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Zhang X, Xu R, Wang T, Li J, Sun Y, Cui S, Xing Z, Lyu X, Yang G, Jiao L, Li W. PTP1B Modulates Carotid Plaque Vulnerability in Atherosclerosis Through Rab5-PDGFRβ-Mediated Endocytosis Disruption and Apoptosis. CNS Neurosci Ther 2024; 30:e70071. [PMID: 39517122 PMCID: PMC11549062 DOI: 10.1111/cns.70071] [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: 03/18/2024] [Revised: 09/06/2024] [Accepted: 09/12/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Protein tyrosine phosphatase 1B (PTP1B) is a protein tyrosine phosphatase and modulates platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) signaling in vascular smooth muscle cells (VSMCs) via endocytosis. However, the related molecular pathways that participated in the interaction of endo-lysosome and the trafficking of PDGFR are largely unknown. This study aims to determine the subcellular regulating mechanism of PTP1B to the endo-lysosome degradation of PDGFR in atherosclerotic carotid plaques, thereby offering a potential therapeutic target for the stabilization of carotid plaques. METHODS The immunohistochemical staining technique was employed to assess the expression levels of both PDGFR-β and Caspase 3 in stable and vulnerable carotid plaques. Tunnel staining was utilized to quantify the apoptosis of carotid plaques. Live-cell imaging was employed to observe endocytic motility, while cell apoptosis was evaluated through Propidium Iodide staining. In an in vivo experiment, ApoE-/- mice were administered a PTP1B inhibitor to investigate the impact of PTP1B on atherosclerosis. RESULTS The heightened expression of PDGFR-β correlates with apoptosis in patients with vulnerable carotid plaques. At the subcellular level of VSMCs, PDGFR-β plays a pivotal role in sustaining a balanced endocytosis system motility, regulated by the expression of Rab5, a key regulator of endocytic motility. And PTP1B modulates PDGFR-β signaling via Rab5-mediated endocytosis. Additionally, disrupted endocytic motility influences the interplay between endosomes and lysosomes, which is crucial for controlling PDGFR-β trafficking. Elevated PTP1B expression induces cellular apoptosis and impedes migration and proliferation of carotid VSMCs. Ultimately, mice with PTP1B deficiency exhibit a reduction in atherosclerosis. CONCLUSION Our results illustrate that PTP1B induces disruption in endocytosis and apoptosis of VSMCs through the Rab5-PDGFRβ pathway, suggesting a potential association with the heightened vulnerability of carotid plaques.
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MESH Headings
- Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism
- Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics
- Animals
- Apoptosis/physiology
- Humans
- Endocytosis/physiology
- Mice
- Plaque, Atherosclerotic/pathology
- Plaque, Atherosclerotic/metabolism
- rab5 GTP-Binding Proteins/metabolism
- rab5 GTP-Binding Proteins/genetics
- Male
- Receptor, Platelet-Derived Growth Factor beta/metabolism
- Female
- Mice, Inbred C57BL
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Middle Aged
- Aged
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/metabolism
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
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Affiliation(s)
- Xiao Zhang
- Department of NeurosurgeryXuanwu Hospital, Capital Medical UniversityBeijingChina
- China International Neuroscience Institute (China‐INI)BeijingChina
| | - Ran Xu
- Department of NeurosurgeryXuanwu Hospital, Capital Medical UniversityBeijingChina
- China International Neuroscience Institute (China‐INI)BeijingChina
| | - Tao Wang
- Department of NeurosurgeryXuanwu Hospital, Capital Medical UniversityBeijingChina
- China International Neuroscience Institute (China‐INI)BeijingChina
| | - Jiayao Li
- Department of NeurosurgeryXuanwu Hospital, Capital Medical UniversityBeijingChina
- China International Neuroscience Institute (China‐INI)BeijingChina
| | - Yixin Sun
- First HospitalPeking UniversityBeijingChina
- Health Science CenterPeking UniversityBeijingChina
| | - Shengyan Cui
- Department of NeurosurgeryXuanwu Hospital, Capital Medical UniversityBeijingChina
- China International Neuroscience Institute (China‐INI)BeijingChina
| | - Zixuan Xing
- Health Science CenterXi'an Jiaotong UniversityShanxiChina
| | | | - Ge Yang
- Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of AutomationChinese Academy of SciencesBeijingChina
- School of Artificial IntelligenceUniversity of Chinese Academy of SciencesBeijingChina
| | - Liqun Jiao
- Department of NeurosurgeryXuanwu Hospital, Capital Medical UniversityBeijingChina
- China International Neuroscience Institute (China‐INI)BeijingChina
- Department of Interventional NeuroradiologyXuanwu Hospital, Capital Medical UniversityBeijingChina
| | - Wenjing Li
- Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of AutomationChinese Academy of SciencesBeijingChina
- School of Artificial IntelligenceUniversity of Chinese Academy of SciencesBeijingChina
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Karnewar S, Karnewar V, Deaton R, Shankman LS, Benavente ED, Williams CM, Bradley X, Alencar GF, Bulut GB, Kirmani S, Baylis RA, Zunder ER, den Ruijter HM, Pasterkamp G, Owens GK. IL-1β Inhibition Partially Negates the Beneficial Effects of Diet-Induced Atherosclerosis Regression in Mice. Arterioscler Thromb Vasc Biol 2024; 44:1379-1392. [PMID: 38695167 PMCID: PMC11111338 DOI: 10.1161/atvbaha.124.320800] [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: 02/02/2024] [Accepted: 04/16/2024] [Indexed: 05/14/2024]
Abstract
BACKGROUND Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions is the global leading cause of death. The most common and effective means to reduce these major adverse cardiovascular events, including myocardial infarction and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, we know little regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering. METHODS Smooth muscle cell lineage-tracing Apoe-/- mice were fed a high-cholesterol Western diet for 18 weeks and then a zero-cholesterol standard laboratory diet for 12 weeks before treating them with an IL (interleukin)-1β or control antibody for 8 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of smooth muscle cell and other lesion cells by smooth muscle cell lineage tracing combined with single-cell RNA sequencing, cytometry by time-of-flight, and immunostaining plus high-resolution confocal microscopic z-stack analysis. RESULTS Lipid lowering by switching Apoe-/- mice from a Western diet to a standard laboratory diet reduced LDL cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden, as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1β antibody treatment after diet-induced reductions in lipids resulted in multiple detrimental changes including increased plaque burden and brachiocephalic artery lesion size, as well as increasedintraplaque hemorrhage, necrotic core area, and senescence as compared with IgG control antibody-treated mice. Furthermore, IL-1β antibody treatment upregulated neutrophil degranulation pathways but downregulated smooth muscle cell extracellular matrix pathways likely important for the protective fibrous cap. CONCLUSIONS Taken together, IL-1β appears to be required for the maintenance of standard laboratory diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.
