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Zhang Y, Su D, Liu Y, He B, Wang H, Shi C, Yang Y. Transcriptomic analysis reveals potential targets associated with hippocampus vulnerability in spatial cognitive dysfunctionof type 2 diabetes mellitus rats. Neuroscience 2025; 579:35-46. [PMID: 40425127 DOI: 10.1016/j.neuroscience.2025.05.036] [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: 10/21/2024] [Revised: 05/14/2025] [Accepted: 05/23/2025] [Indexed: 05/29/2025]
Abstract
BACKGROUND Cognitive dysfunction is one of the major complications of T2DM.However, the precise molecular mechanism underlying this relationship remains unclear. Present study aimed to identify potential predictors of cognitive dysfunction associated with T2DM specifically within the hippocampus. METHODS T2DM was induced by a high-fat diet combined with streptozotocin injections. Morris water maze was employed to assess spatial cognitive ability. HE staining was used to evaluate neurons injury in hippocampus. Transcriptome sequencing was conducted on the hippocampus to identify potential genes. The results obtained from sequencing analysis werevalidated using qRT-PCR. GO and KEGG analyses were performed to investigate the functions of differentially expressed genes (DEGs) and their associated biological pathways. RESULTS Compared with CON rats, thespatial cognitive ability decreased in T2DM rats. Hippocampus neurons reduced in CA1 area of T2DM rats. In total, 123 DEGswere identified bytranscriptome sequencing, including 25 upregulated genes and 98 downregulated genes. The qRT-PCR results verified the RNA-seq. KEGG pathway analysis showed the major enriched pathways were TNF signaling pathway, arachidonic acid metabolism, AGE-RAGE signaling pathway in diabetic complications, and cellular senescence. GO analysis showed that DEGs involved in biological process were mainly related to vasculogenesis, response to hypoxia, regulation of cell proliferation and aging. CONCLUSIONS Our transcriptomic analysis reveals the "cellular senescence" signaling pathway may be implicated in T2DM-induced spatial cognitive dysfunction and Tgfbr2 may be the important DEG involved in this pathway, which will be the primary focus of our future research endeavors.
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Affiliation(s)
- Ying Zhang
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning, Beijing, China
| | - Dongmei Su
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning, Beijing, China
| | - Yuru Liu
- Department of Cardiology, Hebei General Hospital, Shijiazhuang, China
| | - Bin He
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning, Beijing, China
| | - Huiping Wang
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning, Beijing, China
| | - Cuige Shi
- NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning, Beijing, China.
| | - Yishu Yang
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
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Bossardet OL, Holden JM, Del Buono BJ, Schlumpf E, Wareham LK, Calkins DJ. Collagen mimetic peptides as novel therapeutics for vascular disease in the central nervous system. Front Neurosci 2025; 19:1569347. [PMID: 40421131 PMCID: PMC12104236 DOI: 10.3389/fnins.2025.1569347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 04/24/2025] [Indexed: 05/28/2025] Open
Abstract
Background Loss of vascular integrity is a common comorbidity of neurodegenerative diseases of the central nervous system (CNS). Compromised blood flow to the brain and excessive vascular remodeling is evident in chronic systemic cardiovascular diseases such as atherosclerosis, driving neurodegeneration and subsequent cognitive decline. Vascular remodeling occurs in response to changes in the microenvironment, with the extracellular matrix (ECM) as a major component. Collagens within the ECM and vascular basement membrane are integral to endothelial cell (EC) function and maintenance of the blood-brain barrier. Disruption of the ECM and breakdown of collagen with disease may lead to vascular dysfunction and neurodegeneration. Methods We induced hyperglycemia in ApoE-deficient (ApoE-/-) mice by intraperitoneal injection of streptozocin (STZ; 50 mg/Kg) for 5 days and accelerated diabetic atherosclerotic disease through a high fat diet (HFD). Over a 12 weeks period, mice received weekly intravenous treatment of collagen mimetic peptide (CMP) or vehicle (phosphate buffered saline) to assess efficacy in promoting vascular integrity in central brain structures. Results Following the STZ/HFD regimen, diabetic atherosclerotic ApoE-/- mice treated with CMP exhibited increased vascular integrity compared to vehicle in the cortex and in the CA1 and dentate gyrus regions of the hippocampus, as assed by higher levels of the endothelial cell adhesion glycoprotein CD31 and intravascular collagen IV, increased vascular area, and diminished leakage. Interestingly, in hippocampus, astrocytes were closer in proximity to vessels despite being less numerous in the CMP group. Conclusion Collagen integrity is important for maintaining cerebrovascular architecture in disease. Application of CMP which intercalates with and repairs damaged collagen may have therapeutic use in neurodegenerative diseases by preserving vasculature structure and promoting blood-brain barrier integrity. These findings underscore the need to further explore the role of collagen repair as a novel therapeutic for diseases of the brain involving vascular degradation.
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Affiliation(s)
- Olivia L. Bossardet
- Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Joseph M. Holden
- Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, United States
| | | | - Eric Schlumpf
- Sailfish Therapeutics, LLC, Stuart, FL, United States
| | - Lauren K. Wareham
- Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, United States
| | - David J. Calkins
- Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, United States
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Datta S, Rahman MA, Koka S, Boini KM. High Mobility Group Box 1 (HMGB1): Molecular Signaling and Potential Therapeutic Strategies. Cells 2024; 13:1946. [PMID: 39682695 PMCID: PMC11639863 DOI: 10.3390/cells13231946] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/19/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
High Mobility Group Box 1 (HMGB1) is a highly conserved non-histone chromatin-associated protein across species, primarily recognized for its regulatory impact on vital cellular processes, like autophagy, cell survival, and apoptosis. HMGB1 exhibits dual functionality based on its localization: both as a non-histone protein in the nucleus and as an inducer of inflammatory cytokines upon extracellular release. Pathophysiological insights reveal that HMGB1 plays a significant role in the onset and progression of a vast array of diseases, viz., atherosclerosis, kidney damage, cancer, and neurodegeneration. However, a clear mechanistic understanding of HMGB1 release, translocation, and associated signaling cascades in mediating such physiological dysfunctions remains obscure. This review presents a detailed outline of HMGB1 structure-function relationship and its regulatory role in disease onset and progression from a signaling perspective. This review also presents an insight into the status of HMGB1 druggability, potential limitations in understanding HMGB1 pathophysiology, and future perspective of studies that can be undertaken to address the existing scientific gap. Based on existing paradigm of various studies, HMGB1 is a critical regulator of inflammatory cascades and drives the onset and progression of a broad spectrum of dysfunctions. Studies focusing on HMGB1 druggability have enabled the development of biologics with potential clinical benefits. However, deeper understanding of post-translational modifications, redox states, translocation mechanisms, and mitochondrial interactions can potentially enable the development of better courses of therapy against HMGB1-mediated physiological dysfunctions.
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Affiliation(s)
- Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Mohammad Atiqur Rahman
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Saisudha Koka
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA;
| | - Krishna M. Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
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Kitadai E, Yamaguchi K, Ohshimo S, Iwamoto H, Sakamoto S, Horimasu Y, Masuda T, Nakashima T, Hamada H, Bonella F, Guzman J, Costabel U, Hattori N. Serum soluble isoform of receptor for advanced glycation end product is a predictive biomarker for acute exacerbation of idiopathic pulmonary fibrosis: a German and Japanese cohort study. Respir Res 2024; 25:405. [PMID: 39529063 PMCID: PMC11552171 DOI: 10.1186/s12931-024-03014-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND The receptor for advanced glycation end product (RAGE) is a transmembrane receptor accelerating a pro-inflammatory signal. RAGE signalling is promoted by decreased soluble isoform of RAGE (sRAGE), which is a decoy receptor for RAGE ligands, and RAGE SNP rs2070600 minor allele. In Caucasian and Japanese cohorts, low circulatory sRAGE levels and presence of the minor allele are associated with poor survival of idiopathic pulmonary fibrosis (IPF) and increased disease susceptibility to interstitial lung disease, respectively. However, whether sRAGE and RAGE SNP rs2070600 are associated with acute exacerbation of IPF (AE-IPF) is unclear. METHODS This retrospective cohort study evaluated the association between the onset of AE-IPF and serum sRAGE levels in 69 German and 102 Japanese patients with IPF. The association of AE-IPF with RAGE SNP rs2070600 in 51 German and 84 Japanese patients, whose DNA samples were stored, was also investigated. RESULTS In each cohort, the incidence of AE-IPF was significantly and reproducibly higher in the patients with sRAGE < 467.1 pg/mL. In a pooled exploratory analysis, the incidence of AE-IPF was lowest in the patients with higher sRAGE levels and rs2070600 minor allele, although no significant difference in the incidence was observed between the patients with and without the rs2070600 minor allele. CONCLUSIONS Low sRAGE levels were associated with increased incidence of AE-IPF in two independent cohorts of different ethnicities. The combination of rs2070600 and sRAGE levels may stratify patients with IPF for the risk of AE.
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Affiliation(s)
- Erika Kitadai
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan
| | - Kakuhiro Yamaguchi
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan.
| | - Shinichiro Ohshimo
- Department of Emergency and Critical Care Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Iwamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan
| | - Shinjiro Sakamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan
| | - Yasushi Horimasu
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan
| | - Takeshi Masuda
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan
| | - Taku Nakashima
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan
| | - Hironobu Hamada
- Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Francesco Bonella
- Center for Interstitial and Rare Lung Disease, Department of Pneumology, Ruhrlandklinik University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Josune Guzman
- General and Experimental Pathology, Ruhr-University, Bochum, Germany
| | - Ulrich Costabel
- Center for Interstitial and Rare Lung Disease, Department of Pneumology, Ruhrlandklinik University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Noboru Hattori
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan
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Ramasamy R, Shekhtman A, Schmidt AM. RAGE/DIAPH1 Axis and Cardiometabolic Disease: From Nascent Discoveries to Therapeutic Potential. Arterioscler Thromb Vasc Biol 2024; 44:1497-1501. [PMID: 38924438 PMCID: PMC11210684 DOI: 10.1161/atvbaha.124.320142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2024]
Affiliation(s)
- Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, NYU Langone Medical Center (R.R., A.M.S.)
| | | | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, NYU Langone Medical Center (R.R., A.M.S.)
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Najjar JA, Calvert JW. Effects of protein glycation and protective mechanisms against glycative stress. Curr Opin Pharmacol 2024; 76:102464. [PMID: 38796877 PMCID: PMC11229435 DOI: 10.1016/j.coph.2024.102464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/15/2024] [Accepted: 05/03/2024] [Indexed: 05/29/2024]
Abstract
Glycation is a posttranslational modification of proteins that contributes to the vast array of biological information that can be conveyed via a singular proteome. Understanding the role of advanced glycation end-products (AGEs) in human health and pathophysiology can be difficult, as the physiological effects of AGEs have been associated with multiple biological processes and disease state development, including acute myocardial ischemia-reperfusion injury, heart failure, and atherosclerosis, as well as tumor cell migration. The critical role of the glyoxalase system in the detoxification of methylglyoxal and other AGEs has been well established. Recently, evidence has emerged that DJ-1 displays antiglycative activity and may contribute to another mechanism of protection against protein glycation outside of the glyoxalase system. Identification of potential substrates of DJ-1 and determination of the pathways in which DJ-1 operates, is needed to fully understand the role of this protein in modulating biological homeostasis and the development of disease.
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Affiliation(s)
- Jade A Najjar
- Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, USA
| | - John W Calvert
- Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, USA.
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Grauen Larsen H, Sun J, Sjögren M, Borné Y, Engström G, Nilsson P, Orho-Melander M, Goncalves I, Nilsson J, Melander O, Schiopu A. The Gly82Ser polymorphism in the receptor for advanced glycation endproducts increases the risk for coronary events in the general population. Sci Rep 2024; 14:11567. [PMID: 38773223 PMCID: PMC11109115 DOI: 10.1038/s41598-024-62385-5] [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: 11/01/2023] [Accepted: 05/16/2024] [Indexed: 05/23/2024] Open
Abstract
The receptor for advanced glycation endproducts (RAGE) has pro-inflammatory and pro-atherogenic effects. Low plasma levels of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands, have been associated with increased risk for major adverse coronary events (MACE) in the general population. We performed a genome-wide association study to identify genetic determinants of plasma sRAGE in 4338 individuals from the cardiovascular arm of the Malmö Diet and Cancer study (MDC-CV). Further, we explored the associations between these genetic variants, incident first-time MACE and mortality in 24,640 unrelated individuals of European ancestry from the MDC cohort. The minor alleles of four single nucleotide polymorphisms (SNPs): rs2070600, rs204993, rs116653040, and rs7306778 were independently associated with lower plasma sRAGE. The minor T (vs. C) allele of rs2070600 was associated with increased risk for MACE [HR 1.13 95% CI (1.02-1.25), P = 0.016]. Neither SNP was associated with mortality. This is the largest study to demonstrate a link between a genetic sRAGE determinant and CV risk. Only rs2070600, which enhances RAGE function by inducing a Gly82Ser polymorphism in the ligand-binding domain, was associated with MACE. The lack of associations with incident MACE for the other sRAGE-lowering SNPs suggests that this functional RAGE modification is central for the observed relationship.
