gui X, Ma M, Tian Y, Liu X, Meng F, Xiao Y, Sun L. Elevated Expression of Growth Differentiation Factor-15 Is Associated With Acute Exacerbation of Idiopathic Pulmonary Fibrosis. Front Immunol 2022; 13:891448. [PMID: 35784345 PMCID: PMC9241490 DOI: 10.3389/fimmu.2022.891448] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/04/2022] [Indexed: 11/13/2022] Open
Abstract
Backgrounds Growth differentiation factor 15 (GDF-15) is a highly divergent member of the TGF-β superfamily and has been implicated in various biological functions. However, the expression of GDF-15 in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is unclear. Method The study included 47 AE-IPF patients, 61 stable IPF (S-IPF) subjects, and 31 healthy controls (HCs). Serum GDF-15 levels and their expression in the lung were measured. The correlation between serum GDF-15 and other clinical parameters and the risk factors for AE occurrence and the survival of IPF patients were analyzed. Results Serum GDF-15 levels were significantly elevated in AE-IPF patients (1279.22 ± 540.02 pg/ml) as compared with HCs (891.30 ± 479.90 pg/ml) or S-IPF subjects (107.82 ± 14.21 pg/ml) (both p < 0.001). The protein and mRNA expressions of GDF-15 in the lung of AE-IPF patients were significantly increased as compared with S-IPF cases (p = 0.007 and p = 0.026, respectively). The serum GDF-15 level was correlated with the clinical variables of inflammation, metabolism, and disease severity in IPF subjects (all p < 0.05). The GDF-15 serum concentration was significantly higher in decedents than in survivors (p = 0.005). A serum GDF-15 level above 989.3 pg/ml was a risk factor for AE occurrence (p = 0.04), and the level above 1,075.76 pg/ml was an independent predictor for survival in IPF cases (p = 0.007). Conclusions The GDF-15 level was significantly elevated in subjects with AE-IPF. GDF-15 could be a promising biomarker for AE occurrence and survival in IPF patients.
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Affiliation(s)
- Mengshu Cao
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Lina Gu
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lili Guo
- Department of Clinical Laboratory, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Mengying Liu
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Tianzhen Wang
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Ji Zhang
- Wuxi Transplant Center, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Huizhe Zhang
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yufeng Zhang
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yanchen Shi
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yichao Zhao
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaohua Qiu
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xianhua Gui
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Miao Ma
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yaqiong Tian
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiaoqin Liu
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Fanqing Meng
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Lingyun Sun, ; Yonglong Xiao, ; Fanqing Meng,
| | - Yonglong Xiao
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Lingyun Sun, ; Yonglong Xiao, ; Fanqing Meng,
| | - Lingyun Sun
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Lingyun Sun, ; Yonglong Xiao, ; Fanqing Meng,
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Omran F, Kyrou I, Osman F, Lim VG, Randeva HS, Chatha K. Cardiovascular Biomarkers: Lessons of the Past and Prospects for the Future. Int J Mol Sci 2022; 23:5680. [PMID: 35628490 PMCID: PMC9143441 DOI: 10.3390/ijms23105680] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs) are a major healthcare burden on the population worldwide. Early detection of this disease is important in prevention and treatment to minimise morbidity and mortality. Biomarkers are a critical tool to either diagnose, screen, or provide prognostic information for pathological conditions. This review discusses the historical cardiac biomarkers used to detect these conditions, discussing their application and their limitations. Identification of new biomarkers have since replaced these and are now in use in routine clinical practice, but still do not detect all disease. Future cardiac biomarkers are showing promise in early studies, but further studies are required to show their value in improving detection of CVD above the current biomarkers. Additionally, the analytical platforms that would allow them to be adopted in healthcare are yet to be established. There is also the need to identify whether these biomarkers can be used for diagnostic, prognostic, or screening purposes, which will impact their implementation in routine clinical practice.
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Affiliation(s)
- Farah Omran
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Clinical Sciences Research Laboratories, University Hospitals Coventry and Warwickshire, Coventry CV2 2DX, UK
| | - Ioannis Kyrou
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Centre of Applied Biological & Exercise Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry CV1 5FB, UK
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
| | - Faizel Osman
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Department of Cardiology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Ven Gee Lim
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Department of Cardiology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Harpal Singh Randeva
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Clinical Sciences Research Laboratories, University Hospitals Coventry and Warwickshire, Coventry CV2 2DX, UK
| | - Kamaljit Chatha
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Biochemistry and Immunology Department, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
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Evans BR, Yerly A, van der Vorst EPC, Baumgartner I, Bernhard SM, Schindewolf M, Döring Y. Inflammatory Mediators in Atherosclerotic Vascular Remodeling. Front Cardiovasc Med 2022; 9:868934. [PMID: 35600479 PMCID: PMC9114307 DOI: 10.3389/fcvm.2022.868934] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 04/11/2022] [Indexed: 12/23/2022] Open
Abstract
Atherosclerotic vascular disease remains the most common cause of ischemia, myocardial infarction, and stroke. Vascular function is determined by structural and functional properties of the arterial vessel wall, which consists of three layers, namely the adventitia, media, and intima. Key cells in shaping the vascular wall architecture and warranting proper vessel function are vascular smooth muscle cells in the arterial media and endothelial cells lining the intima. Pathological alterations of this vessel wall architecture called vascular remodeling can lead to insufficient vascular function and subsequent ischemia and organ damage. One major pathomechanism driving this detrimental vascular remodeling is atherosclerosis, which is initiated by endothelial dysfunction allowing the accumulation of intimal lipids and leukocytes. Inflammatory mediators such as cytokines, chemokines, and modified lipids further drive vascular remodeling ultimately leading to thrombus formation and/or vessel occlusion which can cause major cardiovascular events. Although it is clear that vascular wall remodeling is an elementary mechanism of atherosclerotic vascular disease, the diverse underlying pathomechanisms and its consequences are still insufficiently understood.