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MESH Headings
- Animals
- Interleukin-1beta/metabolism
- Atherosclerosis/pathology
- Atherosclerosis/prevention & control
- Atherosclerosis/metabolism
- Atherosclerosis/genetics
- Disease Models, Animal
- Plaque, Atherosclerotic
- Mice
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/drug effects
- Mice, Knockout, ApoE
- Male
- Diet, Western
- Mice, Inbred C57BL
- Aorta/pathology
- Aorta/metabolism
- Aorta/drug effects
- Aortic Diseases/pathology
- Aortic Diseases/prevention & control
- Aortic Diseases/genetics
- Aortic Diseases/metabolism
- Diet, High-Fat
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/drug effects
- Brachiocephalic Trunk/pathology
- Brachiocephalic Trunk/metabolism
- Brachiocephalic Trunk/drug effects
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Affiliation(s)
- Santosh Karnewar
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Vaishnavi Karnewar
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Rebecca Deaton
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Laura S. Shankman
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Ernest D. Benavente
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Corey M. Williams
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Xenia Bradley
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Gabriel F. Alencar
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Gamze B. Bulut
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Sara Kirmani
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Richard A. Baylis
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Eli R. Zunder
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Hester M. den Ruijter
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Gerard Pasterkamp
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Gary K. Owens
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
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Diez Benavente E, Hartman RJG, Sakkers TR, Wesseling M, Sloots Y, Slenders L, Boltjes A, Mol BM, de Borst GJ, de Kleijn DPV, Prange KHM, de Winther MPJ, Kuiper J, Civelek M, van der Laan SW, Horvath S, Onland-Moret NC, Mokry M, Pasterkamp G, den Ruijter HM. Atherosclerotic Plaque Epigenetic Age Acceleration Predicts a Poor Prognosis and Is Associated With Endothelial-to-Mesenchymal Transition in Humans. Arterioscler Thromb Vasc Biol 2024; 44:1419-1431. [PMID: 38634280 DOI: 10.1161/atvbaha.123.320692] [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: 01/08/2024] [Accepted: 03/25/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND Epigenetic age estimators (clocks) are predictive of human mortality risk. However, it is not yet known whether the epigenetic age of atherosclerotic plaques is predictive for the risk of cardiovascular events. METHODS Whole-genome DNA methylation of human carotid atherosclerotic plaques (n=485) and of blood (n=93) from the Athero-Express endarterectomy cohort was used to calculate epigenetic age acceleration (EAA). EAA was linked to clinical characteristics, plaque histology, and future cardiovascular events (n=136). We studied whole-genome DNA methylation and bulk and single-cell transcriptomics to uncover molecular mechanisms of plaque EAA. We experimentally confirmed our in silico findings using in vitro experiments in primary human coronary endothelial cells. RESULTS Male and female patients with severe atherosclerosis had a median chronological age of 69 years. The median epigenetic age was 65 years in females (median EAA, -2.2 [interquartile range, -4.3 to 2.2] years) and 68 years in males (median EAA, -0.3 [interquartile range, -2.9 to 3.8] years). Patients with diabetes and a high body mass index had higher plaque EAA. Increased EAA of plaque predicted future events in a 3-year follow-up in a Cox regression model (univariate hazard ratio, 1.7; P=0.0034) and adjusted multivariate model (hazard ratio, 1.56; P=0.02). Plaque EAA predicted outcome independent of blood EAA (hazard ratio, 1.3; P=0.018) and of plaque hemorrhage (hazard ratio, 1.7; P=0.02). Single-cell RNA sequencing in plaque samples from 46 patients in the same cohort revealed smooth muscle and endothelial cells as important cell types in plaque EAA. Endothelial-to-mesenchymal transition was associated with EAA, which was experimentally confirmed by TGFβ-triggered endothelial-to-mesenchymal transition inducing rapid epigenetic aging in coronary endothelial cells. CONCLUSIONS Plaque EAA is a strong and independent marker of poor outcome in patients with severe atherosclerosis. Plaque EAA was linked to mesenchymal endothelial and smooth muscle cells. Endothelial-to-mesenchymal transition was associated with EAA, which was experimentally validated. Epigenetic aging mechanisms may provide new targets for treatments that reduce atherosclerosis complications.
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Affiliation(s)
- Ernest Diez Benavente
- Laboratory of Experimental Cardiology (E.D.B., R.J.G.H., T.R.S., Y.S., M.M., H.M.d.R.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Robin J G Hartman
- Laboratory of Experimental Cardiology (E.D.B., R.J.G.H., T.R.S., Y.S., M.M., H.M.d.R.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Tim R Sakkers
- Laboratory of Experimental Cardiology (E.D.B., R.J.G.H., T.R.S., Y.S., M.M., H.M.d.R.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Marian Wesseling
- Central Diagnostic Laboratory (M.W., L.S., A.B., S.W.v.d.L., M.M., G.P.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Yannicke Sloots
- Laboratory of Experimental Cardiology (E.D.B., R.J.G.H., T.R.S., Y.S., M.M., H.M.d.R.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Lotte Slenders
- Central Diagnostic Laboratory (M.W., L.S., A.B., S.W.v.d.L., M.M., G.P.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Arjan Boltjes
- Central Diagnostic Laboratory (M.W., L.S., A.B., S.W.v.d.L., M.M., G.P.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Barend M Mol
- Department of Vascular Surgery (B.M.M., G.J.d.B., D.P.V.d.K.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Gert J de Borst
- Department of Vascular Surgery (B.M.M., G.J.d.B., D.P.V.d.K.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Dominique P V de Kleijn
- Department of Vascular Surgery (B.M.M., G.J.d.B., D.P.V.d.K.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Koen H M Prange
- Division of Biotherapeutics, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands (K.H.M.P., M.P.J.d.W., J.K.)
| | - Menno P J de Winther
- Division of Biotherapeutics, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands (K.H.M.P., M.P.J.d.W., J.K.)
| | - Johan Kuiper
- Division of Biotherapeutics, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands (K.H.M.P., M.P.J.d.W., J.K.)
| | - Mete Civelek
- Center for Public Health Genomics (M.C.), University of Virginia, Charlottesville
- Department of Biomedical Engineering (M.C.), University of Virginia, Charlottesville
| | - Sander W van der Laan
- Central Diagnostic Laboratory (M.W., L.S., A.B., S.W.v.d.L., M.M., G.P.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Steve Horvath
- Department of Human Genetics, David Geffen School of Medicine (S.H.), University of California, Los Angeles
- Department of Biostatistics, Fielding School of Public Health (S.H.), University of California, Los Angeles
- Altos Labs, Cambridge Institute of Science, United Kingdom (S.H.)
| | - N Charlotte Onland-Moret
- Julius Center for Health Sciences and Primary Care (N.C.O.-M.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Michal Mokry
- Laboratory of Experimental Cardiology (E.D.B., R.J.G.H., T.R.S., Y.S., M.M., H.M.d.R.), University Medical Center Utrecht, Utrecht University, the Netherlands
- Central Diagnostic Laboratory (M.W., L.S., A.B., S.W.v.d.L., M.M., G.P.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Gerard Pasterkamp
- Central Diagnostic Laboratory (M.W., L.S., A.B., S.W.v.d.L., M.M., G.P.), University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Hester M den Ruijter
- Laboratory of Experimental Cardiology (E.D.B., R.J.G.H., T.R.S., Y.S., M.M., H.M.d.R.), University Medical Center Utrecht, Utrecht University, the Netherlands
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Ristow AVB, Massière B, Meirelles GV, Casella IB, Morales MM, Moreira RCR, Procópio RJ, Oliveira TF, de Araujo WJB, Joviliano EE, de Oliveira JCP. Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease. J Vasc Bras 2024; 23:e20230094. [PMID: 39099701 PMCID: PMC11296686 DOI: 10.1590/1677-5449.202300942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 10/16/2023] [Indexed: 08/06/2024] Open
Abstract
Extracranial cerebrovascular disease has been the subject of intense research throughout the world, and is of paramount importance for vascular surgeons. This guideline, written by the Brazilian Society of Angiology and Vascular Surgery (SBACV), supersedes the 2015 guideline. Non-atherosclerotic carotid artery diseases were not included in this document. The purpose of this guideline is to bring together the most robust evidence in this area in order to help specialists in the treatment decision-making process. The AGREE II methodology and the European Society of Cardiology system were used for recommendations and levels of evidence. The recommendations were graded from I to III, and levels of evidence were classified as A, B, or C. This guideline is divided into 11 chapters dealing with the various aspects of extracranial cerebrovascular disease: diagnosis, treatments and complications, based on up-to-date knowledge and the recommendations proposed by SBACV.
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Affiliation(s)
- Arno von Buettner Ristow
- Pontifícia Universidade Católica do Rio de Janeiro – PUC-RIO, Disciplina de Cirurgia Vascular e Endovascular, Rio de Janeiro, RJ, Brasil.
- Sociedade Brasileira de Angiologia e de Cirurgia Vascular – SBACV-RJ, Rio de Janeiro, RJ, Brasil.
| | - Bernardo Massière
- Pontifícia Universidade Católica do Rio de Janeiro – PUC-RIO, Disciplina de Cirurgia Vascular e Endovascular, Rio de Janeiro, RJ, Brasil.
- Sociedade Brasileira de Angiologia e de Cirurgia Vascular – SBACV-RJ, Rio de Janeiro, RJ, Brasil.
| | - Guilherme Vieira Meirelles
- Sociedade Brasileira de Angiologia e de Cirurgia Vascular – SBACV-SP, São Paulo, SP, Brasil.
- Universidade Estadual de Campinas – UNICAMP, Hospital das Clínicas, Disciplina de Cirurgia do Trauma, Campinas, SP, Brasil.
| | - Ivan Benaduce Casella
- Sociedade Brasileira de Angiologia e de Cirurgia Vascular – SBACV-SP, São Paulo, SP, Brasil.