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Affiliation(s)
- Helena Grauen Larsen
- Department of Clinical Sciences Malmö, Lund University, 21428, Malmö, Sweden
- Department of Cardiology, Skåne University Hospital Malmö, 21428, Malmö, Sweden
| | - Jiangming Sun
- Department of Clinical Sciences Malmö, Lund University, 21428, Malmö, Sweden
| | - Marketa Sjögren
- Department of Clinical Sciences Malmö, Lund University, 21428, Malmö, Sweden
| | - Yan Borné
- Department of Clinical Sciences Malmö, Lund University, 21428, Malmö, Sweden
| | - Gunnar Engström
- Department of Clinical Sciences Malmö, Lund University, 21428, Malmö, Sweden
| | - Peter Nilsson
- Department of Clinical Sciences Malmö, Lund University, 21428, Malmö, Sweden
| | - Marju Orho-Melander
- Department of Clinical Sciences Malmö, Lund University, 21428, Malmö, Sweden
| | - Isabel Goncalves
- Department of Clinical Sciences Malmö, Lund University, 21428, Malmö, Sweden
- Department of Cardiology, Skåne University Hospital Malmö, 21428, Malmö, Sweden
| | - Jan Nilsson
- Department of Clinical Sciences Malmö, Lund University, 21428, Malmö, Sweden
| | - Olle Melander
- Department of Clinical Sciences Malmö, Lund University, 21428, Malmö, Sweden
- Department of Internal Medicine, Skane University Hospital Lund, 22242, Lund, Sweden
| | - Alexandru Schiopu
- Department of Internal Medicine, Skane University Hospital Lund, 22242, Lund, Sweden.
- Department of Translational Medicine, Lund University, 21428, Malmö, Sweden.
- Nicolae Simionescu Institute of Cellular Biology and Pathology, 050568, Bucharest, Romania.
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Arivazhagan L, Popp CJ, Ruiz HH, Wilson RA, Manigrasso MB, Shekhtman A, Ramasamy R, Sevick MA, Schmidt AM. The RAGE/DIAPH1 axis: mediator of obesity and proposed biomarker of human cardiometabolic disease. Cardiovasc Res 2024; 119:2813-2824. [PMID: 36448548 PMCID: PMC11484493 DOI: 10.1093/cvr/cvac175] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 12/07/2023] Open
Abstract
Overweight and obesity are leading causes of cardiometabolic dysfunction. Despite extensive investigation, the mechanisms mediating the increase in these conditions are yet to be fully understood. Beyond the endogenous formation of advanced glycation endproducts (AGEs) in overweight and obesity, exogenous sources of AGEs accrue through the heating, production, and consumption of highly processed foods. Evidence from cellular and mouse model systems indicates that the interaction of AGEs with their central cell surface receptor for AGE (RAGE) in adipocytes suppresses energy expenditure and that AGE/RAGE contributes to increased adipose inflammation and processes linked to insulin resistance. In human subjects, the circulating soluble forms of RAGE, which are mutable, may serve as biomarkers of obesity and weight loss. Antagonists of RAGE signalling, through blockade of the interaction of the RAGE cytoplasmic domain with the formin, Diaphanous-1 (DIAPH1), target aberrant RAGE activities in metabolic tissues. This review focuses on the potential roles for AGEs and other RAGE ligands and RAGE/DIAPH1 in the pathogenesis of overweight and obesity and their metabolic consequences.
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Affiliation(s)
- Lakshmi Arivazhagan
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Collin J Popp
- Center for Healthful Behavior Change, Department of Population Health, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Henry H Ruiz
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Robin A Wilson
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Michaele B Manigrasso
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY 12222, USA
| | - Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Mary Ann Sevick
- Center for Healthful Behavior Change, Department of Population Health, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
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Ye D, Miyoshi A, Ushitani T, Kadoya M, Igeta M, Konishi K, Shoji T, Yasuda K, Kitaoka S, Yagi H, Kuroda E, Yamamoto Y, Cheng J, Koyama H. RAGE in circulating immune cells is fundamental for hippocampal inflammation and cognitive decline in a mouse model of latent chronic inflammation. Brain Behav Immun 2024; 116:329-348. [PMID: 38142917 DOI: 10.1016/j.bbi.2023.12.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/29/2023] [Accepted: 12/19/2023] [Indexed: 12/26/2023] Open
Abstract
BACKGROUND Latent chronic inflammation has been proposed as a key mediator of multiple derangements in metabolic syndrome (MetS), which are increasingly becoming recognized as risk factors for age-related cognitive decline. However, the question remains whether latent chronic inflammation indeed induces brain inflammation and cognitive decline. METHODS A mouse model of latent chronic inflammation was constructed by a chronic subcutaneous infusion of low dose lipopolysaccharide (LPS) for four weeks. A receptor for advanced glycation end products (RAGE) knockout mouse, a chimeric myeloid cell specific RAGE-deficient mouse established by bone marrow transplantation and a human endogenous secretory RAGE (esRAGE) overexpressing adenovirus system were utilized to examine the role of RAGE in vivo. The cognitive function was examined by a Y-maze test, and the expression level of genes was determined by quantitative RT-PCR, western blot, immunohistochemical staining, or ELISA assays. RESULTS Latent chronic inflammation induced MetS features in C57BL/6J mice, which were associated with cognitive decline and brain inflammation characterized by microgliosis, monocyte infiltration and endothelial inflammation, without significant changes in circulating cytokines including TNF-α and IL-1β. These changes as well as cognitive impairment were rescued in RAGE knockout mice or chimeric mice lacking RAGE in bone marrow cells. P-selectin glycoprotein ligand-1 (PSGL-1), a critical adhesion molecule, was induced in circulating mononuclear cells in latent chronic inflammation in wild-type but not RAGE knockout mice. These inflammatory changes and cognitive decline induced in the wild-type mice were ameliorated by an adenoviral increase in circulating esRAGE. Meanwhile, chimeric RAGE knockout mice possessing RAGE in myeloid cells were still resistant to cognitive decline and brain inflammation. CONCLUSIONS These findings indicate that RAGE in inflammatory cells is necessary to mediate stimuli of latent chronic inflammation that cause brain inflammation and cognitive decline, potentially by orchestrating monocyte activation via regulation of PSGL-1 expression. Our results also suggest esRAGE-mediated inflammatory regulation as a potential therapeutic option for cognitive dysfunction in MetS with latent chronic inflammation.
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Affiliation(s)
- Dasen Ye
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Akio Miyoshi
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Tomoe Ushitani
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Manabu Kadoya
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Masataka Igeta
- Department of Biostatistics, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Kosuke Konishi
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Takuhito Shoji
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Koubun Yasuda
- Department of Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Shiho Kitaoka
- Department of Pharmacology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Hideshi Yagi
- Department of Anatomy and Cell Biology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Etsushi Kuroda
- Department of Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Jidong Cheng
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan; Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Hidenori Koyama
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan.
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Chen L, Wang Q, Lv Y, Xu W, Jiang G, Li Y, Luo P, He R, Liu L. Association of plasma advanced glycation end-products and their soluble receptor with type 2 diabetes among Chinese adults. Diabetes Metab Res Rev 2024; 40:e3735. [PMID: 37817474 DOI: 10.1002/dmrr.3735] [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: 03/10/2023] [Revised: 09/05/2023] [Accepted: 09/21/2023] [Indexed: 10/12/2023]
Abstract
AIMS Population-based evidence regarding circulating advanced glycation end-products (AGEs) and the risk of type 2 diabetes (T2D) is conflicting and insufficient. We aimed to examine the association of plasma AGEs and plasma soluble receptors for AGEs (sRAGE) with T2D. MATERIALS AND METHODS We conducted a hospital-based case-control study including 1072 pairs (53.9 ± 9.7 years, 56.0% male) of newly diagnosed T2D and age- and sex-matched controls. We further performed a nested case-control study within an ongoing prospective cohort consisting of 127 incident T2D cases and 381 well-matched controls (62.2 ± 5.1 years, 71.7% male). Plasma AGEs were detected using liquid chromatography-tandem mass spectrometry, and plasma sRAGE was measured by enzyme-linked immunosorbent assay. Conditional logistic regression was used to evaluate the association of plasma AGEs and sRAGE concentrations with T2D. RESULTS Higher plasma AGEs and lower sRAGE concentrations were associated with higher odds of T2D. The multivariable-adjusted odds ratios of T2D comparing the highest with the lowest quartile levels were 3.28 (95% CI: 2.14, 5.02) for plasma AGEs and 0.25 (95% CI: 0.16, 0.39) for plasma sRAGE. Participants in the highest quartile of plasma AGEs and the lowest quartile of sRAGE concentrations had the greatest odds of T2D. The positive association of AGEs and inverse association of sRAGE with T2D risk was confirmed in the replication-nested case-control study. CONCLUSIONS Increased circulating AGEs and decreased sRAGE concentrations were associated with elevated T2D risk. Our findings may have implications for the strategies of T2D prevention and management.
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Affiliation(s)
- Liangkai Chen
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiang Wang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanling Lv
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenyuan Xu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Guanhua Jiang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yonggang Li
- Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Ping Luo
- Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Ruikun He
- BYHEALTH Institute of Nutrition & Health, Guangzhou, China
| | - Liegang Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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11
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Robin H, Trudeau C, Robbins A, Chung E, Rahman E, Gangmark-Strickland O, Licari FW, Winden DR, Orr DL, Arroyo JA, Reynolds PR. A Potential Role for the Receptor for Advanced Glycation End-Products (RAGE) in the Development of Secondhand Smoke-Induced Chronic Sinusitis. Curr Issues Mol Biol 2024; 46:729-740. [PMID: 38248349 PMCID: PMC10814859 DOI: 10.3390/cimb46010047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/03/2024] [Accepted: 01/09/2024] [Indexed: 01/23/2024] Open
Abstract
Chronic sinusitis (CS) is characterized by sinonasal inflammation, mucus overproduction, and edematous mucosal tissue. CS impacts one in seven adults and estimates suggest up to 15% of the general U.S. population may be affected. This research sought to assess a potential role for receptors for advanced glycation end-products (RAGE), an inflammatory receptor expressed in tissues exposed to secondhand smoke (SHS). Human sinus tissue sections were stained for RAGE and S100s, common RAGE ligands. Wild-type mice and mice that over-express RAGE in sinonasal epithelium (RAGE TG) were maintained in room air (RA) or exposed to secondhand smoke (SHS) via a nose-only delivery system five days a week for 6 weeks. Mouse sections were stained for RAGE and tissue lysates were assayed for cleaved caspase 3, cytokines, or matrix metalloproteases. We discovered increased RAGE expression in sinus tissue following SHS exposure and in sinuses from RAGE TG mice in the absence of SHS. Cleaved caspase-3, cytokines (IL-1β, IL-3, and TNF-α), and MMPs (-9 and -13) were induced by SHS and in tissues from RAGE TG mice. These results expand the inflammatory role of RAGE signaling, a key axis in disease progression observed in smokers. In this relatively unexplored area, enhanced understanding of RAGE signaling during voluntary and involuntary smoking may help to elucidate potential therapeutic targets that may attenuate the progression of smoke-related CS.
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Affiliation(s)
- Hannah Robin
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA
| | - Courtney Trudeau
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA
| | - Adam Robbins
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA
| | - Emily Chung
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA
| | - Erum Rahman
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA
| | | | - Frank W. Licari
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA
| | - Duane R. Winden
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA
| | - Dan L. Orr
- Oral & Maxillofacial Surgery, University Medical Center, Las Vegas, NV 89102, USA
| | - Juan A. Arroyo
- Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA
| | - Paul R. Reynolds
- Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA
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12
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St. Sauver JL, Weston SA, Atkinson EJ, Mc Gree ME, Mielke MM, White TA, Heeren AA, Olson JE, Rocca WA, Palmer AK, Cummings SR, Fielding RA, Bielinski SJ, LeBrasseur NK. Biomarkers of cellular senescence and risk of death in humans. Aging Cell 2023; 22:e14006. [PMID: 37803875 PMCID: PMC10726868 DOI: 10.1111/acel.14006] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/14/2023] [Accepted: 09/19/2023] [Indexed: 10/08/2023] Open
Abstract
A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults. We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79, 95% confidence interval (CI): 0.76-0.82) than the covariates alone (0.70, CI: 0.67-0.74) (p < 0.001). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death.