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Affiliation(s)
- Bryce R. Evans
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Anaïs Yerly
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Emiel P. C. van der Vorst
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- Institute for Molecular Cardiovascular Research (IMCAR) and Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Iris Baumgartner
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Sarah Maike Bernhard
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Marc Schindewolf
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Yvonne Döring
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- *Correspondence: Yvonne Döring
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Conte M, Giuliani C, Chiariello A, Iannuzzi V, Franceschi C, Salvioli S. GDF15, an emerging key player in human aging. Ageing Res Rev 2022; 75:101569. [PMID: 35051643 DOI: 10.1016/j.arr.2022.101569] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 01/14/2022] [Indexed: 12/20/2022]
Abstract
Growth differentiation factor 15 (GDF15) is recently emerging not only as a stress-related mitokine, but also as a key player in the aging process, being one of the most up-regulated protein with age and associated with a variety of age-related diseases (ARDs). Many data indicate that GDF15 has protective roles in several tissues during different stress and aging, thus playing a beneficial role in apparent contrast with the observed association with many ARDs. A possible detrimental role for this protein is then hypothesized to emerge with age. Therefore, GDF15 can be considered as a pleiotropic factor with beneficial activities that can turn detrimental in old age possibly when it is chronically elevated. In this review, we summarize the current knowledge on the biology of GDF15 during aging. We also propose GDF15 as a part of a dormancy program, where it may play a role as a mediator of defense processes aimed to protect from inflammatory damage and other stresses, according to the life history theory.
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Affiliation(s)
- Maria Conte
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy; Interdepartmental Centre "Alma Mater Research Institute on Global Challenges and Climate Change (Alma Climate)", University of Bologna, Bologna, Italy.
| | - Cristina Giuliani
- Interdepartmental Centre "Alma Mater Research Institute on Global Challenges and Climate Change (Alma Climate)", University of Bologna, Bologna, Italy; Laboratory of Molecular Anthropology & Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy
| | - Antonio Chiariello
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Vincenzo Iannuzzi
- Laboratory of Molecular Anthropology & Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy
| | - Claudio Franceschi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy; Institute of Information Technologies, Mathematics and Mechanics, Lobachevsky University, Nizhniy Novgorod, Russia
| | - Stefano Salvioli
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy; Interdepartmental Centre "Alma Mater Research Institute on Global Challenges and Climate Change (Alma Climate)", University of Bologna, Bologna, Italy
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Patel AR, Frikke-Schmidt H, Bezy O, Sabatini PV, Rittig N, Jessen N, Myers MG, Seeley RJ. LPS induces rapid increase in GDF15 levels in mice, rats, and humans but is not required for anorexia in mice. Am J Physiol Gastrointest Liver Physiol 2022; 322:G247-G255. [PMID: 34935522 PMCID: PMC8799390 DOI: 10.1152/ajpgi.00146.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Growth differentiation factor 15 (GDF15), a TGFβ superfamily cytokine, acts through its receptor, cell line-derived neurotrophic factorfamily receptor α-like (GFRAL), to suppress food intake and promote nausea. GDF15 is broadly expressed at low levels but increases in states of disease such as cancer, cachexia, and sepsis. Whether GDF15 is necessary for inducing sepsis-associated anorexia and body weight loss is currently unclear. To test this we used a model of moderate systemic infection in GDF15KO and GFRALKO mice with lipopolysaccharide (LPS) treatment to define the role of GDF15 signaling in infection-mediated physiologic responses. Since physiological responses to LPS depend on housing temperature, we tested the effects of subthermoneutral and thermoneutral conditions on eliciting anorexia and inducing GDF15. Our data demonstrate a conserved LPS-mediated increase in circulating GDF15 levels in mouse, rat, and human. However, we did not detect differences in LPS-induced anorexia between WT and GDF15KO or GFRALKO mice. Furthermore, there were no differences in anorexia or circulating GDF15 levels at either thermoneutral or subthermoneutral housing conditions in LPS-treated mice. These data demonstrate that GDF15 is not necessary to drive food intake suppression in response to moderate doses of LPS.NEW & NOTEWORTHY Although many responses to LPS depend on housing temperature, the anorexic response to LPS does not. LPS results in a potent and rapid increase in circulating levels of GDF15 in mice, rats, and humans. Nevertheless, GDF15 and its receptor (GFRAL) are not required for the anorexic response to systemic LPS administration. The anorexic response to LPS likely involves a myriad of complex physiological alterations.