- Universidade de São Paulo – USP, Faculdade de Medicina, São Paulo, SP, Brasil.
| | - Marcia Maria Morales
- Sociedade Brasileira de Angiologia e de Cirurgia Vascular – SBACV-SP, São Paulo, SP, Brasil.
- Associação Portuguesa de Beneficência de São José do Rio Preto, Serviço de Cirurgia Vascular, São José do Rio Preto, SP, Brasil.
| | - Ricardo Cesar Rocha Moreira
- Sociedade Brasileira de Angiologia e de Cirurgia Vascular – SBACV-PR, Curitiba, PR, Brasil.
- Pontifícia Universidade Católica do Paraná – PUC-PR, Hospital Cajurú, Serviço de Cirurgia Vascular, Curitiba, PR, Brasil.
| | - Ricardo Jayme Procópio
- Universidade Federal de Minas Gerais – UFMG, Hospital das Clínicas, Setor de Cirurgia Endovascular, Belo Horizonte, MG, Brasil.
- Universidade Federal de Minas Gerais – UFMG, Faculdade de Medicina, Belo Horizonte, MG, Brasil.
- Sociedade Brasileira de Angiologia e de Cirurgia Vascular – SBACV-MG, Belo Horizonte, MG, Brasil.
| | - Tércio Ferreira Oliveira
- Sociedade Brasileira de Angiologia e de Cirurgia Vascular – SBACV-SE, Aracajú, SE, Brasil.
- Universidade de São Paulo – USP, Faculdade de Medicina de Ribeirão Preto – FMRP, Ribeirão Preto, SP, Brasil.
| | - Walter Jr. Boim de Araujo
- Sociedade Brasileira de Angiologia e de Cirurgia Vascular – SBACV-PR, Curitiba, PR, Brasil.
- Universidade Federal do Paraná – UFPR, Hospital das Clínicas – HC, Curitiba, PR, Brasil.
| | - Edwaldo Edner Joviliano
- Sociedade Brasileira de Angiologia e de Cirurgia Vascular – SBACV-SP, São Paulo, SP, Brasil.
- Universidade de São Paulo – USP, Faculdade de Medicina de Ribeirão Preto – FMRP, Ribeirão Preto, SP, Brasil.
| | - Júlio Cesar Peclat de Oliveira
- Sociedade Brasileira de Angiologia e de Cirurgia Vascular – SBACV-SP, São Paulo, SP, Brasil.
- Universidade Federal do Estado do Rio de Janeiro – UNIRIO, Departamento de Cirurgia, Rio de Janeiro, RJ, Brasil.
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Peng Z, Kan Q, Wang K, Deng T, Wang S, Wu R, Yao C. Deciphering smooth muscle cell heterogeneity in atherosclerotic plaques and constructing model: a multi-omics approach with focus on KLF15/IGFBP4 axis. BMC Genomics 2024; 25:490. [PMID: 38760675 PMCID: PMC11102212 DOI: 10.1186/s12864-024-10379-y] [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: 12/11/2023] [Accepted: 05/06/2024] [Indexed: 05/19/2024] Open
Abstract
BACKGROUND Ruptured atherosclerotic plaques often precipitate severe ischemic events, such as stroke and myocardial infarction. Unraveling the intricate molecular mechanisms governing vascular smooth muscle cell (VSMC) behavior in plaque stabilization remains a formidable challenge. METHODS In this study, we leveraged single-cell and transcriptomic datasets from atherosclerotic plaques retrieved from the gene expression omnibus (GEO) database. Employing a combination of single-cell population differential analysis, weighted gene co-expression network analysis (WGCNA), and transcriptome differential analysis techniques, we identified specific genes steering the transformation of VSMCs in atherosclerotic plaques. Diagnostic models were developed and validated through gene intersection, utilizing the least absolute shrinkage and selection operator (LASSO) and random forest (RF) methods. Nomograms for plaque assessment were constructed. Tissue localization and expression validation were performed on specimens from animal models, utilizing immunofluorescence co-localization, western blot, and reverse-transcription quantitative-polymerase chain reaction (RT-qPCR). Various online databases were harnessed to predict transcription factors (TFs) and their interacting compounds, with determination of the cell-specific localization of TF expression using single-cell data. RESULTS Following rigorous quality control procedures, we obtained a total of 40,953 cells, with 6,261 representing VSMCs. The VSMC population was subsequently clustered into 5 distinct subpopulations. Analyzing inter-subpopulation cellular communication, we focused on the SMC2 and SMC5 subpopulations. Single-cell subpopulation and WGCNA analyses revealed significant module enrichments, notably in collagen-containing extracellular matrix and cell-substrate junctions. Insulin-like growth factor binding protein 4 (IGFBP4), apolipoprotein E (APOE), and cathepsin C (CTSC) were identified as potential diagnostic markers for early and advanced plaques. Notably, gene expression pattern analysis suggested that IGFBP4 might serve as a protective gene, a hypothesis validated through tissue localization and expression analysis. Finally, we predicted TFs capable of binding to IGFBP4, with Krüppel-like family 15 (KLF15) emerging as a prominent candidate showing relative specificity within smooth muscle cells. Predictions about compounds associated with affecting KLF15 expression were also made. CONCLUSION Our study established a plaque diagnostic and assessment model and analyzed the molecular interaction mechanisms of smooth muscle cells within plaques. Further analysis revealed that the transcription factor KLF15 may regulate the biological behaviors of smooth muscle cells through the KLF15/IGFBP4 axis, thereby influencing the stability of advanced plaques via modulation of the PI3K-AKT signaling pathway. This could potentially serve as a target for plaque stability assessment and therapy, thus driving advancements in the management and treatment of atherosclerotic plaques.
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MESH Headings
- Animals
- Humans
- Male
- Gene Expression Profiling
- Gene Regulatory Networks
- Insulin-Like Growth Factor Binding Protein 4/metabolism
- Insulin-Like Growth Factor Binding Protein 4/genetics
- Kruppel-Like Transcription Factors/metabolism
- Kruppel-Like Transcription Factors/genetics
- Multiomics
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/cytology
- Myocytes, Smooth Muscle/metabolism
- Plaque, Atherosclerotic/metabolism
- Plaque, Atherosclerotic/genetics
- Plaque, Atherosclerotic/pathology
- Single-Cell Analysis
- Transcriptome
- Rats
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Affiliation(s)
- Zhanli Peng
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Qinghui Kan
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Kangjie Wang
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Tang Deng
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Shenming Wang
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Ridong Wu
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China.
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
| | - Chen Yao
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China.
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
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Salimi M, Tabatabaei N, Villiger M. Artificial neural network for enhancing signal-to-noise ratio and contrast in photothermal optical coherence tomography. Sci Rep 2024; 14:10264. [PMID: 38704427 PMCID: PMC11069506 DOI: 10.1038/s41598-024-60682-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 04/25/2024] [Indexed: 05/06/2024] Open
Abstract
Optical coherence tomography (OCT) is a medical imaging method that generates micron-resolution 3D volumetric images of tissues in-vivo. Photothermal (PT)-OCT is a functional extension of OCT with the potential to provide depth-resolved molecular information complementary to the OCT structural images. PT-OCT typically requires long acquisition times to measure small fluctuations in the OCT phase signal. Here, we use machine learning with a neural network to infer the amplitude of the photothermal phase modulation from a short signal trace, trained in a supervised fashion with the ground truth signal obtained by conventional reconstruction of the PT-OCT signal from a longer acquisition trace. Results from phantom and tissue studies show that the developed network improves signal to noise ratio (SNR) and contrast, enabling PT-OCT imaging with short acquisition times and without any hardware modification to the PT-OCT system. The developed network removes one of the key barriers in translation of PT-OCT (i.e., long acquisition time) to the clinic.
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Affiliation(s)
- Mohammadhossein Salimi
- Department of Mechanical Engineering, Lassonde School of Engineering, York University, Toronto, ON, M3J 1P3, Canada
| | - Nima Tabatabaei
- Department of Mechanical Engineering, Lassonde School of Engineering, York University, Toronto, ON, M3J 1P3, Canada.
- Center for Vision Research, York University, Toronto, ON, M3J 1P3, Canada.
| | - Martin Villiger
- Department of Mechanical Engineering, Lassonde School of Engineering, York University, Toronto, ON, M3J 1P3, Canada.