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Affiliation(s)
| | - Susan A. Weston
- Department of Quantitative Health SciencesMayo ClinicRochesterMinnesotaUSA
| | | | | | - Michelle M. Mielke
- Department of Epidemiology and PreventionWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Thomas A. White
- Robert and Arlene Kogod Center on AgingMayo ClinicRochesterMinnesotaUSA
| | - Amanda A. Heeren
- Robert and Arlene Kogod Center on AgingMayo ClinicRochesterMinnesotaUSA
| | - Janet E. Olson
- Department of Quantitative Health SciencesMayo ClinicRochesterMinnesotaUSA
| | - Walter A. Rocca
- Department of Quantitative Health SciencesMayo ClinicRochesterMinnesotaUSA
- Department of NeurologyMayo ClinicRochesterMinnesotaUSA
- Women's Health Research Center, Mayo ClinicRochesterMinnesotaUSA
| | - Allyson K. Palmer
- Robert and Arlene Kogod Center on AgingMayo ClinicRochesterMinnesotaUSA
- Division of Hospital Internal MedicineMayo ClinicRochesterMinnesotaUSA
| | - Steven R. Cummings
- Departments of Medicine, Epidemiology and BiostatisticsUniversity of California San FranciscoSan FranciscoCaliforniaUSA
- Research Institute, California Pacific Medical CenterSan FranciscoCaliforniaUSA
| | - Roger A. Fielding
- Nutrition, Exercise Physiology and Sarcopenia Laboratory, Jean Mayer USDA Human Nutrition Research Center on AgingTufts UniversityBostonMassachusettsUSA
| | | | - Nathan K. LeBrasseur
- Robert and Arlene Kogod Center on AgingMayo ClinicRochesterMinnesotaUSA
- Paul F. Glenn Center for the Biology of Aging ResearchMayo ClinicRochesterMinnesotaUSA
- Department of Physical Medicine and RehabilitationMayo ClinicRochesterMinnesotaUSA
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13
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Portha B, Liu J. Les AGE (produits terminaux de glycation) : attention danger. Origine, effets toxiques et stratégies thérapeutiques. CAHIERS DE NUTRITION ET DE DIÉTÉTIQUE 2023; 58:376-388. [DOI: 10.1016/j.cnd.2023.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Liao WL, Lin H, Li YH, Yang TY, Chen MC. RAGE potentiates EGFR signaling and interferes with the anticancer effect of gefitinib on NSCLC cells. Am J Physiol Cell Physiol 2023; 325:C1313-C1325. [PMID: 37746694 DOI: 10.1152/ajpcell.00494.2022] [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: 11/09/2022] [Revised: 09/18/2023] [Accepted: 09/18/2023] [Indexed: 09/26/2023]
Abstract
The receptor for advanced glycation end-products (RAGE) has been implicated in tumorigenesis, whereas epidermal growth factor receptor (EGFR) signaling plays a vital role in lung cancer progression. Both RAGE and EGFR are transmembrane receptors that transmit intracellular signals through ligand binding, and their downstream signaling cascades show substantial overlap. However, the interplay between these two molecules remains poorly understood. In the present study, we evaluated the correlation between RAGE and EGFR in the tumorigenesis of non-small cell lung cancer (NSCLC) and evaluated the impact of RAGE on the response of NSCLC cells to gefitinib, an EGFR-tyrosine kinase inhibitor (TKI). The expression and activation of EGFR and the phosphorylation of its downstream molecules, signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (Erk), were increased in RAGE-overexpressed A549 (A549-RAGE) cells. Notably, ligand-triggered activation of EGFR signaling was significantly greater in A549-RAGE compared with A549-parental cells. In addition, gefitinib had less effect on the inhibition of EGFR signaling in A549-RAGE cells. These findings were validated in other NSCLC cell lines, H1299 and H1975. Furthermore, upon gefitinib administration, the antiapoptotic marker B-cell lymphoma 2 (Bcl-2) expression was upregulated in A549-RAGE cells, whereas the apoptotic markers Bcl-2 associated X protein (Bax) and Bcl-2 interacting mediator (Bim) remained at lower levels compared with A549-parental cells. Importantly, our findings provide evidence that RAGE interferes with the anticancer effect of gefitinib by modulating the activation of EGFR-STAT3 and EGFR-Erk pathways. Overall, these significant findings deepen our understanding of the intricate relationship between RAGE and EGFR signaling in NSCLC tumorigenesis and provide new considerations for the clinical treatment of NSCLC.NEW & NOTEWORTHY This study represents a pioneering endeavor in comprehending the intricate interplay between RAGE and EGFR signaling within NSCLC. The findings reveal that RAGE serves to enhance EGFR phosphorylation and activation, consequently modulating apoptosis regulators through the EGFR-STAT3 and EGFR-Erk1/2 signaling pathways. Through this mechanism, RAGE potentially imparts resistance to the toxicity induced by EGFR-TKIs in NSCLC cells.
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Affiliation(s)
- Wan-Ling Liao
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Ho Lin
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Yu-Hsuan Li
- Department of Medical Research, Translational Cell Therapy Center, China Medical University Hospital, Taichung, Taiwan
| | - Tsung-Ying Yang
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Mei-Chih Chen
- Department of Medical Research, Translational Cell Therapy Center, China Medical University Hospital, Taichung, Taiwan
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15
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Sun S, Liu F, Fan F, Chen N, Pan X, Wei Z, Zhang Y. Exploring the mechanism of atherosclerosis and the intervention of traditional Chinese medicine combined with mesenchymal stem cells based on inflammatory targets. Heliyon 2023; 9:e22005. [PMID: 38045166 PMCID: PMC10692769 DOI: 10.1016/j.heliyon.2023.e22005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 11/01/2023] [Accepted: 11/01/2023] [Indexed: 12/05/2023] Open
Abstract
Atherosclerosis (AS) is a chronic inflammatory vascular disease, which is the common pathological basis of cardiovascular and cerebrovascular diseases. The immune inflammatory response throughout the course of AS has been evidenced by studies, in which a large number of immune cells and inflammatory factors play a crucial role in the pathogenesis of AS. The inflammation related to AS is mainly mediated by inflammatory cytokines (IL-1β, IL-6, IL-18, TNF-α, hs-CRP, SAA), inflammatory enzymes (Lp-PLA2, sPLA2-IIA, MMPs), and inflammatory signaling pathways (P38 MAPK signaling pathway, NF-κB signaling pathway, TLR2/4 signaling pathway). It is involved in the pathophysiological process of AS, and the degree of inflammation measured by it can be used to evaluate the risk of progression of AS plaque instability. In recent years, traditional Chinese medicine (TCM) has shown the advantage of minimal side effects in immune regulation and has made some progress in the prevention and treatment of AS. Mesenchymal stem cells (MSCs), as self-renewal, highly differentiated, and pluripotent stem cells with anti-inflammatory properties and immune regulation, have been widely used for AS treatment. They also play an important inflammation-immune regulatory function in AS. Notably, in terms of regulating immune cells and inflammatory factors, compared with TCM and its compound, the combination therapy has obvious anti-inflammatory advantages over the use of MSCs alone. It is an important means to further improve the efficacy of AS and provides a new way for the prevention and treatment of AS.
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Affiliation(s)
- Shibiao Sun
- Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Feixiang Liu
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Feiyan Fan
- Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Na Chen
- Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Xiaolong Pan
- Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Zhihui Wei
- Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Yunke Zhang
- Henan University of Chinese Medicine, Zhengzhou 450000, China
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
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16
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Ramasamy R, Shekhtman A, Schmidt AM. RAGE/DIAPH1 and atherosclerosis through an evolving lens: Viewing the cell from the "Inside - Out". Atherosclerosis 2023; 394:117304. [PMID: 39492058 PMCID: PMC11309734 DOI: 10.1016/j.atherosclerosis.2023.117304] [Citation(s) in RCA: 1] [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: 06/09/2023] [Revised: 08/11/2023] [Accepted: 09/15/2023] [Indexed: 08/13/2024]
Abstract
BACKGROUND AND AIMS In hyperglycemia, inflammation, oxidative stress and aging, Damage Associated Molecular Patterns (DAMPs) accumulate in conditions such as atherosclerosis. Binding of DAMPs to receptors such as the receptor for advanced glycation end products (RAGE) activates signal transduction cascades that contribute to cellular stress. The cytoplasmic domain (tail) of RAGE (ctRAGE) binds to the formin Diaphanous1 (DIAPH1), which is important for RAGE signaling. This Review will detail the evidence linking the RAGE/DIAPH1 signaling pathway to atherosclerosis and envisages future therapeutic opportunities from the "inside-out" point of view in affected cells. METHODS PubMed was searched using a variety of search terms, including "receptor for advanced glycation end products" along with various combinations including "and atherosclerosis," "soluble RAGE and atherosclerosis," "statins and RAGE," "PPAR and RAGE" and "SGLT2 inhibitor and RAGE." RESULTS In non-diabetic and diabetic mice, antagonism or global deletion of Ager (the gene encoding RAGE) retards progression and accelerates regression of atherosclerosis. Global deletion of Diaph1 in mice devoid of the low density lipoprotein receptor (Ldlr) significantly attenuates atherosclerosis; mice devoid of both Diaph1 and Ldlr display significantly lower plasma and liver concentrations of cholesterol and triglyceride compared to mice devoid of Ldlr. Associations between RAGE pathway and human atherosclerosis have been identified based on relationships between plasma/serum concentrations of RAGE ligands, soluble RAGEs and atherosclerosis. CONCLUSIONS Efforts to target RAGE/DIAPH1 signaling through a small molecule antagonist therapeutic strategy hold promise to quell accelerated atherosclerosis in diabetes and in other forms of cardiovascular disease.
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Affiliation(s)
- Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, NYU Langone Medical Center, NY, USA
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY, USA
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, NYU Langone Medical Center, NY, USA.
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17
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Abstract
Advanced glycation end products (AGEs), by-products of glucose metabolism, have been linked to the emergence of cardiovascular disorders (CVD). AGEs can cause tissue damage in four different ways: (1) by altering protein function, (2) by crosslinking proteins, which makes tissue stiffer, (3) by causing the generation of free radicals, and (4) by activating an inflammatory response after binding particular AGE receptors, such as the receptor for advanced glycation end products (RAGE). It is suggested that the soluble form of RAGE (sRAGE) blocks ligand-mediated pro-inflammatory and oxidant activities by serving as a decoy. Therefore, several studies have investigated the possible anti-inflammatory and anti-oxidant characteristics of sRAGE, which may help lower the risk of CVD. According to the results of various studies, the relationship between circulating sRAGE, cRAGE, and esRAGE and CVD is inconsistent. To establish the potential function of sRAGE as a therapeutic target in the treatment of cardiovascular illnesses, additional studies are required to better understand the relationship between sRAGE and CVD. In this review, we explored the potential function of sRAGE in different CVD, highlighting unanswered concerns and outlining the possibilities for further investigation.
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Affiliation(s)
- Charlotte Delrue
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium
| | - Joris R Delanghe
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Marijn M Speeckaert
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium; Research Foundation-Flanders (FWO), Brussels, Belgium.
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18
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Magna M, Hwang GH, McIntosh A, Drews-Elger K, Takabatake M, Ikeda A, Mera BJ, Kwak T, Miller P, Lippman ME, Hudson BI. RAGE inhibitor TTP488 (Azeliragon) suppresses metastasis in triple-negative breast cancer. NPJ Breast Cancer 2023; 9:59. [PMID: 37443146 DOI: 10.1038/s41523-023-00564-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic cancer subtype, which is generally untreatable once it metastasizes. We hypothesized that interfering with the Receptor for Advanced Glycation End-products (RAGE) signaling with the small molecule RAGE inhibitors (TTP488/Azeliragon and FPS-ZM1) would impair TNBC metastasis and impair fundamental mechanisms underlying tumor progression and metastasis. Both TTP488 and FPS-ZM1 impaired spontaneous and experimental metastasis of TNBC models, with TTP488 reducing metastasis to a greater degree than FPS-ZM1. Transcriptomic analysis of primary xenograft tumor and metastatic tissue revealed high concordance in gene and protein changes with both drugs, with TTP488 showing greater potency against metastatic driver pathways. Phenotypic validation of transcriptomic analysis by functional cell assays revealed that RAGE inhibition impaired TNBC cell adhesion to multiple extracellular matrix proteins (including collagens, laminins, and fibronectin), migration, and invasion. Neither RAGE inhibitor impaired cellular viability, proliferation, or cell cycle in vitro. Proteomic analysis of serum from tumor-bearing mice revealed RAGE inhibition affected metastatic driver mechanisms, including multiple cytokines and growth factors. Further mechanistic studies by phospho-proteomic analysis of tumors revealed RAGE inhibition led to decreased signaling through critical BC metastatic driver mechanisms, including Pyk2, STAT3, and Akt. These results show that TTP488 impairs metastasis of TNBC and further clarifies the signaling and cellular mechanisms through which RAGE mediates metastasis. Importantly, as TTP488 displays a favorable safety profile in human studies, our study provides the rationale for evaluating TTP488 in clinical trials to treat or prevent metastatic TNBC.
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Affiliation(s)
- Melinda Magna
- Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Gyong Ha Hwang
- Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Alec McIntosh
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Katherine Drews-Elger
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Masaru Takabatake
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Adam Ikeda
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Barbara J Mera
- Department of Cell Biology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Taekyoung Kwak
- Department of Cell Biology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Philip Miller
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Marc E Lippman
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Barry I Hudson
- Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
- Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
- Department of Cell Biology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
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19
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Reynaert NL, Vanfleteren LEGW, Perkins TN. The AGE-RAGE Axis and the Pathophysiology of Multimorbidity in COPD. J Clin Med 2023; 12:jcm12103366. [PMID: 37240472 DOI: 10.3390/jcm12103366] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/24/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs due to an enhanced inflammatory response, commonly caused by cigarette smoking. Patients with COPD are often multimorbid, as they commonly suffer from multiple chronic (inflammatory) conditions. This intensifies the burden of individual diseases, negatively affects quality of life, and complicates disease management. COPD and comorbidities share genetic and lifestyle-related risk factors and pathobiological mechanisms, including chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) is an important driver of chronic inflammation. Advanced glycation end products (AGEs) are RAGE ligands that accumulate due to aging, inflammation, oxidative stress, and carbohydrate metabolism. AGEs cause further inflammation and oxidative stress through RAGE, but also through RAGE-independent mechanisms. This review describes the complexity of RAGE signaling and the causes of AGE accumulation, followed by a comprehensive overview of alterations reported on AGEs and RAGE in COPD and in important co-morbidities. Furthermore, it describes the mechanisms by which AGEs and RAGE contribute to the pathophysiology of individual disease conditions and how they execute crosstalk between organ systems. A section on therapeutic strategies that target AGEs and RAGE and could alleviate patients from multimorbid conditions using single therapeutics concludes this review.