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Affiliation(s)
- Anita R Patel
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan.,Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | | | - Olivier Bezy
- Was Internal Medicine Research Unit, Pfizer Inc., Cambridge, Massachusetts
| | - Paul V Sabatini
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Nikolaj Rittig
- Department of Diabetes and Hormone Diseases, Aarhus University Hospital, Aarhus, Denmark.,Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Jessen
- Department of Diabetes and Hormone Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Martin G Myers
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, Michigan.,Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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Oller-Rodríguez JE, Vicens Bernabeu E, Gonzalez-Mazarío R, Grau García E, Ortiz Sanjuan FM, Román Ivorra JA. Utility of cytokines CXCL4, CXCL8 and GDF15 as biomarkers in systemic sclerosis. Med Clin (Barc) 2022; 159:359-365. [PMID: 35039167 DOI: 10.1016/j.medcli.2021.12.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 11/25/2021] [Accepted: 12/03/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVES Systemic sclerosis (SSc) is an autoinmune disease that can affect several organs and its mortality is fundamentally related to its pulmonary involvement. There are some cytokines with high serum levels of patients with SSc. Our goal is to determine the role of CXCL4, CXCL8 and GDF15 in the physiopathology of SSc and whether they can be considered organic damage biomarkers. PATIENTS AND METHODS Observational case-control study of SSc patients (ACR/EULAR 2013 criteria). Demographic, clinical, analytical, activity, severity, health perception, and disability variables were collected. Moreover, Videocapillaroscopy, Echocardiography and Respiratory Function Test were made. Serum levels of CXCL4, CXCL8 and GDF15 were measured both in SSc patients and in healthy controls. RESULTS A total of 42 patients were included (95.4% women), with an average age of 59.2 years and a median of 4 years from diagnosis. We also included 42 healthy controls. We found significantly higher levels of GDF15 in SSc patients than in controls (p<0.001), but no higher CXCL4 or CXCL8 levels. GDF15 was associated with Diffuse SSc, pulmonary arterial hypertension, interstitial lung disease, less forced vital capacity, high titles of antiScl70, disease activity, and dilated loops in capillaroscopy. CXCL4 levels were associated to a higher Rodnan punctuation, while CXCL8 was associated to C4 fraction consumption and tortuosities in capillaroscopy. CONCLUSIONS GDF15 high levels were associated with diffuse SSc, lung impairment, disease activity and changes in capillaroscopy. Moreover, CXCL4 was only associated with skin impairment, while CXCL8 was not related to organic damage.
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Affiliation(s)
- José E Oller-Rodríguez
- Servicio de Reumatología, Hospital UyP La Fe, Valencia, Spain; Escuela de Doctorado. Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain.
| | | | | | | | | | - José A Román Ivorra
- Servicio de Reumatología, Hospital UyP La Fe, Valencia, Spain; Escuela de Doctorado. Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain
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Xiao QA, He Q, Zeng J, Xia X. GDF-15, a future therapeutic target of glucolipid metabolic disorders and cardiovascular disease. Biomed Pharmacother 2021; 146:112582. [PMID: 34959119 DOI: 10.1016/j.biopha.2021.112582] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/19/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022] Open
Abstract
Growth and differentiation factor 15 (GDF-15) was discovered as a member of the transforming growth factor β (TGF-β) superfamily and the serum level of GDF-15 was significantly correlated with glucolipid metabolic disorders (GLMD) and cardiovascular diseases. In 2017, a novel identified receptor of GDF-15-glial-derived neurotrophic factor receptor alpha-like (GFRAL) was found to regulate energy homeostasis (such as obesity, diabetes and non-alcoholic fatty liver disease (NAFLD)). The function of GDF-15/GFRAL in suppressing appetite, enhancing glucose/lipid metabolism and vascular remodeling has been gradually revealed. These effects make it a potential therapeutic target for GLMD and vascular diseases. In this narrative review, we included and reviewed 121 articles by screening 524 articles from literature database. We primarily focused on the function of GDF-15 and its role in GLMD/cardiovascular diseases and discuss its potential clinical application.
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Affiliation(s)
- Qing-Ao Xiao
- Department of Endocrinology, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang 443000, China; Third-Grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang 443002, China
| | - Qian He
- Department of Geriatrics, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang 443000, China
| | - Jun Zeng
- Department of Endocrinology, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang 443000, China.
| | - Xuan Xia
- Third-Grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang 443002, China; Department of Physiology and Pathophysiology, Medical College, China Three Gorges University, Yichang 443002, China.
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Negishi K, Hoshide S, Shimpo M, Kanegae H, Kario K. Growth Differentiation Factor-15 Predicts Death and Stroke Event in Outpatients With Cardiovascular Risk Factors: The J-HOP Study. J Am Heart Assoc 2021; 10:e022601. [PMID: 34889104 PMCID: PMC9075247 DOI: 10.1161/jaha.121.022601] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background Growth differentiation factor-15 (GDF-15) has emerged as a novel biomarker to predict all-cause death in community-dwelling individuals and patients with cardiovascular disease. We evaluated the prognostic value of GDF-15 in outpatients with cardiovascular risk factors. Methods and Results GDF-15 levels were measured in 3562 outpatients with cardiovascular risk factors in the J-HOP (Japan Morning Surge-Home Blood Pressure) study, a nationwide prospective study. Participants were stratified according to tertiles of GDF-15 and followed up for all-cause death and cardiovascular disease. During a mean follow-up period of 6.6 years, there were 155 all-cause deaths, 81 stroke events including cerebral infarction and intracranial hemorrhage, and 141 cardiac events including cardiac artery disease and heart failure. Patients with higher GDF-15 levels were associated with risks of all-cause death and stroke events (except for cardiac events) after adjustment for traditional risk factors and other prognostic biomarkers (NT-proBNP [N-terminal pro-B-type natriuretic peptide], high-sensitivity troponin T; all-cause death, hazard ratio, 2.38; 95% CI, 1.26-4.48; P=0.007; stroke events, hazard ratio, 2.93; 95% CI, 1.31-6.56, P=0.009; compared with the lowest tertile). Furthermore, incorporating GDF-15 to the predictive models for all-cause death improved discrimination and reclassification significantly. For stroke events, GDF-15 showed similar diagnostic accuracy to NT-proBNP and high-sensitivity troponin T. Conclusions In Japanese outpatients with cardiovascular risk factors, GDF-15 improves risk stratification for all-cause death when compared with NT-proBNP and high-sensitivity troponin T. GDF-15 was associated with increased risks of stroke events beyond conventional risk factors and other prognostic markers; however, the predictive ability for stroke events was equivalent to NT-proBNP and high-sensitivity troponin T. Registration URL: http://www.umin.ac.jp/ctr.; Unique identifier: UMIN000000894.