- Harvard Medical School, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
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7
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Lee CY, Park JM, Yeom MI. Risk factors of internal carotid artery stenosis in patients with proliferative diabetic retinopathy: an analysis using optical coherence tomography and optical coherence tomography angiography. BMC Ophthalmol 2024; 24:156. [PMID: 38594643 PMCID: PMC11003116 DOI: 10.1186/s12886-024-03391-z] [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: 06/06/2023] [Accepted: 03/11/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND This research investigates the correlation between the severity of internal carotid artery (ICA) stenosis and retinal parameters in patients with proliferative diabetic retinopathy (PDR), aiming to uncover potential risk factors. METHODS A retrospective analysis of 68 patients (136 eyes) diagnosed with bilateral PDR from January 1, 2017, to December 31, 2021, was conducted. Carotid artery stenosis (CAS) was assessed using neck computed tomography angiography (CTA) and carotid duplex ultrasound (CDUS), with stenosis classified into two groups: normal (group 1) and mild or above (group 2), based on the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Optical coherence tomography (OCT) and OCT angiography (OCTA) measured several retinal parameters, including sub foveal choroidal thickness (SFCT), retinal nerve fiber layer (RNFL) thickness, ganglion cell-inner plexiform layer (GCIPL) thickness, vessel density (VD), and foveal avascular zone (FAZ) area. Statistical analyses determined correlations between ICA degrees and retinal parameters. RESULTS This study showed significant differences between groups in total VD, FAZ area, total RNFL thickness, and temporal RNFL thickness, indicating that patients with more severe ICA stenosis had noticeable retinal changes. Other parameters such as hyperlipidemia, total cholesterol levels, and intraocular pressure (IOP) also differed significantly, while no notable differences were observed in SFCT, central VD, average GCIPL, and superior, nasal, and inferior RNFL thickness. CONCLUSION The study findings highlight retinal changes, such as an increased FAZ area, decreased total VD, and a total and thinner temporal RNFL, which suggest the need for carotid artery evaluation in patients. These findings have important clinical implications for the need for carotid work up in patients with PDR.
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Affiliation(s)
- Chae Yoon Lee
- Department of Ophthalmology, Maryknoll Hospital, 121 Junggu-ro, Jung-gu, 48972, Busan, Korea
| | - Jung Min Park
- Department of Ophthalmology, Maryknoll Hospital, 121 Junggu-ro, Jung-gu, 48972, Busan, Korea
| | - Myeong In Yeom
- Department of Ophthalmology, Maryknoll Hospital, 121 Junggu-ro, Jung-gu, 48972, Busan, Korea.
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8
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Aherrahrou R, Baig F, Theofilatos K, Lue D, Beele A, Örd T, Kaikkonen MU, Aherrahrou Z, Cheng Q, Ghosh S, Karnewar S, Karnewar V, Finn A, Owens GK, Joner M, Mayr M, Civelek M. Secreted Protein Profiling of Human Aortic Smooth Muscle Cells Identifies Vascular Disease Associations. Arterioscler Thromb Vasc Biol 2024; 44:898-914. [PMID: 38328934 PMCID: PMC10978267 DOI: 10.1161/atvbaha.123.320274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 01/26/2024] [Indexed: 02/09/2024]
Abstract
BACKGROUND Smooth muscle cells (SMCs), which make up the medial layer of arteries, are key cell types involved in cardiovascular disease, the leading cause of mortality and morbidity worldwide. In response to microenvironment alterations, SMCs dedifferentiate from a contractile to a synthetic phenotype characterized by an increased proliferation, migration, production of ECM (extracellular matrix) components, and decreased expression of SMC-specific contractile markers. These phenotypic changes result in vascular remodeling and contribute to the pathogenesis of cardiovascular disease, including coronary artery disease, stroke, hypertension, and aortic aneurysms. Here, we aim to identify the genetic variants that regulate ECM secretion in SMCs and predict the causal proteins associated with vascular disease-related loci identified in genome-wide association studies. METHODS Using human aortic SMCs from 123 multiancestry healthy heart transplant donors, we collected the serum-free media in which the cells were cultured for 24 hours and conducted liquid chromatography-tandem mass spectrometry-based proteomic analysis of the conditioned media. RESULTS We measured the abundance of 270 ECM and related proteins. Next, we performed protein quantitative trait locus mapping and identified 20 loci associated with secreted protein abundance in SMCs. We functionally annotated these loci using a colocalization approach. This approach prioritized the genetic variant rs6739323-A at the 2p22.3 locus, which is associated with lower expression of LTBP1 (latent-transforming growth factor beta-binding protein 1) in SMCs and atherosclerosis-prone areas of the aorta, and increased risk for SMC calcification. We found that LTBP1 expression is abundant in SMCs, and its expression at mRNA and protein levels was reduced in unstable and advanced atherosclerotic plaque lesions. CONCLUSIONS Our results unravel the SMC proteome signature associated with vascular disorders, which may help identify potential therapeutic targets to accelerate the pathway to translation.
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Affiliation(s)
- Rédouane Aherrahrou
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland
- Institute for Cardiogenetics, Universität zu Lübeck; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany; University Heart Centre Lübeck, Germany
| | - Ferheen Baig
- King’s British Heart Foundation Centre, King’s College London, London, United Kingdom
| | | | - Dillon Lue
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America
| | - Alicia Beele
- CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD
| | - Tiit Örd
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland
| | - Minna U Kaikkonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland
| | - Zouhair Aherrahrou
- Institute for Cardiogenetics, Universität zu Lübeck; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany; University Heart Centre Lübeck, Germany
| | - Qi Cheng
- CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD
| | - Saikat Ghosh
- CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD
| | - Santosh Karnewar
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Vaishnavi Karnewar
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Aloke Finn
- CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD
| | - Gary K. Owens
- Department of Molecular Physiology and Biological Physics, Department of Medicine, Division of Cardiology, Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, United States of America
| | - Michael Joner
- Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technical University Munich, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Manuel Mayr
- National Heart & Lung Institute, Imperial College London, London, United Kingdom
| | - Mete Civelek
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
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Albricker ACL, Freire CMV, Santos SND, Alcantara MLD, Cantisano AL, Porto CLL, Amaral SID, Veloso OCG, Morais Filho DD, Teodoro JAR, Petisco ACGP, Saleh MH, Barros MVLD, Barros FS, Engelhorn ALDV, Engelhorn CA, Nardino ÉP, Silva MADM, Biagioni LC, Souza AJD, Sarpe AKP, Oliveira ACD, Moraes MRDS, Francisco Neto MJ, Françolin PC, Rochitte CE, Iquizli R, Santos AASMDD, Muglia VF, Naves BDL. Recommendation Update for Vascular Ultrasound Evaluation of Carotid and Vertebral Artery Disease: DIC, CBR and SABCV - 2023. Arq Bras Cardiol 2023; 120:e20230695. [PMID: 37991060 DOI: 10.36660/abc.20230695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2023] Open
Affiliation(s)
- Ana Cristina Lopes Albricker
- Centro Universitário de Belo Horizonte (UniBH), Belo Horizonte, MG - Brasil
- IMEDE - Instituto Mineiro de Ultrassonografia, Belo Horizonte, MG - Brasil
| | - Claudia Maria Vilas Freire
- Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG - Brasil
- Empresa Brasileira de Serviços Hospitalares (UBSERH), Brasília, DF - Brasil
| | | | | | | | | | | | - Orlando Carlos Glória Veloso
- Rede UnitedHealth Group (UHG), Rio de Janeiro, RJ - Brasil
- Hospital Pasteur, Rio de Janeiro, RJ - Brasil
- Hospital Américas, Rio de Janeiro, RJ - Brasil
- Hospital de Clínicas Mário Lioni, Rio de Janeiro, RJ - Brasil
| | | | | | | | | | | | | | | | | | - Érica Patrício Nardino
- Faculdade de Medicina do ABC Paulista, SP - Brasil
- Faculdade de Medicina Unoeste, Guarujá, SP - Brasil
| | | | | | | | | | | | | | | | - Peter Célio Françolin
- Instituto do Coração (InCor) da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP - Brasil
| | - Carlos Eduardo Rochitte
- Instituto do Coração (InCor) da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP - Brasil
- Hospital do Coração (Hcor), São Paulo, SP - Brasil
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10
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Aherrahrou R, Baig F, Theofilatos K, Lue D, Beele A, Örd T, Kaikkonen MU, Aherrahrou Z, Cheng Q, Ghosh S, Karnewar S, Karnewar V, Finn A, Owens GK, Joner M, Mayr M, Civelek M. Secreted protein profiling of human aortic smooth muscle cells identifies vascular disease associations. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.11.10.23298351. [PMID: 37986932 PMCID: PMC10659471 DOI: 10.1101/2023.11.10.23298351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
Background Smooth muscle cells (SMCs), which make up the medial layer of arteries, are key cell types involved in cardiovascular diseases (CVD), the leading cause of mortality and morbidity worldwide. In response to microenvironment alterations, SMCs dedifferentiate from a "contractile" to a "synthetic" phenotype characterized by an increased proliferation, migration, production of extracellular matrix (ECM) components, and decreased expression of SMC-specific contractile markers. These phenotypic changes result in vascular remodeling and contribute to the pathogenesis of CVD, including coronary artery disease (CAD), stroke, hypertension, and aortic aneurysms. Here, we aim to identify the genetic variants that regulate ECM secretion in SMCs and predict the causal proteins associated with vascular disease-related loci identified in genome-wide association studies (GWAS). Methods Using human aortic SMCs from 123 multi-ancestry healthy heart transplant donors, we collected the serum-free media in which the cells were cultured for 24 hours and conducted Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis of the conditioned media. Results We measured the abundance of 270 ECM and related proteins. Next, we performed protein quantitative trait locus mapping (pQTL) and identified 20 loci associated with secreted protein abundance in SMCs. We functionally annotated these loci using a colocalization approach. This approach prioritized the genetic variant rs6739323-A at the 2p22.3 locus, which is associated with lower expression of LTBP1 in SMCs and atherosclerosis-prone areas of the aorta, and increased risk for SMC calcification. We found that LTBP1 expression is abundant in SMCs, and its expression at mRNA and protein levels was reduced in unstable and advanced atherosclerotic plaque lesions. Conclusions Our results unravel the SMC proteome signature associated with vascular disorders, which may help identify potential therapeutic targets to accelerate the pathway to translation.