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Affiliation(s)
- Niki L Reynaert
- Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
| | - Lowie E G W Vanfleteren
- COPD Center, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
| | - Timothy N Perkins
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
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20
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Kim Y. Blood and Tissue Advanced Glycation End Products as Determinants of Cardiometabolic Disorders Focusing on Human Studies. Nutrients 2023; 15:nu15082002. [PMID: 37111220 PMCID: PMC10144557 DOI: 10.3390/nu15082002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 04/29/2023] Open
Abstract
Cardiometabolic disorders are characterised by a cluster of interactive risk determinants such as increases in blood glucose, lipids and body weight, as well as elevated inflammation and oxidative stress and gut microbiome changes. These disorders are associated with onset of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). T2DM is strongly associated with CVD. Dietary advanced glycation end products (dAGEs) attributable from modern diets high in sugar and/or fat, highly processed foods and high heat-treated foods can contribute to metabolic etiologies of cardiometabolic disorders. This mini review aims to determine whether blood dAGEs levels and tissue dAGEs levels are determinants of the prevalence of cardiometabolic disorders through recent human studies. ELISA (enzyme-linked immunosorbent assay), high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) for blood dAGEs measurement and skin auto fluorescence (SAF) for skin AGEs measurement can be used. Recent human studies support that a diet high in AGEs can negatively influence glucose control, body weight, blood lipid levels and vascular health through the elevated oxidative stress, inflammation, blood pressure and endothelial dysfunction compared with a diet low in AGEs. Limited human studies suggested a diet high in AGEs could negatively alter gut microbiota. SAF could be considered as one of the predictors affecting risks for cardiometabolic disorders. More intervention studies are needed to determine how dAGEs are associated with the prevalence of cardiometabolic disorders through gut microbiota changes. Further human studies are conducted to find the association between CVD events, CVD mortality and total mortality through SAF measurement, and a consensus on whether tissue dAGEs act as a predictor of CVD is required.
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Affiliation(s)
- Yoona Kim
- Department of Food and Nutrition, Institute of Agriculture and Life Science, Gyeongsang National University, 501 Jinju-daero, Jinju 52828, Gyeongsangnam-do, Republic of Korea
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21
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Rietjens RGJ, Wang G, van der Velden AIM, Koudijs A, Avramut MC, Kooijman S, Rensen PCN, van der Vlag J, Rabelink TJ, Heijs B, van den Berg BM. Phosphatidylinositol metabolism of the renal proximal tubule S3 segment is disturbed in response to diabetes. Sci Rep 2023; 13:6261. [PMID: 37069341 PMCID: PMC10110589 DOI: 10.1038/s41598-023-33442-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/12/2023] [Indexed: 04/19/2023] Open
Abstract
Diabetes is a main risk factor for kidney disease, causing diabetic nephropathy in close to half of all patients with diabetes. Metabolism has recently been identified to be decisive in cell fate decisions and repair. Here we used mass spectrometry imaging (MSI) to identify tissue specific metabolic dysregulation, in order to better understand early diabetes-induced metabolic changes of renal cell types. In our experimental diabetes mouse model, early glomerular glycocalyx barrier loss and systemic metabolic changes were observed. In addition, MSI targeted at small molecule metabolites and glycero(phospho)lipids exposed distinct changes upon diabetes in downstream nephron segments. Interestingly, the outer stripe of the outer medullar proximal tubular segment (PT_S3) demonstrated the most distinct response compared to other segments. Furthermore, phosphatidylinositol lipid metabolism was altered specifically in PT_S3, with one of the phosphatidylinositol fatty acid tails being exchanged from longer unsaturated fatty acids to shorter, more saturated fatty acids. In acute kidney injury, the PT_S3 segment and its metabolism are already recognized as important factors in kidney repair processes. The current study exposes early diabetes-induced changes in membrane lipid composition in this PT_S3 segment as a hitherto unrecognized culprit in the early renal response to diabetes.
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Affiliation(s)
- Rosalie G J Rietjens
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
| | - Gangqi Wang
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
| | - Anouk I M van der Velden
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Angela Koudijs
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - M Cristina Avramut
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Department of Cell and Chemical Biology (Electron Microscopy), Leiden University Medical Center, Leiden, The Netherlands
| | - Sander Kooijman
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Department of Internal Medicine (Endocrinology), Leiden University Medical Center, Leiden, The Netherlands
| | - Patrick C N Rensen
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Department of Internal Medicine (Endocrinology), Leiden University Medical Center, Leiden, The Netherlands
| | - Johan van der Vlag
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ton J Rabelink
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
| | - Bram Heijs
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Bernard M van den Berg
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands.
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands.
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22
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Castelli R, Gidaro A, Casu G, Merella P, Profili NI, Donadoni M, Maioli M, Delitala AP. Aging of the Arterial System. Int J Mol Sci 2023; 24:6910. [PMID: 37108072 PMCID: PMC10139087 DOI: 10.3390/ijms24086910] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
Aging of the vascular system is associated with deep changes of the structural proprieties of the arterial wall. Arterial hypertension, diabetes mellitus, and chronic kidney disease are the major determinants for the loss of elasticity and reduced compliance of vascular wall. Arterial stiffness is a key parameter for assessing the elasticity of the arterial wall and can be easily evaluated with non-invasive methods, such as pulse wave velocity. Early assessment of vessel stiffness is critical because its alteration can precede clinical manifestation of cardiovascular disease. Although there is no specific pharmacological target for arterial stiffness, the treatment of its risk factors helps to improve the elasticity of the arterial wall.
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Affiliation(s)
- Roberto Castelli
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Antonio Gidaro
- Department of Biomedical and Clinical Sciences Luigi Sacco, Luigi Sacco Hospital, University of Milan, 20157 Milan, Italy
| | - Gavino Casu
- Cardiology Unit, Azienda Ospedaliero, Universitaria di Sassari, 07100 Sassari, Italy
| | - Pierluigi Merella
- Cardiology Unit, Azienda Ospedaliero, Universitaria di Sassari, 07100 Sassari, Italy
| | - Nicia I. Profili
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Mattia Donadoni
- Department of Biomedical and Clinical Sciences Luigi Sacco, Luigi Sacco Hospital, University of Milan, 20157 Milan, Italy
| | - Margherita Maioli
- Department of Biochemical Science, University of Sassari, 07100 Sassari, Italy
| | - Alessandro P. Delitala
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
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23
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Terasaki M, Shibata K, Mori Y, Saito T, Matsui T, Ohara M, Fukui T, Hasumi K, Higashimoto Y, Nobe K, Yamagishi SI. SMTP-44D Inhibits Atherosclerotic Plaque Formation in Apolipoprotein-E Null Mice Partly by Suppressing the AGEs-RAGE Axis. Int J Mol Sci 2023; 24:ijms24076505. [PMID: 37047475 PMCID: PMC10094964 DOI: 10.3390/ijms24076505] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/24/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in atherosclerotic cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental atherosclerosis by suppressing the AGEs–RAGE axis. In this study, we investigated the effects of SMTP-44D on atherosclerotic plaque formation and expression of AGEs in apolipoprotein-E null (Apoe−/−) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from Apoe−/− mice ex vivo. Although administration of SMTP-44D to Apoe−/− mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and gene expression of RAGE, cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated Apoe−/− mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit atherosclerotic plaque formation in Apoe−/− mice partly by blocking the AGEs-RAGE-induced ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway.
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24
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Senatus L, Egaña-Gorroño L, López-Díez R, Bergaya S, Aranda JF, Amengual J, Arivazhagan L, Manigrasso MB, Yepuri G, Nimma R, Mangar KN, Bernadin R, Zhou B, Gugger PF, Li H, Friedman RA, Theise ND, Shekhtman A, Fisher EA, Ramasamy R, Schmidt AM. DIAPH1 mediates progression of atherosclerosis and regulates hepatic lipid metabolism in mice. Commun Biol 2023; 6:280. [PMID: 36932214 PMCID: PMC10023694 DOI: 10.1038/s42003-023-04643-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/01/2023] [Indexed: 03/19/2023] Open
Abstract
Atherosclerosis evolves through dysregulated lipid metabolism interwoven with exaggerated inflammation. Previous work implicating the receptor for advanced glycation end products (RAGE) in atherosclerosis prompted us to explore if Diaphanous 1 (DIAPH1), which binds to the RAGE cytoplasmic domain and is important for RAGE signaling, contributes to these processes. We intercrossed atherosclerosis-prone Ldlr-/- mice with mice devoid of Diaph1 and fed them Western diet for 16 weeks. Compared to male Ldlr-/- mice, male Ldlr-/- Diaph1-/- mice displayed significantly less atherosclerosis, in parallel with lower plasma concentrations of cholesterol and triglycerides. Female Ldlr-/- Diaph1-/- mice displayed significantly less atherosclerosis compared to Ldlr-/- mice and demonstrated lower plasma concentrations of cholesterol, but not plasma triglycerides. Deletion of Diaph1 attenuated expression of genes regulating hepatic lipid metabolism, Acaca, Acacb, Gpat2, Lpin1, Lpin2 and Fasn, without effect on mRNA expression of upstream transcription factors Srebf1, Srebf2 or Mxlipl in male mice. We traced DIAPH1-dependent mechanisms to nuclear translocation of SREBP1 in a manner independent of carbohydrate- or insulin-regulated cues but, at least in part, through the actin cytoskeleton. This work unveils new regulators of atherosclerosis and lipid metabolism through DIAPH1.
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Affiliation(s)
- Laura Senatus
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Lander Egaña-Gorroño
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Raquel López-Díez
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Sonia Bergaya
- The Leon H. Charney Division of Cardiology, Department of Medicine, The Marc and Ruti Bell Program in Vascular Biology, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Juan Francisco Aranda
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Jaume Amengual
- The Leon H. Charney Division of Cardiology, Department of Medicine, The Marc and Ruti Bell Program in Vascular Biology, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Lakshmi Arivazhagan
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Michaele B Manigrasso
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Gautham Yepuri
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Ramesh Nimma
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Kaamashri N Mangar
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Rollanda Bernadin
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Boyan Zhou
- Department of Population Health, Division of Biostatistics, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Paul F Gugger
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Huilin Li
- Department of Population Health, Division of Biostatistics, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Richard A Friedman
- Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA
| | - Neil D Theise
- Department of Pathology, NYU Grossman School of Medicine, NYU Langone Health, New York, USA
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY, USA
| | - Edward A Fisher
- The Leon H. Charney Division of Cardiology, Department of Medicine, The Marc and Ruti Bell Program in Vascular Biology, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA.
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25
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Dorenkamp M, Nasiry M, Semo D, Koch S, Löffler I, Wolf G, Reinecke H, Godfrey R. Pharmacological Targeting of the RAGE-NFκB Signalling Axis Impedes Monocyte Activation under Diabetic Conditions through the Repression of SHP-2 Tyrosine Phosphatase Function. Cells 2023; 12:cells12030513. [PMID: 36766855 PMCID: PMC9914555 DOI: 10.3390/cells12030513] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/19/2022] [Accepted: 09/23/2022] [Indexed: 02/09/2023] Open
Abstract
Monocytes play a vital role in the development of cardiovascular diseases. Type 2 diabetes mellitus (T2DM) is a major CVD risk factor, and T2DM-induced aberrant activation and enhanced migration of monocytes is a vital pathomechanism that leads to atherogenesis. We recently reported the upregulation of SHP-2 phosphatase expression in mediating the VEGF resistance of T2DM patient-derived monocytes or methylglyoxal- (MG, a glucose metabolite and advanced glycation end product (AGE) precursor) treated monocytes. However, the exact mechanisms leading to SHP-2 upregulation in hyperglycemic monocytes are unknown. Since inflammation and accumulation of AGEs is a hallmark of T2DM, we hypothesise that inflammation and AGE-RAGE (Receptor-for-AGEs) signalling drive SHP-2 expression in monocytes and blockade of these pathways will repress SHP-2 function. Indeed, monocytes from T2DM patients revealed an elevated SHP-2 expression. Under normoglycemic conditions, the serum from T2DM patients strongly induced SHP-2 expression, indicating that the T2DM serum contains critical factors that directly regulate SHP-2 expression. Activation of pro-inflammatory TNFα signalling cascade drove SHP-2 expression in monocytes. In line with this, linear regression analysis revealed a significant positive correlation between TNFα expression and SHP-2 transcript levels in T2DM monocytes. Monocytes exposed to MG or AGE mimetic AGE-BSA, revealed an elevated SHP-2 expression and co-treatment with an NFκB inhibitor or genetic inhibition of p65 reversed it. The pharmacological inhibition of RAGE was sufficient to block MG- or AGE-BSA-induced SHP-2 expression and activity. Confirming the importance of RAGE-NFκB signalling in regulating SHP-2 expression, the elevated binding of NFκB to the SHP-2 promoter-induced by MG or AGE-BSA-was reversed by RAGE and NFκB inhibition. Besides, we detected elevated RAGE levels in human and murine T2DM monocytes and monocytes exposed to MG or AGE-BSA. Importantly, MG and AGE-BSA treatment of non-T2DM monocytes phenocopied the aberrant pro-migratory phenotype of T2DM monocytes, which was reversed entirely by either SHP-2- or RAGE inhibition. In conclusion, these findings suggest a new therapeutic approach to prevent accelerated atherosclerosis in T2DM patients since inhibiting the RAGE-NFκB-SHP-2 axis impeded the T2DM-driven, SHP-2-dependent monocyte activation.