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Affiliation(s)
- Keita Negishi
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University Tochigi Japan
| | - Satoshi Hoshide
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University Tochigi Japan
| | - Masahisa Shimpo
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University Tochigi Japan
| | - Hiroshi Kanegae
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University Tochigi Japan.,Genki Plaza Medical Center for Health Care Tokyo Japan
| | - Kazuomi Kario
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University Tochigi Japan
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Sen T, Li J, Neuen BL, Arnott C, Neal B, Perkovic V, Mahaffey KW, Shaw W, Canovatchel W, Hansen MK, Heerspink HJL. Association Between Circulating GDF-15 and Cardio-Renal Outcomes and Effect of Canagliflozin: Results From the CANVAS Trial. J Am Heart Assoc 2021; 10:e021661. [PMID: 34854308 PMCID: PMC9075362 DOI: 10.1161/jaha.121.021661] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Background Studies have suggested that sodium glucose co‐transporter 2 inhibitors exert anti‐inflammatory effects. We examined the association of baseline growth differentiation factor‐15 (GDF‐15), a marker of inflammation and cellular injury, with cardiovascular events, hospitalization for heart failure (HF), and kidney outcomes in patients with type 2 diabetes in the CANVAS (Canagliflozin Cardiovascular Assessment Study) and determined the effect of the sodium glucose co‐transporter 2 inhibitor canagliflozin on circulating GDF‐15. Methods and Results The CANVAS trial randomized 4330 people with type 2 diabetes at high cardiovascular risk to canagliflozin or placebo. The association between baseline GDF‐15 and cardiovascular (non‐fatal myocardial infarction, non‐fatal stroke, cardiovascular death), HF, and kidney (40% estimated glomerular filtration rate decline, end‐stage kidney disease, renal death) outcomes was assessed using multivariable adjusted Cox regression models. During median follow‐up of 6.1 years (N=3549 participants with available samples), 555 cardiovascular, 129 HF, and 137 kidney outcomes occurred. Each doubling in baseline GDF‐15 was significantly associated with a higher risk of cardiovascular (hazard ratio [HR], 1.2; 95% CI, 1.0‒1.3), HF (HR, 1.5; 95% CI, 1.2‒2.0) and kidney (HR, 1.5; 95% CI, 1.2‒2.0) outcomes. Baseline GDF‐15 did not modify canagliflozin’s effect on cardiovascular, HF, and kidney outcomes. Canaglifozin treatment modestly lowered GDF‐15 compared with placebo; however, GDF‐15 did not mediate the protective effect of canagliflozin on cardiovascular, HF, or kidney outcomes. Conclusions In patients with type 2 diabetes at high cardiovascular risk, higher GDF‐15 levels were associated with a higher risk of cardiovascular, HF, and kidney outcomes. Canagliflozin modestly lowered GDF‐15, but GDF‐15 reduction did not mediate the protective effect of canagliflozin.
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Affiliation(s)
- Taha Sen
- Department of Clinical Pharmacy and PharmacologyUniversity of GroningenThe Netherlands
| | - Jingwei Li
- The George Institute for Global HealthUNSW SydneySydneyAustralia
| | - Brendon L. Neuen
- The George Institute for Global HealthUNSW SydneySydneyAustralia
| | - Clare Arnott
- The George Institute for Global HealthUNSW SydneySydneyAustralia
| | - Bruce Neal
- The George Institute for Global HealthUNSW SydneySydneyAustralia
| | - Vlado Perkovic
- The George Institute for Global HealthUNSW SydneySydneyAustralia
| | - Kenneth W. Mahaffey
- Department of MedicineStanford Center for Clinical ResearchStanford University School of MedicineStanfordCA
| | - Wayne Shaw
- Janssen Research & Development, LLCRaritanNJ
| | | | | | - Hiddo J. L. Heerspink
- Department of Clinical Pharmacy and PharmacologyUniversity of GroningenThe Netherlands
- The George Institute for Global HealthUNSW SydneySydneyAustralia
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Farahi L, Sinha SK, Lusis AJ. Roles of Macrophages in Atherogenesis. Front Pharmacol 2021; 12:785220. [PMID: 34899348 PMCID: PMC8660976 DOI: 10.3389/fphar.2021.785220] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/04/2021] [Indexed: 12/18/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disease that may ultimately lead to local proteolysis, plaque rupture, and thrombotic vascular disease, resulting in myocardial infarction, stroke, and sudden cardiac death. Circulating monocytes are recruited to the arterial wall in response to inflammatory insults and differentiate into macrophages which make a critical contribution to tissue damage, wound healing, and also regression of atherosclerotic lesions. Within plaques, macrophages take up aggregated lipoproteins which have entered the vessel wall to give rise to cholesterol-engorged foam cells. Also, the macrophage phenotype is influenced by various stimuli which affect their polarization, efferocytosis, proliferation, and apoptosis. The heterogeneity of macrophages in lesions has recently been addressed by single-cell sequencing techniques. This article reviews recent advances regarding the roles of macrophages in different stages of disease pathogenesis from initiation to advanced atherosclerosis. Macrophage-based therapies for atherosclerosis management are also described.