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Affiliation(s)
- Rédouane Aherrahrou
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland
- Institute for Cardiogenetics, Universität zu Lübeck; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany; University Heart Centre Lübeck, Germany
| | - Ferheen Baig
- King’s British Heart Foundation Centre, King’s College London, London, United Kingdom
| | | | - Dillon Lue
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America
| | - Alicia Beele
- CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD
| | - Tiit Örd
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland
| | - Minna U Kaikkonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland
| | - Zouhair Aherrahrou
- Institute for Cardiogenetics, Universität zu Lübeck; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany; University Heart Centre Lübeck, Germany
| | - Qi Cheng
- CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD
| | - Saikat Ghosh
- CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD
| | - Santosh Karnewar
- Department of Molecular Physiology and Biological Physics, Department of Medicine, Division of Cardiology, Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, United States of America
| | - Vaishnavi Karnewar
- Department of Molecular Physiology and Biological Physics, Department of Medicine, Division of Cardiology, Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, United States of America
| | - Aloke Finn
- CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD
| | - Gary K. Owens
- Department of Molecular Physiology and Biological Physics, Department of Medicine, Division of Cardiology, Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, United States of America
| | - Michael Joner
- Klinik für Herz-und Kreislauferkrankungen, Deutsches Herzzentrum München, Technical University Munich, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Manuel Mayr
- King’s British Heart Foundation Centre, King’s College London, London, United Kingdom
| | - Mete Civelek
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
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11
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Daoud FC, Catargi B, Karjalainen PP, Gerbaud E. Five-Year Efficacy and Safety of TiNO-Coated Stents Versus Drug-Eluting Stents in Acute Coronary Syndrome: A Meta-Analysis. J Clin Med 2023; 12:6952. [PMID: 37959416 PMCID: PMC10649952 DOI: 10.3390/jcm12216952] [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: 09/04/2023] [Revised: 10/08/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
(1) Background: Percutaneous coronary interventions (PCI) in patients with acute coronary syndrome (ACS) are performed with titanium-nitride-oxide-coated stents (TiNOSs) or drug-eluting stents (DESs). The initial completion of this prospective systematic literature review (SLR) of prospective randomized controlled trials (RCTs) showed that TiNOSs are non-inferior to DESs in major adverse cardiac event (MACE) rates and present a lower risk of recurrent myocardial infarction (MI) at 1-year follow-up. This iteration of the SLR protocol performs the critical assessment of 5-year follow-up outcomes with clinical validity and generalizability assessments. (2) Methods: The previously described SLR and meta-analysis protocol, per PRISMA, Cochrane methods, and GRADE, was applied to 5-year follow-up outcomes. (3) Results: Three RCTs were eligible, comprising 1620 patients with TiNOS vs. 1123 with DES. The pooled risk ratios (RRs) and 95% confidence intervals were MACE 0.82 [0.68, 0.99], MI 0.58 [0.44, 0.78], cardiac death (CD) 0.46 [0.28, 0.76], ischemia-driven target lesion revascularization (TLR) 1.03 [0.79, 1.33], probable or definite stent thrombosis (ST) 0.32 [0.21, 0.59], and all-cause mortality (TD) 0.84 [0.63, 1.12]. The evidence certainty was high in MACE, CD, MI, and ST, and moderate in TLR and TD. (4) Conclusions: TiNOSs in ACS at 5-year follow-up appear safer than DESs and equally efficacious. The pooled RRs stratified by clinical presentation and stent type will be required to test this meta-analysis's clinical validity and generalize its results to patient populations with varying proportions of clinical presentations and DES options.
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Affiliation(s)
- Frederic C. Daoud
- Endocrinology-Metabolic Diseases, Hôpital Saint-André, Bordeaux University, 33000 Bordeaux, France; (F.C.D.); (B.C.)
| | - Bogdan Catargi
- Endocrinology-Metabolic Diseases, Hôpital Saint-André, Bordeaux University, 33000 Bordeaux, France; (F.C.D.); (B.C.)
| | - Pasi P. Karjalainen
- Cardiac Unit, Heart and Lung Center, Helsinki University Hospital, Helsinki University, 00280 Helsinki, Finland;
| | - Edouard Gerbaud
- Cardiology Intensive Care Unit and Interventional Cardiology, Hôpital Cardiologique du Haut-Lévêque, 33604 Pessac, France
- Bordeaux Cardio-Thoracic Research Centre, U1045, Bordeaux University, 33076 Bordeaux, France
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12
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Laera N, Malerba P, Vacanti G, Nardin S, Pagnesi M, Nardin M. Impact of Immunity on Coronary Artery Disease: An Updated Pathogenic Interplay and Potential Therapeutic Strategies. Life (Basel) 2023; 13:2128. [PMID: 38004268 PMCID: PMC10672143 DOI: 10.3390/life13112128] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 10/23/2023] [Accepted: 10/24/2023] [Indexed: 11/26/2023] Open
Abstract
Coronary artery disease (CAD) is the leading cause of death worldwide. It is a result of the buildup of atherosclerosis within the coronary arteries. The role of the immune system in CAD is complex and multifaceted. The immune system responds to damage or injury to the arterial walls by initiating an inflammatory response. However, this inflammatory response can become chronic and lead to plaque formation. Neutrophiles, macrophages, B lymphocytes, T lymphocytes, and NKT cells play a key role in immunity response, both with proatherogenic and antiatherogenic signaling pathways. Recent findings provide new roles and activities referring to endothelial cells and vascular smooth muscle cells, which help to clarify the intricate signaling crosstalk between the involved actors. Research is ongoing to explore immunomodulatory therapies that target the immune system to reduce inflammation and its contribution to atherosclerosis. This review aims to summarize the pathogenic interplay between immunity and CAD and the potential therapeutic strategies, and explore immunomodulatory therapies that target the immune system to reduce inflammation and its contribution to atherosclerosis.