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Affiliation(s)
- Marc Dorenkamp
- Vascular Signalling, Molecular Cardiology, Department of Cardiology I—Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, 48149 Münster, Germany
| | - Madina Nasiry
- Vascular Signalling, Molecular Cardiology, Department of Cardiology I—Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, 48149 Münster, Germany
| | - Dilvin Semo
- Vascular Signalling, Molecular Cardiology, Department of Cardiology I—Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, 48149 Münster, Germany
| | - Sybille Koch
- Vascular Signalling, Molecular Cardiology, Department of Cardiology I—Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, 48149 Münster, Germany
| | - Ivonne Löffler
- Department of Internal Medicine III, University Hospital Jena, 07743 Jena, Germany
| | - Gunter Wolf
- Department of Internal Medicine III, University Hospital Jena, 07743 Jena, Germany
| | - Holger Reinecke
- Vascular Signalling, Molecular Cardiology, Department of Cardiology I—Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, 48149 Münster, Germany
| | - Rinesh Godfrey
- Vascular Signalling, Molecular Cardiology, Department of Cardiology I—Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, 48149 Münster, Germany
- Correspondence: ; Tel.: +49-251-83-57089; Fax: +49-251-83-55747
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26
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Lai SWT, Lopez Gonzalez EDJ, Zoukari T, Ki P, Shuck SC. Methylglyoxal and Its Adducts: Induction, Repair, and Association with Disease. Chem Res Toxicol 2022; 35:1720-1746. [PMID: 36197742 PMCID: PMC9580021 DOI: 10.1021/acs.chemrestox.2c00160] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Metabolism is an essential part of life that provides energy for cell growth. During metabolic flux, reactive electrophiles are produced that covalently modify macromolecules, leading to detrimental cellular effects. Methylglyoxal (MG) is an abundant electrophile formed from lipid, protein, and glucose metabolism at intracellular levels of 1-4 μM. MG covalently modifies DNA, RNA, and protein, forming advanced glycation end products (MG-AGEs). MG and MG-AGEs are associated with the onset and progression of many pathologies including diabetes, cancer, and liver and kidney disease. Regulating MG and MG-AGEs is a potential strategy to prevent disease, and they may also have utility as biomarkers to predict disease risk, onset, and progression. Here, we review recent advances and knowledge surrounding MG, including its production and elimination, mechanisms of MG-AGEs formation, the physiological impact of MG and MG-AGEs in disease onset and progression, and the latter in the context of its receptor RAGE. We also discuss methods for measuring MG and MG-AGEs and their clinical application as prognostic biomarkers to allow for early detection and intervention prior to disease onset. Finally, we consider relevant clinical applications and current therapeutic strategies aimed at targeting MG, MG-AGEs, and RAGE to ultimately improve patient outcomes.
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Affiliation(s)
- Seigmund Wai Tsuen Lai
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Edwin De Jesus Lopez Gonzalez
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Tala Zoukari
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Priscilla Ki
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Sarah C Shuck
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
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27
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Scavello F, Piacentini L, Castiglione S, Zeni F, Macrì F, Casaburo M, Vinci MC, Colombo GI, Raucci A. Effects of RAGE Deletion on the Cardiac Transcriptome during Aging. Int J Mol Sci 2022; 23:ijms231911130. [PMID: 36232442 PMCID: PMC9569842 DOI: 10.3390/ijms231911130] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 09/15/2022] [Accepted: 09/19/2022] [Indexed: 11/25/2022] Open
Abstract
Cardiac aging is characterized by increased cardiomyocyte hypertrophy, myocardial stiffness, and fibrosis, which enhance cardiovascular risk. The receptor for advanced glycation end-products (RAGE) is involved in several age-related diseases. RAGE knockout (Rage−/−) mice show an acceleration of cardiac dimension changes and interstitial fibrosis with aging. This study identifies the age-associated cardiac gene expression signature induced by RAGE deletion. We analyzed the left ventricle transcriptome of 2.5-(Young), 12-(Middle age, MA), and 21-(Old) months-old female Rage−/− and C57BL/6N (WT) mice. By comparing Young, MA, and Old Rage−/− versus age-matched WT mice, we identified 122, 192, and 12 differently expressed genes, respectively. Functional inference analysis showed that RAGE deletion is associated with: (i) down-regulation of genes involved in antigen processing and presentation of exogenous antigen, adaptive immune response, and cellular responses to interferon beta and gamma in Young animals; (ii) up-regulation of genes related to fatty acid oxidation, cardiac structure remodeling and cellular response to hypoxia in MA mice; (iii) up-regulation of few genes belonging to complement activation and triglyceride biosynthetic process in Old animals. Our findings show that the age-dependent cardiac phenotype of Rage−/− mice is associated with alterations of genes related to adaptive immunity and cardiac stress pathways.
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Affiliation(s)
- Francesco Scavello
- Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
| | - Luca Piacentini
- Bioinformatics and Artificial Intelligence Facility, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
| | - Stefania Castiglione
- Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
| | - Filippo Zeni
- Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
| | - Federica Macrì
- Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
| | - Manuel Casaburo
- Animal Facility, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
| | - Maria Cristina Vinci
- Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
| | - Gualtiero I. Colombo
- Unit of Immunology and Functional Genomics, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
- Correspondence: (G.I.C.); (A.R.); Tel.: +39-025-800-2464 (G.I.C.); +39-025-800-2802 (A.R.); Fax: +39-025-800-2342 (G.I.C. & A.R.)
| | - Angela Raucci
- Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
- Animal Facility, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
- Correspondence: (G.I.C.); (A.R.); Tel.: +39-025-800-2464 (G.I.C.); +39-025-800-2802 (A.R.); Fax: +39-025-800-2342 (G.I.C. & A.R.)
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28
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Li W, Jin K, Luo J, Xu W, Wu Y, Zhou J, Wang Y, Xu R, Jiao L, Wang T, Yang G. NF-κB and its crosstalk with endoplasmic reticulum stress in atherosclerosis. Front Cardiovasc Med 2022; 9:988266. [PMID: 36204587 PMCID: PMC9530249 DOI: 10.3389/fcvm.2022.988266] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
Atherosclerosis (AS) is a common cardiovascular disease with complex pathogenesis, in which multiple pathways and their interweaving regulatory mechanism remain unclear. The primary transcription factor NF-κB plays a critical role in AS via modulating the expression of a series of inflammatory mediators under various stimuli such as cytokines, microbial antigens, and intracellular stresses. Endoplasmic reticulum (ER) stress, caused by the disrupted synthesis and secretion of protein, links inflammation, metabolic signals, and other cellular processes via the unfolded protein response (UPR). Both NF-κB and ER stress share the intersection regarding their molecular regulation and function and are regarded as critical individual contributors to AS. In this review, we summarize the multiple interactions between NF-κB and ER stress activation, including the UPR, NLRP3 inflammasome, and reactive oxygen species (ROS) generation, which have been ignored in the pathogenesis of AS. Given the multiple links between NF-κB and ER stress, we speculate that the integrated network contributes to the understanding of molecular mechanisms of AS. This review aims to provide an insight into these interactions and their underlying roles in the progression of AS, highlighting potential pharmacological targets against the atherosclerotic inflammatory process.
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Affiliation(s)
- Wenjing Li
- Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China
- School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China
| | - Kehan Jin
- Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jichang Luo
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- China International Neuroscience Institute (China-INI), Beijing, China
| | - Wenlong Xu
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- China International Neuroscience Institute (China-INI), Beijing, China
| | - Yujie Wu
- Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China
| | - Jia Zhou
- Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yilin Wang
- Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Ran Xu
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- China International Neuroscience Institute (China-INI), Beijing, China
| | - Liqun Jiao
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- China International Neuroscience Institute (China-INI), Beijing, China
- Department of Interventional Radiology, Xuanwu Hospital, Capital Medical University, Beijing, China
- *Correspondence: Liqun Jiao,
| | - Tao Wang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- China International Neuroscience Institute (China-INI), Beijing, China
- Tao Wang,
| | - Ge Yang
- Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China
- School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China
- Tao Wang,
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Liu D, Chen J, Xie Y, Mei X, Xu C, Liu J, Cao X. Investigating the molecular mechanisms of glyoxal-induced cytotoxicity in human embryonic kidney cells: Insights from network toxicology and cell biology experiments. ENVIRONMENTAL TOXICOLOGY 2022; 37:2269-2280. [PMID: 35621379 DOI: 10.1002/tox.23593] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/28/2022] [Accepted: 05/14/2022] [Indexed: 06/15/2023]
Abstract
Glyoxal, a reactive carbonyl species, can be generated both endogenously (glucose metabolism) and exogenously (cigarette smoke and food system). Increasing evidence demonstrates that glyoxal exacerbates the development and progression of diabetic nephropathy, but the underlying mechanisms of glyoxal toxicity to human embryonic kidney (HEK293) cells remain unclear. In this work, the molecular mechanisms of glyoxal-induced cytotoxicity in HEK293 cells were explored with network toxicology and cell biology experiments. Network toxicology results showed that oxidative stress and advanced glycation end products (AGEs)/RAGE signaling pathways played a crucial role in glyoxal toxicity. Next, further validation was performed at the cellular level. Glyoxal activated the AGEs-RAGE signaling pathway, caused the increase of cellular ROS, and activated the p38MAPK and JNK signaling pathways, causing cellular oxidative stress. Furthermore, glyoxal caused the activation of the NF-κB signaling pathway and increased the expression of TGF-β1, indicating that glyoxal caused cellular inflammation. Moreover, glyoxal caused cellular DNA damage accompanied by the activation of DNA damage response pathways. Finally, the mitochondrial apoptosis pathway was activated. The results that obtained in cell biology were consistent with network toxicology, which corroborated each other and together indicated that glyoxal induced HEK293 cells damage via the process of oxidative stress, the AGEs-RAGE pathway, and their associated signaling pathways. This study provides the experimental basis for the cytotoxicity of glyoxal on HEK293 cells.
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Affiliation(s)
- Dan Liu
- School of life Science, Liaoning University, Shenyang, China
| | - Junliang Chen
- School of life Science, Liaoning University, Shenyang, China
| | - Yanzhen Xie
- School of life Science, Liaoning University, Shenyang, China
| | - Xueying Mei
- School of life Science, Liaoning University, Shenyang, China
| | - Chengbin Xu
- School of Environment Science, Liaoning University, Shenyang, China
| | - Jianli Liu
- School of life Science, Liaoning University, Shenyang, China
| | - Xiangyu Cao
- School of life Science, Liaoning University, Shenyang, China
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Aftermath of AGE-RAGE Cascade in the pathophysiology of cardiovascular ailments. Life Sci 2022; 307:120860. [PMID: 35940220 DOI: 10.1016/j.lfs.2022.120860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 07/20/2022] [Accepted: 08/01/2022] [Indexed: 11/21/2022]
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Advanced Glycation End Product (AGE) and Soluble Receptor of AGE (sRAGE) Levels in Relation to Periodontitis Severity and as Putative 3-Year Outcome Predictors in Patients Undergoing Coronary Artery Bypass Grafting (CABG). J Clin Med 2022; 11:jcm11144105. [PMID: 35887868 PMCID: PMC9317367 DOI: 10.3390/jcm11144105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 06/22/2022] [Accepted: 07/13/2022] [Indexed: 12/03/2022] Open
Abstract
Tissue concentrations of advanced glycation end product (AGE) and peripheral soluble receptor of AGE (sRAGE) levels may be associated with periodontitis severity. Both parameters and periodontitis might serve as outcome predictors for patients undergoing coronary artery bypass grafting (CABG). This study aimed to investigate possible associations between periodontitis and AGE/sRAGE. Ultimately, we wanted to examine whether AGE, sRAGE, and severe periodontitis are associated with the incidence of new cardiovascular events within 3 years of follow-up after CABG. Ninety-five patients with coronary vascular disease (CVD) (age 69 years, 88.3% males) needing CABG surgery were included. Periodontal diagnosis was made according to the guidelines of the “Centers for Disease Control and Prevention (CDC)” (2007) and staged according to the new classification of periodontal diseases (2018). AGE tissue concentrations were assessed as skin autofluorescence (sAF). sRAGE levels were determined by using a commercially available enzyme-linked immunoabsorbance assay (ELISA) kit. Univariate and multivariate baseline and survival analyses were carried out with Mann–Whitney U test, Chi² test, Kaplan–Meier curves with Log-Rank test, and logistic and Cox regression. sAF was identified as an independent risk indicator for severe periodontitis with respect to the cofactors age, gender, plaque index, and diabetes (adjusted odds ratio [OR] = 2.9, p = 0.028). The degree of subgingival inflammation assessed as a percentage of sites with bleeding on probing (BOP) was inversely correlated with sRAGE concentration (r = −0.189, p = 0.034). Both sAF (Hazard Ratio [HR] = 2.4, p = 0.004) and sRAGE (HR = 1.9, p = 0.031) increased the crude risk for new adverse events after CABG. The occurrence of severe periodontitis trends towards a higher risk for new cardiovascular events (HR = 1.8, p = 0.115). Applying multivariate Cox regression, only peripheral arterial disease (adjusted HR = 2.7, p = 0.006) and history of myocardial infarction (adjusted HR = 2.8, p = 0.010) proved to be independent risk factors for cardiovascular outcome. We conclude that sAF may represent a new, independent risk indicator for severe periodontitis. In contrast, sAF, sRAGE, and severe periodontitis were not independent prognostic factors for postoperative outcome in patients undergoing CABG.