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Affiliation(s)
- Lia Farahi
- Monoclonal Antibody Research Center, Avicenna Research Institute, Tehran, Iran
| | - Satyesh K. Sinha
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Aldons J. Lusis
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, Steinberg GR. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat Rev Endocrinol 2021; 17:592-607. [PMID: 34381196 DOI: 10.1038/s41574-021-00529-7] [Citation(s) in RCA: 231] [Impact Index Per Article: 57.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/17/2021] [Indexed: 02/06/2023]
Abstract
Growth differentiation factor 15 (GDF15) is a member of the TGFβ superfamily whose expression is increased in response to cellular stress and disease as well as by metformin. Elevations in GDF15 reduce food intake and body mass in animal models through binding to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and the recruitment of the receptor tyrosine kinase RET in the hindbrain. This effect is largely independent of other appetite-regulating hormones (for example, leptin, ghrelin or glucagon-like peptide 1). Consistent with an important role for the GDF15-GFRAL signalling axis, some human genetic studies support an interrelationship with human obesity. Furthermore, findings in both mice and humans have shown that metformin and exercise increase circulating levels of GDF15. GDF15 might also exert anti-inflammatory effects through mechanisms that are not fully understood. These unique and distinct mechanisms for suppressing food intake and inflammation makes GDF15 an appealing candidate to treat many metabolic diseases, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular disease and cancer cachexia. Here, we review the mechanisms regulating GDF15 production and secretion, GDF15 signalling in different cell types, and how GDF15-targeted pharmaceutical approaches might be effective in the treatment of metabolic diseases.
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Affiliation(s)
- Dongdong Wang
- Centre for Metabolism, Obesity and Diabetes Research and the Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Emily A Day
- Centre for Metabolism, Obesity and Diabetes Research and the Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Logan K Townsend
- Centre for Metabolism, Obesity and Diabetes Research and the Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Djordje Djordjevic
- Global Obesity and Liver Disease Research, Novo Nordisk A/S, Maaloev, Denmark
| | | | - Gregory R Steinberg
- Centre for Metabolism, Obesity and Diabetes Research and the Department of Medicine, McMaster University, Hamilton, ON, Canada.
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Alyami RM, Alhowikan AM. Effect of supervised exercise training on exercise capacity, pulmonary function and growth differentiation factor 15 levels in patients with interstitial lung disease: A preliminary study. ISOKINET EXERC SCI 2021. [DOI: 10.3233/ies-210123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND: Interstitial lung disease is characterized by exertion dyspnea, exercise limitation and reduced quality of life. The role of exercise training in this diverse patient group is unclear. The growth differentiation factor 15 (GDF15) is a stress-sensitive circulating factor that regulates systemic energy balance and could be a possible biomarker in interstitial lung disease. OBJECTIVE: To evaluate the effect of supervised exercise (endurance and resistance) training (SET) on exercise capacity, pulmonary function parameters and GDF15 levels in patients with interstitial lung disease (PwILD). METHODS: In this non-randomized case-control trial, the experimental group comprised of 10 PwILD (7 women and 3 men) while the control group consisted of of 18 apparently healthy participants s 11 women and 7 men). All subjects completed an 8-week supervised exercise training program, at a rate of twice a week. Dyspnea was evaluated using the Shortness of Breath Respiratory Questionnaire. Exercise capacity was measured using the 6-min walk test while the heart rate (HR) was monitored before and after the exercise training. GDF15 levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: PwILD had significantly shorter 6-min walk distance than the control subjects at both the 1st and the 15th visit. However, both groups improved significantly in this test. The change (pre to post-exercise) in HR value was smaller in PwILD compared to the controls. Moreover, PwILD had higher Shortness of Breath Respiratory Questionnaire score than controls. While the mean pre-post GDF15 change values in both groups remained statistically unchanged the GDF15 values of the PwILD patients were significantly higher compared to the controls with respect to pre-post exercise training respectively. CONCLUSION: Supervised exercise training did not affect GDF15 levels in both patient and control groups but its values in PwILD were significantly higher compared to those of controls (p⩽0.05). The exercise capacity and dyspnea in these patients improved after exercise training program.