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Affiliation(s)
- Nicola Laera
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy;
- Second Medicine Division, Department of Medicine, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Paolo Malerba
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy;
- Division of Medicine, Department of Medicine, ASST Spedali Civili di Montichiari, 25018 Montichiari, Italy
| | - Gaetano Vacanti
- Medical Clinic IV, Department of Cardiology, Municipal Hospital, 76133 Karlsruhe, Germany;
| | - Simone Nardin
- U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
- Department of Internal Medicine and Medical Sciences, School of Medicine, University of Genova, 16126 Genova, Italy
| | - Matteo Pagnesi
- Division of Cardiology, ASST Spedali Civili of Brescia, 25123 Brescia, Italy;
| | - Matteo Nardin
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090 Milan, Italy;
- Third Medicine Division, Department of Medicine, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
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Karnewar S, Karnewar V, Deaton R, Shankman LS, Benavente ED, Williams CM, Bradley X, Alencar GF, Bulut GB, Kirmani S, Baylis RA, Zunder ER, den Ruijter HM, Pasterkamp G, Owens GK. IL-1β inhibition partially negates the beneficial effects of diet-induced lipid lowering. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.13.562255. [PMID: 37873280 PMCID: PMC10592822 DOI: 10.1101/2023.10.13.562255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Background Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions are the leading cause of death in the world. The most common and effective means to reduce these major adverse cardiovascular events (MACE), including myocardial infarction (MI) and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, little is known regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering. Methods Smooth muscle cell (SMC)-lineage tracing Apoe-/- mice were fed a Western diet (WD) for 18 weeks and then switched to a low-fat chow diet for 12 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery (BCA) lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of SMC, and other lesion cells by SMC-lineage tracing combined with scRNA-seq, CyTOF, and immunostaining plus high resolution confocal microscopic z-stack analysis. In addition, to determine if treatment with a potent inhibitor of inflammation could augment the benefits of chow diet-induced reductions in LDL-cholesterol, SMC-lineage tracing Apoe-/- mice were fed a WD for 18 weeks and then chow diet for 12 weeks prior to treating them with an IL-1β or control antibody (Ab) for 8-weeks. Results Lipid-lowering by switching Apoe-/- mice from a WD to a chow diet reduced LDL-cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1β Ab treatment resulted in multiple detrimental changes including increased plaque burden, BCA lesion size, as well as increased cholesterol crystal accumulation, intra-plaque hemorrhage, necrotic core area, and senescence as compared to IgG control Ab treated mice. Furthermore, IL-1β Ab treatment upregulated neutrophil degranulation pathways but down-regulated SMC extracellular matrix pathways likely important for the protective fibrous cap. Conclusions Taken together, IL-1β appears to be required for chow diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.
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Affiliation(s)
- Santosh Karnewar
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Vaishnavi Karnewar
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Rebecca Deaton
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Laura S. Shankman
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Ernest D. Benavente
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Corey M. Williams
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Xenia Bradley
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Gabriel F. Alencar
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Gamze B. Bulut
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Sara Kirmani
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Richard A. Baylis
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Eli R. Zunder
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
| | - Hester M. den Ruijter
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Gerard Pasterkamp
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Gary K. Owens
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA
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14
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Fernández-Alvarez V, Linares-Sánchez M, Suárez C, López F, Guntinas-Lichius O, Mäkitie AA, Bradley PJ, Ferlito A. Novel Imaging-Based Biomarkers for Identifying Carotid Plaque Vulnerability. Biomolecules 2023; 13:1236. [PMID: 37627301 PMCID: PMC10452902 DOI: 10.3390/biom13081236] [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: 06/25/2023] [Revised: 07/30/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Carotid artery disease has traditionally been assessed based on the degree of luminal narrowing. However, this approach, which solely relies on carotid stenosis, is currently being questioned with regard to modern risk stratification approaches. Recent guidelines have introduced the concept of the "vulnerable plaque," emphasizing specific features such as thin fibrous caps, large lipid cores, intraplaque hemorrhage, plaque rupture, macrophage infiltration, and neovascularization. In this context, imaging-based biomarkers have emerged as valuable tools for identifying higher-risk patients. Non-invasive imaging modalities and intravascular techniques, including ultrasound, computed tomography, magnetic resonance imaging, intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy, have played pivotal roles in characterizing and detecting unstable carotid plaques. The aim of this review is to provide an overview of the evolving understanding of carotid artery disease and highlight the significance of imaging techniques in assessing plaque vulnerability and informing clinical decision-making.
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Affiliation(s)
- Verónica Fernández-Alvarez
- Department of Vascular and Endovascular Surgery, Hospital Universitario de Cabueñes, 33394 Gijón, Spain;
| | - Miriam Linares-Sánchez
- Department of Vascular and Endovascular Surgery, Hospital Universitario de Cabueñes, 33394 Gijón, Spain;
| | - Carlos Suárez
- Instituto de Investigacion Sanitaria del Principado de Asturias, 33011 Oviedo, Spain; (C.S.); (F.L.)
| | - Fernando López
- Instituto de Investigacion Sanitaria del Principado de Asturias, 33011 Oviedo, Spain; (C.S.); (F.L.)
- Department of Otorhinolaryngology, Hospital Universitario Central de Asturias, Instituto Universitario de Oncologia del Principado de Asturias, University of Oviedo, CIBERONC, 33011 Oviedo, Spain
| | | | - Antti A. Mäkitie
- Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, University of Helsinki, P.O. Box 263, 00029 Helsinki, Finland;
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
- Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institute and Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Patrick J. Bradley
- Department of ORLHNS, Queens Medical Centre Campus, Nottingham University Hospitals, Derby Road, Nottingham NG7 2UH, UK;
| | - Alfio Ferlito
- Coordinator of the International Head and Neck Scientific Group, 35100 Padua, Italy;
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15
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Yang D, Elkind MSV. Current perspectives on the clinical management of cryptogenic stroke. Expert Rev Neurother 2023; 23:213-226. [PMID: 36934333 PMCID: PMC10166643 DOI: 10.1080/14737175.2023.2192403] [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: 01/29/2023] [Accepted: 03/14/2023] [Indexed: 03/20/2023]
Abstract
INTRODUCTION Cryptogenic stroke is a heterogeneous entity defined as an ischemic stroke for which no probable cause is identified despite thorough diagnostic evaluation. Since about a quarter of all ischemic strokes are classified as cryptogenic, it is a commonly encountered problem for providers as secondary stroke prevention is guided by stroke etiology. AREAS COVERED In this review, the authors provide an overview of stroke subtype classification schemes and diagnostic evaluation in cryptogenic stroke. They then detail putative cryptogenic stroke mechanisms, their therapeutic implications, and ongoing research. This review synthesizes the available evidence on PubMed up to December 2022. EXPERT OPINION Cryptogenic stroke is an evolving concept that changes with ongoing research. Investigations are focused on improving our diagnostic capabilities and solidifying useful constructs within cryptogenic stroke that could become therapeutically targetable subgroups within an otherwise nonspecific entity. Advances in technology may help move specific proposed cryptogenic stroke mechanisms from undetermined to known source of ischemic stroke.
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Affiliation(s)
- Dixon Yang
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Mitchell S. V. Elkind
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
- American Heart Association
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16
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ANGPTL4 stabilizes atherosclerotic plaques and modulates the phenotypic transition of vascular smooth muscle cells through KLF4 downregulation. Exp Mol Med 2023; 55:426-442. [PMID: 36782020 PMCID: PMC9981608 DOI: 10.1038/s12276-023-00937-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 11/29/2022] [Accepted: 12/08/2022] [Indexed: 02/15/2023] Open
Abstract
Atherosclerosis, the leading cause of death, is a vascular disease of chronic inflammation. We recently showed that angiopoietin-like 4 (ANGPTL4) promotes cardiac repair by suppressing pathological inflammation. Given the fundamental contribution of inflammation to atherosclerosis, we assessed the role of ANGPTL4 in the development of atherosclerosis and determined whether ANGPTL4 regulates atherosclerotic plaque stability. We injected ANGPTL4 protein twice a week into atherosclerotic Apoe-/- mice and analyzed the atherosclerotic lesion size, inflammation, and plaque stability. In atherosclerotic mice, ANGPTL4 reduced atherosclerotic plaque size and vascular inflammation. In the atherosclerotic lesions and fibrous caps, the number of α-SMA(+), SM22α(+), and SM-MHC(+) cells was higher, while the number of CD68(+) and Mac2(+) cells was lower in the ANGPTL4 group. Most importantly, the fibrous cap was significantly thicker in the ANGPTL4 group than in the control group. Smooth muscle cells (SMCs) isolated from atherosclerotic aortas showed significantly increased expression of CD68 and Krüppel-like factor 4 (KLF4), a modulator of the vascular SMC phenotype, along with downregulation of α-SMA, and these changes were attenuated by ANGPTL4 treatment. Furthermore, ANGPTL4 reduced TNFα-induced NADPH oxidase 1 (NOX1), a major source of reactive oxygen species, resulting in the attenuation of KLF4-mediated SMC phenotypic changes. We showed that acute myocardial infarction (AMI) patients with higher levels of ANGPTL4 had fewer vascular events than AMI patients with lower levels of ANGPTL4 (p < 0.05). Our results reveal that ANGPTL4 treatment inhibits atherogenesis and suggest that targeting vascular stability and inflammation may serve as a novel therapeutic strategy to prevent and treat atherosclerosis. Even more importantly, ANGPTL4 treatment inhibited the phenotypic changes of SMCs into macrophage-like cells by downregulating NOX1 activation of KLF4, leading to the formation of more stable plaques.