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Yamaguchi K, Iwamoto H, Sakamoto S, Horimasu Y, Masuda T, Miyamoto S, Nakashima T, Fujitaka K, Hamada H, Hattori N. Association of the RAGE/RAGE-ligand axis with interstitial lung disease and its acute exacerbation. Respir Investig 2022; 60:531-542. [PMID: 35504814 DOI: 10.1016/j.resinv.2022.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/10/2022] [Accepted: 04/12/2022] [Indexed: 06/14/2023]
Abstract
The receptor for advanced glycation end product (RAGE) is a transmembrane receptor highly expressed in type 1 pneumocytes of healthy lungs. RAGE is considered to play a homeostatic role in the lung, as RAGE knockout mice develop lung fibrosis as they age. In contrast, RAGE can bind numerous ligands, including high-mobility group box 1 (HMGB1). These interactions initiate pro-inflammatory signaling associated with the pathogenesis of lung injury and interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF). ILD is a broad category of diffuse parenchymal lung disease characterized by various extents of lung fibrosis and inflammation, and IPF is a common and progressive ILD of unknown cause. The prognosis of patients with IPF is poor, and acute exacerbation of IPF (AE-IPF) is one of the main causes of death. Recent reports indicate that acute exacerbations can occur in other ILDs (AE-ILD). Notably, ILD is frequently observed in patients with lung cancer, and AE-ILD after surgical procedures or the initiation of chemotherapy for concomitant lung cancer are clinically important due to their association with increased mortality. In this review, we summarize the associations of RAGE/soluble RAGE (sRAGE)/RAGE ligands with the pathogenesis and clinical course of ILD, including IPF and AE-IPF. Additionally, the potential use of sRAGE and RAGE ligands as predictive markers of AE-IPF and cancer treatment-triggered AE-ILD is also discussed.
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Affiliation(s)
- Kakuhiro Yamaguchi
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan.
| | - Hiroshi Iwamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Shinjiro Sakamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Yasushi Horimasu
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Takeshi Masuda
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Shintaro Miyamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Taku Nakashima
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Kazunori Fujitaka
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
| | - Hironobu Hamada
- Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Noboru Hattori
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan
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Bornfeldt KE. The Remnant Lipoprotein Hypothesis of Diabetes-Associated Cardiovascular Disease. Arterioscler Thromb Vasc Biol 2022; 42:819-830. [PMID: 35616031 DOI: 10.1161/atvbaha.122.317163] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Both type 1 and type 2 diabetes are associated with an increased risk of atherosclerotic cardiovascular disease (CVD). Research based on human-first or bedside-to-bench approaches has provided new insights into likely mechanisms behind this increased risk. Although both forms of diabetes are associated with hyperglycemia, it is becoming increasingly clear that altered lipoprotein metabolism also plays a critical role in predicting CVD risk in people with diabetes. This review examines recent findings indicating that increased levels of circulating remnant lipoproteins could be a missing link between diabetes and CVD. Although CVD risk associated with diabetes is clearly multifactorial in nature, these findings suggest that we should increase efforts in evaluating whether remnant lipoproteins or the proteins that govern their metabolism are biomarkers of incident CVD in people living with diabetes and whether reducing remnant lipoproteins will prevent the increased CVD risk associated with diabetes.
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Affiliation(s)
- Karin E Bornfeldt
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition and Department of Laboratory Medicine and Pathology, University of Washington Medicine Diabetes Institute, Seattle
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Advanced Glycation End Products (AGEs) and Chronic Kidney Disease: Does the Modern Diet AGE the Kidney? Nutrients 2022; 14:nu14132675. [PMID: 35807857 PMCID: PMC9268915 DOI: 10.3390/nu14132675] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 12/13/2022] Open
Abstract
Since the 1980s, chronic kidney disease (CKD) affecting all ages has increased by almost 25%. This increase may be partially attributable to lifestyle changes and increased global consumption of a “western” diet, which is typically energy dense, low in fruits and vegetables, and high in animal protein and ultra-processed foods. These modern food trends have led to an increase in the consumption of advanced glycation end products (AGEs) in conjunction with increased metabolic dysfunction, obesity and diabetes, which facilitates production of endogenous AGEs within the body. When in excess, AGEs can be pathological via both receptor-mediated and non-receptor-mediated pathways. The kidney, as a major site for AGE clearance, is particularly vulnerable to AGE-mediated damage and increases in circulating AGEs align with risk of CKD and all-cause mortality. Furthermore, individuals with significant loss of renal function show increased AGE burden, particularly with uraemia, and there is some evidence that AGE lowering via diet or pharmacological inhibition may be beneficial for CKD. This review discusses the pathways that drive AGE formation and regulation within the body. This includes AGE receptor interactions and pathways of AGE-mediated pathology with a focus on the contribution of diet on endogenous AGE production and dietary AGE consumption to these processes. We then analyse the contribution of AGEs to kidney disease, the evidence for dietary AGEs and endogenously produced AGEs in driving pathogenesis in diabetic and non-diabetic kidney disease and the potential for AGE targeted therapies in kidney disease.
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35
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Arivazhagan L, López-Díez R, Shekhtman A, Ramasamy R, Schmidt AM. Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) - Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease. Front Cardiovasc Med 2022; 9:937071. [PMID: 35811725 PMCID: PMC9263181 DOI: 10.3389/fcvm.2022.937071] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 05/30/2022] [Indexed: 12/25/2022] Open
Abstract
Obesity and non-alcoholic fatty liver disease (NAFLD) are on the rise world-wide; despite fervent advocacy for healthier diets and enhanced physical activity, these disorders persist unabated and, long-term, are major causes of morbidity and mortality. Numerous fundamental biochemical and molecular pathways participate in these events at incipient, mid- and advanced stages during atherogenesis and impaired regression of established atherosclerosis. It is proposed that upon the consumption of high fat/high sugar diets, the production of receptor for advanced glycation end products (RAGE) ligands, advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), contribute to the development of foam cells, endothelial injury, vascular inflammation, and, ultimately, atherosclerosis and its consequences. RAGE/Diaphanous-1 (DIAPH1) increases macrophage foam cell formation; decreases cholesterol efflux and causes foam cells to produce and release damage associated molecular patterns (DAMPs) molecules, which are also ligands of RAGE. DAMPs stimulate upregulation of Interferon Regulatory Factor 7 (IRF7) in macrophages, which exacerbates vascular inflammation and further perturbs cholesterol metabolism. Obesity and NAFLD, characterized by the upregulation of AGEs, ALEs and DAMPs in the target tissues, contribute to insulin resistance, hyperglycemia and type two diabetes. Once in motion, a vicious cycle of RAGE ligand production and exacerbation of RAGE/DIAPH1 signaling ensues, which, if left unchecked, augments cardiometabolic disease and its consequences. This Review focuses on RAGE/DIAPH1 and its role in perturbation of metabolism and processes that converge to augur cardiovascular disease.
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Affiliation(s)
- Lakshmi Arivazhagan
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
| | - Raquel López-Díez
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY, United States
| | - Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States,*Correspondence: Ann Marie Schmidt
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36
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Gisterå A, Ketelhuth DFJ, Malin SG, Hansson GK. Animal Models of Atherosclerosis-Supportive Notes and Tricks of the Trade. Circ Res 2022; 130:1869-1887. [PMID: 35679358 DOI: 10.1161/circresaha.122.320263] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Atherosclerotic cardiovascular disease is a major cause of death among humans. Animal models have shown that cholesterol and inflammation are causatively involved in the disease process. Apolipoprotein B-containing lipoproteins elicit immune reactions and instigate inflammation in the vessel wall. Still, a treatment that is specific to vascular inflammation is lacking, which motivates continued in vivo investigations of the immune-vascular interactions that drive the disease. In this review, we distill old notions with emerging concepts into a contemporary understanding of vascular disease models. Pros and cons of different models are listed and the complex integrative interplay between cholesterol homeostasis, immune activation, and adaptations of the vascular system is discussed. Key limitations with atherosclerosis models are highlighted, and we suggest improvements that could accelerate progress in the field. However, excessively rigid experimental guidelines or limiting usage to certain animal models can be counterproductive. Continued work in improved models, as well as the development of new models, should be of great value in research and could aid the development of cardiovascular disease diagnostics and therapeutics of the future.
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Affiliation(s)
- Anton Gisterå
- Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (A.G., D.F.J.K., S.G.M., G.K.H.)
| | - Daniel F J Ketelhuth
- Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (A.G., D.F.J.K., S.G.M., G.K.H.).,Department of Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark (SDU), Odense, Denmark (D.F.J.K)
| | - Stephen G Malin
- Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (A.G., D.F.J.K., S.G.M., G.K.H.)
| | - Göran K Hansson
- Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (A.G., D.F.J.K., S.G.M., G.K.H.)
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Sabbatinelli J, Castiglione S, Macrì F, Giuliani A, Ramini D, Vinci MC, Tortato E, Bonfigli AR, Olivieri F, Raucci A. Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study. Cardiovasc Diabetol 2022; 21:95. [PMID: 35668468 PMCID: PMC9169316 DOI: 10.1186/s12933-022-01535-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 05/26/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Advanced glycation end-products (AGEs) and their interaction with the receptor for advanced glycation end-products (RAGE) play a pivotal role in the development and progression of type 2 diabetes. In this retrospective cohort study, we explored the association of circulating levels of soluble RAGE (sRAGE) isoforms, i.e., endogenous secretory esRAGE and cleaved cRAGE, AGEs and their respective ratios with 15-year all-cause mortality in type 2 diabetes. METHODS Baseline AGEs and sRAGE isoforms concentration were measured by ELISA in 362 patients with type 2 diabetes and in 125 age- and gender-matched healthy control subjects (CTR). Independent predictors of mortality were determined using Cox proportional-hazards models and used to build and validate a nomogram for all-cause mortality prediction in type 2 diabetes. RESULTS AGEs, total sRAGE, cRAGE and the AGEs/sRAGE and AGEs/esRAGE ratios were significantly increased in patients with type 2 diabetes compared to CTR (p < 0.001). In CTR subjects, but not in type 2 diabetes patients, a significant negative correlation between cRAGE and age was confirmed (p = 0.003), whereas the AGEs/sRAGE (p = 0.032) and AGEs/cRAGE (p = 0.006) ratios were positively associated with age. At an average follow-up of 15 years (4,982 person-years), 130 deaths were observed. The increase in the AGEs/cRAGE ratio was accompanied by a higher risk of all-cause mortality in patients with type 2 diabetes (HR per each SD increment = 1.30, 95% CI 1.15-1.47; p < 0.001). Moreover, sRAGE was associated with the development of major adverse cardiovascular events (MACE) in type 2 diabetes patients without previous MACE (OR for each SD increase: 1.48, 95% CI 1.11-1.89). A nomogram based on age, sex, HbA1c, systolic blood pressure, and the AGEs/cRAGE ratio was built to predict 5-, 10- and 15-year survival in type 2 diabetes. Patients were categorized into quartiles of the monogram scores and Kaplan-Meier survival curves confirmed the prognostic accuracy of the model (log-rank p = 6.5 × 10- 13). CONCLUSIONS The ratio between AGEs and the cRAGE isoform is predictive of 15-year survival in patients with type 2 diabetes. Our data support the assessment of circulating AGEs and soluble RAGE isoforms in patients with type 2 diabetes as predictors of MACE and all-cause mortality.