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Affiliation(s)
- Rahmah Mohammad Alyami
- College of Medicine, Department of Physiology, King Saud University, Riyadh, Saudi Arabia
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GDF-15 Suppresses Atherosclerosis by Inhibiting oxLDL-Induced Lipid Accumulation and Inflammation in Macrophages. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6497568. [PMID: 34539804 PMCID: PMC8443352 DOI: 10.1155/2021/6497568] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/08/2021] [Indexed: 11/18/2022]
Abstract
The growth differentiation factor-15 (GDF-15) may be involved in atherosclerosis. However, the role of GDF-15 in atherosclerosis remains unclear. The main goal of this study was to verify the role and mechanism of GDF-15 in atherogenesis. We first compared the serum GDF-15 level between patients with coronary atherosclerosis and healthy people. And then one ApoE-/- mouse model of atherosclerosis was used to explore the effects of GDF-15 on oxidized low-density lipoprotein (oxLDL) accumulation, atherosclerosis-related gene expression, and lipid accumulation-related protein expression in mouse macrophages. As a result, the level of serum GDF-15 in patients with coronary atherosclerosis was significantly higher than that in healthy people. In the mouse model, GDF-15 expression was elevated in the core of plaque, and it was secreted mainly by the macrophages. In addition, GDF-15 decreased oxLDL-induced lipid accumulation and inflammation activation in macrophages. GDF-15 decreased the mRNA expressions of CD36, LOX1, and TLR4 that are associated with lipoprotein accumulation in macrophages. Further study showed that GDF-15 might suppress oxLDL-induced lipoprotein accumulation via inhibiting CD36 and LOX1 and decrease inflammation in macrophages by inhibiting TLR4. Thus, GDF-15 may suppress atherosclerosis and plaque formation by inhibiting lipoprotein accumulation and inflammation activation.
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Heduschke A, Ackermann K, Wilhelm B, Mey L, Bonaterra GA, Kinscherf R, Schwarz A. GDF-15 Deficiency Reduces Autophagic Activity in Human Macrophages In Vitro and Decreases p62-Accumulation in Atherosclerotic Lesions in Mice. Cells 2021; 10:2346. [PMID: 34571994 PMCID: PMC8470202 DOI: 10.3390/cells10092346] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/31/2021] [Accepted: 09/04/2021] [Indexed: 12/26/2022] Open
Abstract
(1) Background: Growth differentiation factor-15 (GDF-15) is associated with cardiovascular diseases and autophagy in human macrophages (MΦ). Thus, we are interested in investigating autophagic mechanisms with special respect to the role of GDF-15. (2) Methods: Recombinant (r)GDF-15 and siRNA GDF-15 were used to investigate the effects of GDF-15 on autophagic and lysosomal activity, as well as autophagosome formation by transmission electron microscopy (TEM) in MΦ. To ascertain the effects of GDF-15-/- on the progression of atherosclerotic lesions, we used GDF-15-/-/ApoE-/- and ApoE-/- mice under a cholesterol-enriched diet (CED). Body weight, body mass index (BMI), blood lipid levels and lumen stenosis in the brachiocephalic trunk (BT) were analyzed. Identification of different cell types and localization of autophagy-relevant proteins in atherosclerotic plaques were performed by immunofluorescence. (3) Results: siGDF-15 reduced and, conversely, rGDF-15 increased the autophagic activity in MΦ, whereas lysosomal activity was unaffected. Autophagic degradation after starvation and rGDF-15 treatment was observed by TEM. GDF-15-/-/ApoE-/- mice, after CED, showed reduced lumen stenosis in the BT, while body weight, BMI and triglycerides were increased compared with ApoE-/- mice. GDF-15-/- decreased p62-accumulation in atherosclerotic lesions, especially in endothelial cells (ECs). (4) Conclusion: GDF-15 seems to be an important factor in the regulation of autophagy, especially in ECs of atherosclerotic lesions, indicating its crucial pathophysiological function during atherosclerosis development.
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Affiliation(s)
| | | | | | | | | | | | - Anja Schwarz
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, Philipps-University of Marburg, 35032 Marburg, Germany; (A.H.); (K.A.); (B.W.); (L.M.); (G.A.B.); (R.K.)
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Resl M, Vila G, Heinzl M, Luger A, Neuhold S, Prager R, Wurm R, Hülsmann M, Clodi M. Changes in the prognostic values of modern cardiovascular biomarkers in relation to duration of diabetes mellitus. J Diabetes Complications 2021; 35:107990. [PMID: 34294516 DOI: 10.1016/j.jdiacomp.2021.107990] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Based on the complex pathophysiology of type 2 diabetes and atherosclerosis we hypothesized a dynamic change in prognostic value of cardiovascular biomarkers over time. METHODS In this prospective study 746 patients with type 2 diabetes mellitus, being followed up for 60 months were analysed. The primary endpoint was defined as unplanned hospitalization for cardiovascular disease or death. Beside others, especially the prognostic performance of the biomarkers of interest (GDF-15, NT-proBNP, hs-TnT) was evaluated in relation to quartiles of diabetes duration. RESULTS In patients having a diabetes duration below 7 years lnGDF-15 (HR 2.84; p < 0.01) and lnhs-TnT (HR 2.96; p < 0.01) were significant predictors of the primary endpoint. LnAge (HR 40.01; p < 0.01) and lnNT-proBNP (HR 1.56; p = 0.03) were significant predictors in patients with a diabetes duration between 7 and 12 years. In the third quartile (diabetes duration 12-22 years) lnurinary albumin to creatinine ratio (HR 1.25; p = 0.005) and lnNT-proBNP (HR 2.13, p < 0.001) predicted the endpoint. In patients with a diabetes duration above 22 years, lnAge (HR 75.35; p = 0.001) and lnNT-proBNP (HR 2.0; p < 0.01) were the only significant predictors of the endpoint. CONCLUSION Prognostic power of cardiovascular biomarkers changes dynamically in relation to duration of type 2 diabetes mellitus. In patients with shorter duration of the disease markers of subclinical cardiovascular dysfunction and inflammation perform better than markers of systemic advanced organ dysfunction and cardiovascular disease.