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17
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Finney AC, Das S, Kumar D, McKinney MP, Cai B, Yurdagul A, Rom O. The interplay between nonalcoholic fatty liver disease and atherosclerotic cardiovascular disease. Front Cardiovasc Med 2023; 10:1116861. [PMID: 37200978 PMCID: PMC10185914 DOI: 10.3389/fcvm.2023.1116861] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 03/23/2023] [Indexed: 05/20/2023] Open
Abstract
Therapeutic approaches that lower circulating low-density lipoprotein (LDL)-cholesterol significantly reduced the burden of cardiovascular disease over the last decades. However, the persistent rise in the obesity epidemic is beginning to reverse this decline. Alongside obesity, the incidence of nonalcoholic fatty liver disease (NAFLD) has substantially increased in the last three decades. Currently, approximately one third of world population is affected by NAFLD. Notably, the presence of NAFLD and particularly its more severe form, nonalcoholic steatohepatitis (NASH), serves as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), thus, raising interest in the relationship between these two diseases. Importantly, ASCVD is the major cause of death in patients with NASH independent of traditional risk factors. Nevertheless, the pathophysiology linking NAFLD/NASH with ASCVD remains poorly understood. While dyslipidemia is a common risk factor underlying both diseases, therapies that lower circulating LDL-cholesterol are largely ineffective against NASH. While there are no approved pharmacological therapies for NASH, some of the most advanced drug candidates exacerbate atherogenic dyslipidemia, raising concerns regarding their adverse cardiovascular consequences. In this review, we address current gaps in our understanding of the mechanisms linking NAFLD/NASH and ASCVD, explore strategies to simultaneously model these diseases, evaluate emerging biomarkers that may be useful to diagnose the presence of both diseases, and discuss investigational approaches and ongoing clinical trials that potentially target both diseases.
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Affiliation(s)
- Alexandra C. Finney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Sandeep Das
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Dhananjay Kumar
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - M. Peyton McKinney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Bishuang Cai
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, United States
| | - Arif Yurdagul
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Correspondence: Arif Yurdagul Oren Rom
| | - Oren Rom
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Correspondence: Arif Yurdagul Oren Rom
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18
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Tornifoglio B, Stone AJ, Kerskens C, Lally C. Ex Vivo Study Using Diffusion Tensor Imaging to Identify Biomarkers of Atherosclerotic Disease in Human Cadaveric Carotid Arteries. Arterioscler Thromb Vasc Biol 2022; 42:1398-1412. [PMID: 36172867 PMCID: PMC9592180 DOI: 10.1161/atvbaha.122.318112] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND This study aims to address the potential of ex vivo diffusion tensor imaging to provide insight into the microstructural composition and morphological arrangement of aged human atherosclerotic carotid arteries. METHODS In this study, whole human carotid arteries were investigated both anatomically and by comparing healthy and diseased regions. Nonrigid image registration was used with unsupervised segmentation to investigate the influence of elastin, collagen, cell density, glycosaminoglycans, and calcium on diffusion tensor imaging derived metrics (fractional anisotropy and mean diffusivity). Early stage atherosclerotic features were also investigated in terms of microstructural components and diffusion tensor imaging metrics. RESULTS All vessels displayed a dramatic decrease in fractional anisotropy compared with healthy animal arterial tissue, while the mean diffusivity was sensitive to regions of advanced disease. Elastin content strongly correlated with both fractional anisotropy (r>0.7, P<0.001) and mean diffusivity (r>-0.79, P<0.0002), and the thickened intima was also distinguishable from arterial media by these metrics. CONCLUSIONS These different investigations point to the potential of diffusion tensor imaging to identify characteristics of arterial disease progression, at early and late-stage lesion development.
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Affiliation(s)
- Brooke Tornifoglio
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute (B.T., A.J.S., C.K., C.L.), Ireland.,Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering (B.T., A.J.S., C.L.), Ireland
| | - Alan J. Stone
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute (B.T., A.J.S., C.K., C.L.), Ireland.,Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering (B.T., A.J.S., C.L.), Ireland.,Department of Medical Physics and Clinical Engineering, St. Vincent’s University Hospital, Dublin, Ireland (A.J.S.)
| | - Christian Kerskens
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute (B.T., A.J.S., C.K., C.L.), Ireland.,Trinity College Institute of Neuroscience (C.K.), Ireland
| | - Caitríona Lally
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute (B.T., A.J.S., C.K., C.L.), Ireland.,Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering (B.T., A.J.S., C.L.), Ireland.,Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin (C.L.), Ireland
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19
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Gole S, Tkachenko S, Masannat T, Baylis RA, Cherepanova OA. Endothelial-to-Mesenchymal Transition in Atherosclerosis: Friend or Foe? Cells 2022; 11:cells11192946. [PMID: 36230908 PMCID: PMC9563961 DOI: 10.3390/cells11192946] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/16/2022] [Accepted: 09/18/2022] [Indexed: 11/16/2022] Open
Abstract
Despite many decades of research, complications of atherosclerosis resulting from the rupture or erosion of unstable plaques remain the leading cause of death worldwide. Advances in cellular lineage tracing techniques have allowed researchers to begin investigating the role of individual cell types in the key processes regulating plaque stability, including maintenance of the fibrous cap, a protective collagen-rich structure that underlies the endothelium. This structure was previously thought to be entirely derived from smooth muscle cells (SMC), which migrated from the vessel wall. However, recent lineage tracing studies have identified endothelial cells (EC) as an essential component of this protective barrier through an endothelial-to-mesenchymal transition (EndoMT), a process that has previously been implicated in pulmonary, cardiac, and kidney fibrosis. Although the presence of EndoMT in atherosclerotic plaques has been shown by several laboratories using EC-lineage tracing mouse models, whether EndoMT is detrimental (i.e., worsening disease progression) or beneficial (i.e., an athero-protective response that prevents plaque instability) remains uncertain as there are data to support both possibilities, which will be further discussed in this review.
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Affiliation(s)
- Sarin Gole
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NB5, Cleveland, OH 44195, USA
| | - Svyatoslav Tkachenko
- Genetics and Genome Sciences, Case Western Reserve University, 2109 Adelbert, RD, BRB, Cleveland, OH 44106, USA
| | - Tarek Masannat
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NB5, Cleveland, OH 44195, USA
| | - Richard A. Baylis
- Department of Medicine, Massachusetts General Hospital, 55 Fruit St Gray 730, Boston, MA 02114, USA
| | - Olga A. Cherepanova
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NB5, Cleveland, OH 44195, USA
- Correspondence: ; Tel.: +1-216-445-7491
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20
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Mattesini A, Demola P, Shlofmitz R, Shlofmitz E, Waksman R, Jaffer FA, Di Mario C. Optical Coherence Tomography, Near‐Infrared Spectroscopy, and Near‐Infrared Fluorescence Molecular Imaging. Interv Cardiol 2022. [DOI: 10.1002/9781119697367.ch9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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21
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Yurdagul A. Crosstalk Between Macrophages and Vascular Smooth Muscle Cells in Atherosclerotic Plaque Stability. Arterioscler Thromb Vasc Biol 2022; 42:372-380. [PMID: 35172605 PMCID: PMC8957544 DOI: 10.1161/atvbaha.121.316233] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Most acute cardiovascular events are due to plaque rupture, with atheromas containing large necrotic cores and thin fibrous caps being more susceptible to rupture and lesions with small necrotic cores and thick fibrous caps being more protected from rupture. Atherosclerotic plaques are comprised various extracellular matrix proteins, modified lipoprotein particles, and cells of different origins, that is, vascular cells and leukocytes. Although much has been revealed about the mechanisms that lead to plaque instability, several key areas remain incompletely understood. This In-Focus Review highlights processes related to cellular crosstalk and the role of the tissue microenvironment in determining cell function and plaque stability. Recent advances highlight critical underpinnings of atherosclerotic plaque vulnerability, particularly impairments in the ability of macrophages to clear dead cells and phenotypic switching of vascular smooth muscle cells. However, these processes do not occur in isolation, as crosstalk between macrophages and vascular smooth muscle cells and interactions with their surrounding microenvironment play a significant role in determining plaque stability. Understanding these aspects of cellular crosstalk within an atherosclerotic plaque may shed light on how to modify cell behavior and identify novel approaches to transform rupture-prone atheromas into stable lesions.