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Affiliation(s)
- Jacopo Sabbatinelli
- Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
- Laboratory Medicine Unit, Azienda Ospedaliero Universitaria "Ospedali Riuniti", Ancona, Italy
| | - Stefania Castiglione
- Experimental Cardio-Oncology and Cardiovascular Aging Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy
| | - Federica Macrì
- Experimental Cardio-Oncology and Cardiovascular Aging Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy
| | - Angelica Giuliani
- Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy.
| | - Deborah Ramini
- Clinical Laboratory and Molecular Diagnostic, IRCCS INRCA, Ancona, Italy
| | - Maria Cristina Vinci
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Milan, Italy
| | - Elena Tortato
- Metabolic Diseases and Diabetology Department, IRCCS INRCA, Ancona, Italy
| | | | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
- Clinical Laboratory and Molecular Diagnostic, IRCCS INRCA, Ancona, Italy
| | - Angela Raucci
- Experimental Cardio-Oncology and Cardiovascular Aging Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy
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Jutant EM, Tu L, Thuillet R, Picard V, Guignabert C, Parent F, Sitbon O, Humbert M, Savale L, Huertas A. Erythrocytes are altered in pulmonary arterial hypertension. Eur Respir J 2022; 59:13993003.00506-2022. [PMID: 35595313 DOI: 10.1183/13993003.00506-2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 03/20/2022] [Indexed: 11/05/2022]
Affiliation(s)
- Etienne-Marie Jutant
- Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.,INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France.,Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Ly Tu
- Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.,INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | - Raphaël Thuillet
- Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.,INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | - Véronique Picard
- Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.,Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Biological Haematology, Constitutional Hematopoietic Disorders National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Christophe Guignabert
- Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.,INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | - Florence Parent
- Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.,INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France.,Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Olivier Sitbon
- Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.,INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France.,Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Marc Humbert
- Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.,INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France.,Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Laurent Savale
- Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.,INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France.,Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Alice Huertas
- Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France .,INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France.,Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
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Zhu BT. Biochemical mechanism underlying the pathogenesis of diabetic retinopathy and other diabetic complications in humans: the methanol-formaldehyde-formic acid hypothesis. Acta Biochim Biophys Sin (Shanghai) 2022; 54:415-451. [PMID: 35607958 PMCID: PMC9828688 DOI: 10.3724/abbs.2022012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/18/2021] [Indexed: 11/25/2022] Open
Abstract
Hyperglycemia in diabetic patients is associated with abnormally-elevated cellular glucose levels. It is hypothesized that increased cellular glucose will lead to increased formation of endogenous methanol and/or formaldehyde, both of which are then metabolically converted to formic acid. These one-carbon metabolites are known to be present naturally in humans, and their levels are increased under diabetic conditions. Mechanistically, while formaldehyde is a cross-linking agent capable of causing extensive cytotoxicity, formic acid is an inhibitor of mitochondrial cytochrome oxidase, capable of inducing histotoxic hypoxia, ATP deficiency and cytotoxicity. Chronic increase in the production and accumulation of these toxic one-carbon metabolites in diabetic patients can drive the pathogenesis of ocular as well as other diabetic complications. This hypothesis is supported by a large body of experimental and clinical observations scattered in the literature. For instance, methanol is known to have organ- and species-selective toxicities, including the characteristic ocular lesions commonly seen in humans and non-human primates, but not in rodents. Similarly, some of the diabetic complications (such as ocular lesions) also have a characteristic species-selective pattern, closely resembling methanol intoxication. Moreover, while alcohol consumption or combined use of folic acid plus vitamin B is beneficial for mitigating acute methanol toxicity in humans, their use also improves the outcomes of diabetic complications. In addition, there is also a large body of evidence from biochemical and cellular studies. Together, there is considerable experimental support for the proposed hypothesis that increased metabolic formation of toxic one-carbon metabolites in diabetic patients contributes importantly to the development of various clinical complications.
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Affiliation(s)
- Bao Ting Zhu
- Shenzhen Key Laboratory of Steroid Drug Discovery and DevelopmentSchool of MedicineThe Chinese University of Hong KongShenzhen518172China
- Department of PharmacologyToxicology and TherapeuticsSchool of MedicineUniversity of Kansas Medical CenterKansas CityKS66160USA
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Ramasamy R, Shekhtman A, Schmidt AM. The RAGE/DIAPH1 Signaling Axis & Implications for the Pathogenesis of Diabetic Complications. Int J Mol Sci 2022; 23:ijms23094579. [PMID: 35562970 PMCID: PMC9102165 DOI: 10.3390/ijms23094579] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/13/2022] [Accepted: 04/17/2022] [Indexed: 02/08/2023] Open
Abstract
Increasing evidence links the RAGE (receptor for advanced glycation end products)/DIAPH1 (Diaphanous 1) signaling axis to the pathogenesis of diabetic complications. RAGE is a multi-ligand receptor and through these ligand-receptor interactions, extensive maladaptive effects are exerted on cell types and tissues targeted for dysfunction in hyperglycemia observed in both type 1 and type 2 diabetes. Recent evidence indicates that RAGE ligands, acting as damage-associated molecular patterns molecules, or DAMPs, through RAGE may impact interferon signaling pathways, specifically through upregulation of IRF7 (interferon regulatory factor 7), thereby heralding and evoking pro-inflammatory effects on vulnerable tissues. Although successful targeting of RAGE in the clinical milieu has, to date, not been met with success, recent approaches to target RAGE intracellular signaling may hold promise to fill this critical gap. This review focuses on recent examples of highlights and updates to the pathobiology of RAGE and DIAPH1 in diabetic complications.
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Affiliation(s)
- Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA;
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY 12222, USA;
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA;
- Correspondence:
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Tajbakhsh A, Gheibihayat SM, Taheri RA, Fasihi-Ramandi M, Bajestani AN, Taheri A. Potential diagnostic and prognostic of efferocytosis-related unwanted soluble receptors/ligands as new non-invasive biomarkers in disorders: a review. Mol Biol Rep 2022; 49:5133-5152. [PMID: 35419645 DOI: 10.1007/s11033-022-07224-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 02/02/2022] [Indexed: 11/25/2022]
Abstract
Efferocytosis is the process by which apoptotic cells are removed without inflammation to maintain tissue homeostasis, prevent unwanted inflammatory responses, and inhibit autoimmune responses. Coordination of efferocytosis occurs via many surfaces and chemotactic molecules and adaptors. Recently, soluble positive or negative mediators of efferocytosis, have been more noticeable as non-invasive valuable biomarkers in prognosis and targeted therapy. These soluble factors can be detected in different bodily fluids, such as serum, plasma, and urine as a non-invasive method. There are lots of studies that have tried to show the importance of receptors and ligands in disorders; while a few studies tried to indicate the importance of soluble forms of receptors/ligands and their clinical aspects as a systemic compound and shedding of targets related to efferocytosis. Some of these soluble forms also can be as sensitive as specific biomarkers for certain diseases compared with routine biomarkers, such as soluble circulatory Lectin-like oxidized low-density lipoprotein receptor-1 vs. troponin T in the acute coronary syndrome. Thus, this review tried to gain more understanding about efferocytosis-related unwanted soluble receptors/ligands, their roles, the clinical significance, and potential for diagnosis, and prognosis related to different diseases.
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Affiliation(s)
- Amir Tajbakhsh
- Molecular Biology Research Center, Systems Biology and Poisoning Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Gheibihayat
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ramezan Ali Taheri
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mahdi Fasihi-Ramandi
- Molecular Biology Research Center, Systems Biology and Poisoning Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Abolfazl Nesaei Bajestani
- Department of Medical Genetics, Ayatollah Madani Hospital, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Abolfazl Taheri
- School of Medicine, New Hearing Technologies Research Center, Baghiyyatollah Al-Azam Hospital, Baqiyatallah University of Medical Sciences, Tehran, Iran.
- Department of ENT, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Wu HP, Chu CM, Liu PH, Leu SW, Lin SW, Hu HC, Kao KC, Li LF, Yu CC. Increased Production of Interleukin-10 and Tumor Necrosis Factor-Alpha in Stimulated Peripheral Blood Mononuclear Cells after Inhibition of S100A12. Curr Issues Mol Biol 2022; 44:1701-1712. [PMID: 35723375 PMCID: PMC9164026 DOI: 10.3390/cimb44040117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/02/2022] [Accepted: 04/06/2022] [Indexed: 11/24/2022] Open
Abstract
Sepsis may induce immunosuppression and result in death. S100A12 can bind to the receptor for advanced glycation end-products (RAGE) and Toll-like receptor (TLR)4 following induction of various inflammatory responses. It is unclear whether S100A12 significantly influences the immune system, which may be associated with sepsis-related mortality. We measured plasma S100A12 levels and cytokine responses (mean ± standard error mean) of lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) after S100A12 inhibition in healthy controls and patients with sepsis on days one and seven. Day one plasma soluble RAGE (sRAGE) and S100A12 levels in patients with sepsis were significantly higher than those in controls (2481.3 ± 295.0 vs. 1273.0 ± 108.2 pg/mL, p < 0.001; 530.3 ± 18.2 vs. 310.1 ± 28.1 pg/mL, p < 0.001, respectively). Day seven plasma S100A12 levels in non-survivors were significantly higher than those in survivors (593.1 ± 12.7 vs. 499.3 ± 23.8 pg/mL, p = 0.002, respectively). In survivors, plasma sRAGE levels were significantly decreased after 6 days (2297.3 ± 320.3 vs. 1530.1 ± 219.1 pg/mL, p = 0.009, respectively), but not in non-survivors. Inhibiting S100A12 increased the production of tumor necrosis factor (TNF)-α and interleukin (IL)-10 in stimulated PBMCs for both controls and patients. Therefore, S100A12 plays an important role in sepsis pathogenesis. S100A12 may competitively bind to TLR4 and RAGE, resulting in decreased IL-10 and TNF-α production.
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Affiliation(s)
- Huang-Pin Wu
- Division of Pulmonary, Critical Care and Sleep Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan; (H.-P.W.); (C.-M.C.); (L.-F.L.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-W.L.); (S.-W.L.); (H.-C.H.); (K.-C.K.)
| | - Chien-Ming Chu
- Division of Pulmonary, Critical Care and Sleep Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan; (H.-P.W.); (C.-M.C.); (L.-F.L.)
| | - Pi-Hua Liu
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Shaw-Woei Leu
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-W.L.); (S.-W.L.); (H.-C.H.); (K.-C.K.)
- Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Shih-Wei Lin
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-W.L.); (S.-W.L.); (H.-C.H.); (K.-C.K.)
- Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Han-Chung Hu
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-W.L.); (S.-W.L.); (H.-C.H.); (K.-C.K.)
- Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Kuo-Chin Kao
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-W.L.); (S.-W.L.); (H.-C.H.); (K.-C.K.)
- Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Li-Fu Li
- Division of Pulmonary, Critical Care and Sleep Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan; (H.-P.W.); (C.-M.C.); (L.-F.L.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-W.L.); (S.-W.L.); (H.-C.H.); (K.-C.K.)
| | - Chung-Chieh Yu
- Division of Pulmonary, Critical Care and Sleep Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan; (H.-P.W.); (C.-M.C.); (L.-F.L.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (S.-W.L.); (S.-W.L.); (H.-C.H.); (K.-C.K.)
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Vascular Permeability in Diseases. Int J Mol Sci 2022; 23:ijms23073645. [PMID: 35409010 PMCID: PMC8998843 DOI: 10.3390/ijms23073645] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/20/2022] [Accepted: 03/24/2022] [Indexed: 02/06/2023] Open
Abstract
Vascular permeability is a selective mechanism that maintains the exchange between vessels, tissues, and organs. The regulation was mostly studied during the nineteenth century by physiologists who defined physical laws and equations, taking blood, tissue interstitial, and oncotic pressure into account. During the last decades, a better knowledge of vascular cell functions and blood-vessel interactions opens a new area of vascular biology. Endothelial cell receptors vascular cell adhesion molecule (VCAM), intercellular cell adhesion molecule (ICAM), vascular endothelial growth factor receptor (VEGFR-2), receptor for advanced glycation end products (RAGE), and mediators were identified and their role in homeostasis and pathological situations was described. The molecular differences of endothelial cell junctions (tight, gap, and adherens junctions) and their role in vascular permeability were characterized in different organs. The main mediators of vasomotricity and permeability, such as prostaglandins, nitric oxide (NO), prostacyclin, vascular growth factor (VEGF), and cytokines, have been demonstrated to possess major functions in steady state and pathological situations. Leukocytes were shown to adhere to endothelium and migrate during inflammatory situations and infectious diseases. Increased vascular permeability is linked to endothelium integrity. Glycocalyx, when intact, may limit cancer cell metastasis. Biological modifications of blood and tissue constituents occurring in diabetes mellitus were responsible for increased permeability and, consequently, ocular and renal complications. Vascular pressure and fluidity are major determinants of pulmonary and cerebral edema. Beside the treatment of the infectious disease, of the blood circulation dysfunction and inflammatory condition, drugs (cyclooxygenase inhibitors) and specific antibodies anti-cytokine (anti-VEGF) have been demonstrated to reduce the severity and the mortality in diseases that exhibited enhanced vascular permeability.
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Steenbeke M, Speeckaert R, Desmedt S, Glorieux G, Delanghe JR, Speeckaert MM. The Role of Advanced Glycation End Products and Its Soluble Receptor in Kidney Diseases. Int J Mol Sci 2022; 23:ijms23073439. [PMID: 35408796 PMCID: PMC8998875 DOI: 10.3390/ijms23073439] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/20/2022] [Accepted: 03/21/2022] [Indexed: 02/06/2023] Open
Abstract
Patients with chronic kidney disease (CKD) are more prone to oxidative stress and chronic inflammation, which may lead to an increase in the synthesis of advanced glycation end products (AGEs). Because AGEs are mostly removed by healthy kidneys, AGE accumulation is a result of both increased production and decreased kidney clearance. On the other hand, AGEs may potentially hasten decreasing kidney function in CKD patients, and are independently related to all-cause mortality. They are one of the non-traditional risk factors that play a significant role in the underlying processes that lead to excessive cardiovascular disease in CKD patients. When AGEs interact with their cell-bound receptor (RAGE), cell dysfunction is initiated by activating nuclear factor kappa-B (NF-κB), increasing the production and release of inflammatory cytokines. Alterations in the AGE-RAGE system have been related to the development of several chronic kidney diseases. Soluble RAGE (sRAGE) is a decoy receptor that suppresses membrane-bound RAGE activation and AGE-RAGE-related toxicity. sRAGE, and more specifically, the AGE/sRAGE ratio, may be promising tools for predicting the prognosis of kidney diseases. In the present review, we discuss the potential role of AGEs and sRAGE as biomarkers in different kidney pathologies.