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Affiliation(s)
- M Resl
- Department of Medicine, St. John of God's Hospital Linz, Institute for Cardiometabolic Research JKU, Linz, Austria
| | - G Vila
- Department of Medicine III, Division of Endocrinology, Medical University of Vienna, Austria
| | - M Heinzl
- Department of Medicine, St. John of God's Hospital Linz, Institute for Cardiometabolic Research JKU, Linz, Austria
| | - A Luger
- Department of Medicine III, Division of Endocrinology, Medical University of Vienna, Austria
| | - S Neuhold
- Department of Medicine IV, Kaiser Franz Joseph Spital Vienna
| | - R Prager
- Karl Landsteiner Institute for Nephrology and Diabetes, Hietzing Hospital Vienna, Austria
| | - R Wurm
- Department of Medicine II, Division of Cardiology, Medical University of Vienna, Austria
| | - M Hülsmann
- Department of Medicine II, Division of Cardiology, Medical University of Vienna, Austria
| | - M Clodi
- Department of Medicine, St. John of God's Hospital Linz, Institute for Cardiometabolic Research JKU, Linz, Austria.
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Buchholz K, Antosik P, Grzanka D, Gagat M, Smolińska M, Grzanka A, Gzil A, Kasperska A, Klimaszewska-Wiśniewska A. Expression of the Body-Weight Signaling Players: GDF15, GFRAL and RET and their clinical relevance in Gastric Cancer. J Cancer 2021; 12:4698-4709. [PMID: 34149933 PMCID: PMC8210553 DOI: 10.7150/jca.55511] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 05/10/2021] [Indexed: 01/01/2023] Open
Abstract
The existence, the functional role and clinical relevance of GDF15 and its signaling through a GFRAL/RET-dependent complex in gastric cancer (GC) and other human tumors remain to be elucidated, despite the widespread recognition of obesity as an important cancer-predisposing factor. Therefore, we aimed to analyze the expression levels of GDF15, GFRAL and RET in GC tissues in relation to each other and clinicopathological features, including patient survival, in order to establish a potential implication of the body-weight signaling pathway in the pathology and clinical outcome of GC. Protein expression was examined by immunohistochemistry on tissue microarrays containing 104 and 30 consecutive GC and normal gastric mucosa samples, whereas gene expression data for The Cancer Genome Atlas cohort of 413 GC patients were obtained from public sources. We found that the protein expression of GDF15, GFRAL and RET was significantly elevated and positively correlated in our set of GC tissues, which was reflected in their tendency to be overexpressed in low-grade and intermediate-grade tumors rather than high-grade ones. No other relationships between the expression status of the examined proteins and clinicopathological characteristics of GC patients were found. Through in silico data analysis, we showed that high GDF15 expression was associated with better overall survival (OS) of GC patients, whereas the opposite was true for high levels of GFRAL or RET. Specifically, GFRAL and RET emerged as independent prognostic factors associated with poor OS. Furthermore, high combined expression of the three markers: GDF15+GFRAL+RET was significantly associated with reduced OS, and it was an independent prognostic factor of borderline significance in terms of OS, when adjusted for covariates. If validated in large-scale studies, the individual and combined expression of GDF15, GFRAL and RET may provide significant clinical implications for the prognosis prediction of GC patients.
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Affiliation(s)
- Karolina Buchholz
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland.,Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland
| | - Paulina Antosik
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland
| | - Maciej Gagat
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland
| | - Marta Smolińska
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland
| | - Alina Grzanka
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland
| | - Arkadiusz Gzil
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland
| | - Anna Kasperska
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland
| | - Anna Klimaszewska-Wiśniewska
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland
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Weng JH, Koch PD, Luan HH, Tu HC, Shimada K, Ngan I, Ventura R, Jiang R, Mitchison TJ. Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation. Nat Metab 2021; 3:513-522. [PMID: 33846641 PMCID: PMC8175070 DOI: 10.1038/s42255-021-00366-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 02/18/2021] [Indexed: 02/01/2023]
Abstract
Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action.