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Affiliation(s)
- Mieke Steenbeke
- Nephrology Unit, Department of Internal Medicine and Pediatrics, Ghent University Hospital, 9000 Ghent, Belgium; (M.S.); (S.D.); (G.G.)
| | - Reinhart Speeckaert
- Department of Dermatology, Ghent University Hospital, 9000 Ghent, Belgium;
- Research Foundation Flanders, 1000 Brussels, Belgium
| | - Stéphanie Desmedt
- Nephrology Unit, Department of Internal Medicine and Pediatrics, Ghent University Hospital, 9000 Ghent, Belgium; (M.S.); (S.D.); (G.G.)
| | - Griet Glorieux
- Nephrology Unit, Department of Internal Medicine and Pediatrics, Ghent University Hospital, 9000 Ghent, Belgium; (M.S.); (S.D.); (G.G.)
| | - Joris R. Delanghe
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium;
| | - Marijn M. Speeckaert
- Nephrology Unit, Department of Internal Medicine and Pediatrics, Ghent University Hospital, 9000 Ghent, Belgium; (M.S.); (S.D.); (G.G.)
- Research Foundation Flanders, 1000 Brussels, Belgium
- Correspondence:
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Teissier T, Temkin V, Pollak RD, Cox LS. Crosstalk Between Senescent Bone Cells and the Bone Tissue Microenvironment Influences Bone Fragility During Chronological Age and in Diabetes. Front Physiol 2022; 13:812157. [PMID: 35388291 PMCID: PMC8978545 DOI: 10.3389/fphys.2022.812157] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/27/2022] [Indexed: 01/10/2023] Open
Abstract
Bone is a complex organ serving roles in skeletal support and movement, and is a source of blood cells including adaptive and innate immune cells. Structural and functional integrity is maintained through a balance between bone synthesis and bone degradation, dependent in part on mechanical loading but also on signaling and influences of the tissue microenvironment. Bone structure and the extracellular bone milieu change with age, predisposing to osteoporosis and increased fracture risk, and this is exacerbated in patients with diabetes. Such changes can include loss of bone mineral density, deterioration in micro-architecture, as well as decreased bone flexibility, through alteration of proteinaceous bone support structures, and accumulation of senescent cells. Senescence is a state of proliferation arrest accompanied by marked morphological and metabolic changes. It is driven by cellular stress and serves an important acute tumor suppressive mechanism when followed by immune-mediated senescent cell clearance. However, aging and pathological conditions including diabetes are associated with accumulation of senescent cells that generate a pro-inflammatory and tissue-destructive secretome (the SASP). The SASP impinges on the tissue microenvironment with detrimental local and systemic consequences; senescent cells are thought to contribute to the multimorbidity associated with advanced chronological age. Here, we assess factors that promote bone fragility, in the context both of chronological aging and accelerated aging in progeroid syndromes and in diabetes, including senescence-dependent alterations in the bone tissue microenvironment, and glycation changes to the tissue microenvironment that stimulate RAGE signaling, a process that is accelerated in diabetic patients. Finally, we discuss therapeutic interventions targeting RAGE signaling and cell senescence that show promise in improving bone health in older people and those living with diabetes.
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Affiliation(s)
- Thibault Teissier
- Department of Biochemistry, University of Oxford, Oxford, United Kingdom
| | - Vladislav Temkin
- Division of Medicine, Department of Endocrinology and Metabolism, The Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Rivka Dresner Pollak
- Division of Medicine, Department of Endocrinology and Metabolism, The Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Lynne S. Cox
- Department of Biochemistry, University of Oxford, Oxford, United Kingdom
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Gaul S, Shahzad K, Medert R, Gadi I, Mäder C, Schumacher D, Wirth A, Ambreen S, Fatima S, Boeckel JN, Khawaja H, Haas J, Brune M, Nawroth PP, Isermann B, Laufs U, Freichel M. Novel Nongenetic Murine Model of Hyperglycemia and Hyperlipidemia-Associated Aggravated Atherosclerosis. Front Cardiovasc Med 2022; 9:813215. [PMID: 35350534 PMCID: PMC8957812 DOI: 10.3389/fcvm.2022.813215] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 02/02/2022] [Indexed: 01/24/2023] Open
Abstract
Objective Atherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients. Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s). Methods and Results Wild-type mice were injected with gain-of-function PCSK9D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis, two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery) were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi) mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic plaques of HGHCi HFD animals were larger, showed a less stable phenotype (measured by the increased necrotic core area, reduced fibrous cap thickness, and less α-SMA-positive area) and had more inflammation (increased plasma IL-1β level, aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA) after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and extracellular matrix degradation (Adamts4 and Mmp14). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks. Hyperlipidemic and hyperglycemic mice fed a PD (HGHCi PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells) within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks. Conclusion We established a nongenetically inducible mouse model allowing comparative analyses of atherosclerosis in HCi and HGHCi conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice.
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Affiliation(s)
- Susanne Gaul
- Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Khurrum Shahzad
- Department of Diagnostics, Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital Leipzig, Leipzig, Germany
| | - Rebekka Medert
- Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany
| | - Ihsan Gadi
- Department of Diagnostics, Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital Leipzig, Leipzig, Germany
| | - Christina Mäder
- Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Dagmar Schumacher
- Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany
| | - Angela Wirth
- Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
| | - Saira Ambreen
- Department of Diagnostics, Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital Leipzig, Leipzig, Germany
| | - Sameen Fatima
- Department of Diagnostics, Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital Leipzig, Leipzig, Germany
| | - Jes-Niels Boeckel
- Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Hamzah Khawaja
- Department of Diagnostics, Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital Leipzig, Leipzig, Germany
| | - Jan Haas
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany
- Department of Internal Medicine III, Heidelberg University, Heidelberg, Germany
| | - Maik Brune
- Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), Heidelberg University, Heidelberg, Germany
| | - Peter P. Nawroth
- Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), Heidelberg University, Heidelberg, Germany
| | - Berend Isermann
- Department of Diagnostics, Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital Leipzig, Leipzig, Germany
| | - Ulrich Laufs
- Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Marc Freichel
- Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany
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Behl T, Gupta A, Chigurupati S, Singh S, Sehgal A, Badavath VN, Alhowail A, Mani V, Bhatia S, Al-Harrasi A, Bungau S. Natural and Synthetic Agents Targeting Reactive Carbonyl Species against Metabolic Syndrome. Molecules 2022; 27:1583. [PMID: 35268685 PMCID: PMC8911959 DOI: 10.3390/molecules27051583] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/24/2022] [Accepted: 02/24/2022] [Indexed: 12/31/2022] Open
Abstract
Reactive carbonyl species (RCS) may originate from the oxidation of unsaturated fatty acids and sugar in conditions of pathology. They are known to have high reactivity towards DNA as well as nucleophilic sites of proteins, resulting in cellular dysfunction. It has been considered that various pathological conditions are associated with an increased level of RCS and their reaction products. Thus, regulating the levels of RCS may be associated with the mitigation of various metabolic and neurodegenerative disorders. In order to perform a comprehensive review, various literature databases, including MEDLINE, EMBASE, along with Google Scholar, were utilized to obtain relevant articles. The voluminous review concluded that various synthetic and natural agents are available or in pipeline research that hold tremendous potential to be used as a drug of choice in the therapeutic management of metabolic syndrome, including obesity, dyslipidemia, diabetes, and diabetes-associated complications of atherosclerosis, neuropathy, and nephropathy. From the available data, it may be emphasized that various synthetic agents, such as carnosine and simvastatin, and natural agents, such as polyphenols and terpenoids, can become a drug of choice in the therapeutic management for combating metabolic syndromes that involve RCS in their pathophysiology. Since the RCS are known to regulate the biological processes, future research warrants detailed investigations to decipher the precise mechanism.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, India; (A.G.); (S.S.); (A.S.); (V.N.B.)
| | - Amit Gupta
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, India; (A.G.); (S.S.); (A.S.); (V.N.B.)
| | - Sridevi Chigurupati
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraidah 52571, Saudi Arabia;
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, India; (A.G.); (S.S.); (A.S.); (V.N.B.)
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, India; (A.G.); (S.S.); (A.S.); (V.N.B.)
| | - Vishnu Nayak Badavath
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, India; (A.G.); (S.S.); (A.S.); (V.N.B.)
| | - Ahmad Alhowail
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah 51452, Saudi Arabia; (A.A.); (V.M.)
| | - Vasudevan Mani
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah 51452, Saudi Arabia; (A.A.); (V.M.)
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Centre, University of Nizwa, Birkat Al Mauz, Nizwa P.O. Box 33, Oman; (S.B.); (A.A.-H.)
- School of Health Science, University of Petroleum and Energy Studies, Dehradun 248007, India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Centre, University of Nizwa, Birkat Al Mauz, Nizwa P.O. Box 33, Oman; (S.B.); (A.A.-H.)
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
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Advanced Glycation End Products: A Sweet Flavor That Embitters Cardiovascular Disease. Int J Mol Sci 2022; 23:ijms23052404. [PMID: 35269546 PMCID: PMC8910157 DOI: 10.3390/ijms23052404] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/16/2022] [Accepted: 02/17/2022] [Indexed: 12/24/2022] Open
Abstract
Epidemiological studies demonstrate the role of early and intensive glycemic control in the prevention of micro and macrovascular disease in both type 1 and type 2 diabetes mellitus (DM). Hyperglycemia elicits several pathways related to the etiopathogenesis of cardiovascular disease (CVD), including the generation of advanced glycation end products (AGEs). In this review, we revisit the role played by AGEs in CVD based in clinical trials and experimental evidence. Mechanistic aspects concerning the recognition of AGEs by the advanced glycosylation end product-specific receptor (AGER) and its counterpart, the dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST) and soluble AGER are discussed. A special focus is offered to the AGE-elicited pathways that promote cholesterol accumulation in the arterial wall by enhanced oxidative stress, inflammation, endoplasmic reticulum stress and impairment in the reverse cholesterol transport (RCT).
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Li M, Ong CY, Langouët-Astrié CJ, Tan L, Verma A, Yang Y, Zhang X, Shah DK, Schmidt EP, Xu D. Heparan sulfate-dependent RAGE oligomerization is indispensable for pathophysiological functions of RAGE. eLife 2022; 11:e71403. [PMID: 35137686 PMCID: PMC8863369 DOI: 10.7554/elife.71403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 02/01/2022] [Indexed: 12/13/2022] Open
Abstract
RAGE, a druggable inflammatory receptor, is known to function as an oligomer but the exact oligomerization mechanism remains poorly understood. Previously we have shown that heparan sulfate (HS) plays an active role in RAGE oligomerization. To understand the physiological significance of HS-induced RAGE oligomerization in vivo, we generated RAGE knock-in mice (AgerAHA/AHA) by introducing point mutations to specifically disrupt HS-RAGE interaction. The RAGE mutant demonstrated normal ligand-binding but impaired capacity of HS-binding and oligomerization. Remarkably, AgerAHA/AHA mice phenocopied Ager-/- mice in two different pathophysiological processes, namely bone remodeling and neutrophil-mediated liver injury, which demonstrates that HS-induced RAGE oligomerization is essential for RAGE signaling. Our findings suggest that it should be possible to block RAGE signaling by inhibiting HS-RAGE interaction. To test this, we generated a monoclonal antibody that targets the HS-binding site of RAGE. This antibody blocks RAGE signaling in vitro and in vivo, recapitulating the phenotype of AgerAHA/AHA mice. By inhibiting HS-RAGE interaction genetically and pharmacologically, our work validated an alternative strategy to antagonize RAGE. Finally, we have performed RNA-seq analysis of neutrophils and lungs and found that while Ager-/- mice had a broad alteration of transcriptome in both tissues compared to wild-type mice, the changes of transcriptome in AgerAHA/AHA mice were much more restricted. This unexpected finding suggests that by preserving the expression of RAGE protein (in a dominant-negative form), AgerAHA/AHA mouse might represent a cleaner genetic model to study physiological roles of RAGE in vivo compared to Ager-/- mice.
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Affiliation(s)
- Miaomiao Li
- Department of Oral Biology, University at Buffalo, State University of New YorkBuffaloUnited States
| | - Chih Yean Ong
- Department of Oral Biology, University at Buffalo, State University of New YorkBuffaloUnited States
| | - Christophe J Langouët-Astrié
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Lisi Tan
- Department of Oral Biology, University at Buffalo, State University of New YorkBuffaloUnited States
- Department of Periodontics, School of Stomatology, China Medical UniversityShenyangChina
| | - Ashwni Verma
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New YorkBuffaloUnited States
| | - Yimu Yang
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Xiaoxiao Zhang
- Department of Oral Biology, University at Buffalo, State University of New YorkBuffaloUnited States
| | - Dhaval K Shah
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New YorkBuffaloUnited States
| | - Eric P Schmidt
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Ding Xu
- Department of Oral Biology, University at Buffalo, State University of New YorkBuffaloUnited States
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Pan J, Bao X, Gonçalves I, Jujić A, Engström G. Skin autofluorescence, a measure of tissue accumulation of advanced glycation end products, is associated with subclinical atherosclerosis in coronary and carotid arteries. Atherosclerosis 2022; 345:26-32. [DOI: 10.1016/j.atherosclerosis.2022.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 11/02/2022]
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