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Affiliation(s)
- Jui-Hsia Weng
- Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
| | - Peter David Koch
- Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA
| | | | - Ho-Chou Tu
- Alnylam Pharmaceuticals, Inc., Cambridge, MA, USA
| | - Kenichi Shimada
- Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Iris Ngan
- NGM Biopharmaceuticals, South San Francisco, CA, USA
| | | | - Ruomu Jiang
- Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Timothy J Mitchison
- Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
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X‑irradiation induces acute and early term inflammatory responses in atherosclerosis‑prone ApoE‑/‑ mice and in endothelial cells. Mol Med Rep 2021; 23:399. [PMID: 33786610 PMCID: PMC8025474 DOI: 10.3892/mmr.2021.12038] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 12/09/2020] [Indexed: 01/09/2023] Open
Abstract
Thoracic radiotherapy is an effective treatment for many types of cancer; however it is also associated with an increased risk of developing cardiovascular disease (CVD), appearing mainly ≥10 years after radiation exposure. The present study investigated acute and early term physiological and molecular changes in the cardiovascular system after ionizing radiation exposure. Female and male ApoE‑/‑ mice received a single exposure of low or high dose X‑ray thoracic irradiation (0.1 and 10 Gy). The level of cholesterol and triglycerides, as well as a large panel of inflammatory markers, were analyzed in serum samples obtained at 24 h and 1 month after irradiation. The secretion of inflammatory markers was further verified in vitro in coronary artery and microvascular endothelial cell lines after exposure to low and high dose of ionizing radiation (0.1 and 5 Gy). Local thoracic irradiation of ApoE‑/‑ mice increased serum growth differentiation factor‑15 (GDF‑15) and C‑X‑C motif chemokine ligand 10 (CXCL10) levels in both female and male mice 24 h after high dose irradiation, which were also secreted from coronary artery and microvascular endothelial cells in vitro. Sex‑specific responses were observed for triglyceride and cholesterol levels, and some of the assessed inflammatory markers as detailed below. Male ApoE‑/‑ mice demonstrated elevated intercellular adhesion molecule‑1 and P‑selectin at 24 h, and adiponectin and plasminogen activator inhibitor‑1 at 1 month after irradiation, while female ApoE‑/‑ mice exhibited decreased monocyte chemoattractant protein‑1 and urokinase‑type plasminogen activator receptor at 24 h, and basic fibroblast growth factor 1 month after irradiation. The inflammatory responses were mainly significant following high dose irradiation, but certain markers showed significant changes after low dose exposure. The present study revealed that acute/early inflammatory responses occurred after low and high dose thoracic irradiation. However, further research is required to elucidate early asymptomatic changes in the cardiovascular system post thoracic X‑irradiation and to investigate whether GDF‑15 and CXCL10 could be considered as potential biomarkers for the early detection of CVD risk in thoracic radiotherapy‑treated patients.
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Chaudhary PK, Kim S. The GRKs Reactome: Role in Cell Biology and Pathology. Int J Mol Sci 2021; 22:ijms22073375. [PMID: 33806057 PMCID: PMC8036551 DOI: 10.3390/ijms22073375] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/21/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023] Open
Abstract
G protein-coupled receptor kinases (GRKs) are protein kinases that function in concert with arrestins in the regulation of a diverse class of G protein-coupled receptors (GPCRs) signaling. Although GRKs and arrestins are key participants in the regulation of GPCR cascades, the complex regulatory mechanisms of GRK expression, its alternation, and their function are not thoroughly understood. Several studies together with the work from our lab in recent years have revealed the critical role of these kinases in various physiological and pathophysiological processes, including cardiovascular biology, inflammation and immunity, neurodegeneration, thrombosis, and hemostasis. A comprehensive understanding of the mechanisms underlying functional interactions with multiple receptor proteins and how these interactions take part in the development of various pathobiological processes may give rise to novel diagnostic and therapeutic strategies. In this review, we summarize the current research linking the role of GRKs to various aspects of cell biology, pathology, and therapeutics, with a particular focus on thrombosis and hemostasis.
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Growth differentiation factor 15 levels are similar in primary aldosteronism and essential hypertension and do not predict arterial inflammation. J Hypertens 2021; 39:593-596. [PMID: 33543888 DOI: 10.1097/hjh.0000000000002727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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ElTanbouly MA, Zhao Y, Schaafsma E, Burns CM, Mabaera R, Cheng C, Noelle RJ. VISTA: A Target to Manage the Innate Cytokine Storm. Front Immunol 2021; 11:595950. [PMID: 33643285 PMCID: PMC7905033 DOI: 10.3389/fimmu.2020.595950] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022] Open
Abstract
In recent years, the success of immunotherapy targeting immunoregulatory receptors (immune checkpoints) in cancer have generated enthusiastic support to target these receptors in a wide range of other immune related diseases. While the overwhelming focus has been on blockade of these inhibitory pathways to augment immunity, agonistic triggering via these receptors offers the promise of dampening pathogenic inflammatory responses. V-domain Ig suppressor of T cell activation (VISTA) has emerged as an immunoregulatory receptor with constitutive expression on both the T cell and myeloid compartments, and whose agonistic targeting has proven a unique avenue relative to other checkpoint pathways to suppress pathologies mediated by the innate arm of the immune system. VISTA agonistic targeting profoundly changes the phenotype of human monocytes towards an anti-inflammatory cell state, as highlighted by striking suppression of the canonical markers CD14 and Fcγr3a (CD16), and the almost complete suppression of both the interferon I (IFN-I) and antigen presentation pathways. The insights from these very recent studies highlight the impact of VISTA agonistic targeting of myeloid cells, and its potential therapeutic implications in the settings of hyperinflammatory responses such as cytokine storms, driven by dysregulated immune responses to viral infections (with a focus on COVID-19) and autoimmune diseases. Collectively, these findings suggest that the VISTA pathway plays a conserved, non-redundant role in myeloid cell function.
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Affiliation(s)
- Mohamed A. ElTanbouly
- Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States
| | - Yanding Zhao
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Evelien Schaafsma
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
| | | | - Rodwell Mabaera
- Department of Medicine, Norris Cotton Cancer Center, Lebanon, NH, United States
| | - Chao Cheng
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, United States
| | - Randolph J. Noelle
- Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States
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