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Affiliation(s)
- Arif Yurdagul
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences, Shreveport
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22
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Stanton KM, Liu H, Kienzle V, Bursill C, Bao S, Celermajer DS. The Effects of Exercise on Plaque Volume and Composition in a Mouse Model of Early and Late Life Atherosclerosis. Front Cardiovasc Med 2022; 9:837371. [PMID: 35419434 PMCID: PMC8995971 DOI: 10.3389/fcvm.2022.837371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/17/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundExercise is associated with a less atherogenic lipid profile; however, there is limited research on the effect of exercise on atherosclerotic plaque composition and markers of plaque stability.MethodsA total of 110 apolipoprotein (apo)E−/− mice were placed on a chow diet and randomly assigned to control or exercise for a period of 10 weeks, commencing either at 12 weeks of age (the early-stage atherosclerosis, EA group) or at 40 weeks of age (the late-stage atherosclerosis, LA group). At the end of the exercise period, blood was assayed for lipids. Histologic analysis of the aortic sinus was undertaken to assess plaque size and composition that includes macrophage content, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase-2 (MMP-2), and tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and 2).ResultsA total of 103 mice (38 EA, 65 LA) completed the protocol. In the EA group, exercise reduced plasma total cholesterol (TC) (−16%), free cholesterol (−13%), triglyceride (TG) (−35%), and phospholipid (−27%) levels, when compared to sedentary control mice (p < 0.01). In the EA group, exercise also significantly reduced plaque stenosis (−25%, p < 0.01), and there were higher levels of elastin (3-fold increase, p < 0.0001) and collagen (11-fold increase, p < 0.0001) in plaques, compared to control mice. There was an increase in plaque MMP-2 content in the exercise group (13% increase, p < 0.05) but no significant difference in macrophage or MCP-1 content. In the LA group, exercise reduced plaque stenosis (−18%, p < 0.05), but there was no significant difference in plaque composition. There was no difference in macrophage, MCP-1, or MMP-2 content in the LA groups. TIMP-1 was lower with exercise in both the EA and LA groups (−59%, p < 0.01 and −51%, p < 0.01 respectively); however, there was no difference in TIMP-2 levels.ConclusionA 10-week exercise period reduces atherosclerotic plaque stenosis when commenced at both early- and late-stage atherosclerosis. Intervening earlier with exercise had a greater beneficial effect on lipids and plaque composition than when starting exercise at a later disease stage.
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Affiliation(s)
- Kelly M. Stanton
- Clinical Research Group, Heart Research Institute, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- *Correspondence: Kelly M. Stanton
| | - Hongjuan Liu
- Discipline of Pathology and School of Medical Science, University of Sydney, Sydney, NSW, Australia
| | - Vivian Kienzle
- Clinical Research Group, Heart Research Institute, Sydney, NSW, Australia
| | - Christina Bursill
- Clinical Research Group, Heart Research Institute, Sydney, NSW, Australia
- Vascular Research Centre, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, Australia
| | - Shisan Bao
- Discipline of Pathology and School of Medical Science, University of Sydney, Sydney, NSW, Australia
| | - David S. Celermajer
- Clinical Research Group, Heart Research Institute, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
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23
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Liu H, Pietersz G, Peter K, Wang X. Nanobiotechnology approaches for cardiovascular diseases: site-specific targeting of drugs and nanoparticles for atherothrombosis. J Nanobiotechnology 2022; 20:75. [PMID: 35135581 PMCID: PMC8822797 DOI: 10.1186/s12951-022-01279-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 01/21/2022] [Indexed: 02/18/2023] Open
Abstract
Atherosclerosis and atherothrombosis, the major contributors to cardiovascular diseases (CVDs), represent the leading cause of death worldwide. Current pharmacological therapies have been associated with side effects or are insufficient at halting atherosclerotic progression effectively. Pioneering work harnessing the passive diffusion or endocytosis properties of nanoparticles and advanced biotechnologies in creating recombinant proteins for site-specific delivery have been utilized to overcome these limitations. Since CVDs are complex diseases, the most challenging aspect of developing site-specific therapies is the identification of an individual and unique antigenic epitope that is only expressed in lesions or diseased areas. This review focuses on the pathological mechanism of atherothrombosis and discusses the unique targets that are important during disease progression. We review recent advances in site-specific therapy using novel targeted drug-delivery and nanoparticle-carrier systems. Furthermore, we explore the limitations and future perspectives of site-specific therapy for CVDs.
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Affiliation(s)
- Haikun Liu
- Molecular Imaging and Theranostics Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Geoffrey Pietersz
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Burnet Institute, Melbourne, VIC, Australia.,Department of Cardiometabolic Health, University of Melbourne, VIC, Australia
| | - Karlheinz Peter
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Cardiometabolic Health, University of Melbourne, VIC, Australia.,Department of Medicine, Monash University, Melbourne, VIC, Australia.,La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Xiaowei Wang
- Molecular Imaging and Theranostics Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia. .,Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. .,Department of Cardiometabolic Health, University of Melbourne, VIC, Australia. .,Department of Medicine, Monash University, Melbourne, VIC, Australia. .,La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia.
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24
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Homorodean C, Leucuta DC, Ober M, Homorodean R, Spinu M, Olinic M, Tataru D, Olinic DM. Intravascular ultrasound insights into the unstable features of the coronary atherosclerotic plaques: A systematic review and meta-analysis. Eur J Clin Invest 2022; 52:e13671. [PMID: 34411283 DOI: 10.1111/eci.13671] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 08/07/2021] [Accepted: 08/16/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND There is a lack of a comprehensive picture of plaque geometry and composition of unstable atherosclerotic lesions as observed with intravascular ultrasound techniques. We analysed through a systematic review with meta-analysis 39 characteristics of atherosclerotic plaques in three scenarios involving culprit and non-culprit lesions from acute coronary syndromes vs stable angina pectoris patients, and culprit vs non-culprit lesions in acute coronary syndromes patients. METHODS A systematic search of PubMed and EMBASE, from inception to April 2020 was performed. The combined odds ratios or mean differences of all IVUS characteristics were calculated with random-effects models. RESULTS Twenty-eight studies involving 5434 subjects, and 5618 lesions were included. Culprit lesions in acute coronary syndromes have larger plaque areas and remodeling indexes (MD = 0.13 [0.08; 0.17], p < 0.001) and contained larger necrotic cores (MD = 0.67 (95% CI 0.19;1.15), p = 0.006) that stable angina culprit lesions. In acute patients, culprit plaques were also more remodeled, had larger necrotic cores and had more frequently a Thin-Cap Fibroatheroma morphology (OR = 1.79 (95% CI 1.21; 2.65), p = 0.004) than non-culprit lesions. Non-culprit lesions in acute syndromes were more often ruptured (OR = 2.25 (95% CI:1.05; 4.82), p = 0.037) or Thin-Cap Fibroatheromas than in stable angina. CONCLUSION Culprit lesions from acute coronary patients are larger, more positively remodeled and contained more lipids as compared to stable angina lesions or non-culprit in acute patients. Non culprit lesions are also more often complicated or vulnerable in acute than stable patients.
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Affiliation(s)
- Calin Homorodean
- Internal Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Emergency County Hospital Cluj Napoca, Cluj-Napoca, Romania
| | - Daniel-Corneliu Leucuta
- Medical Informatics and Biostatistics Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Mihai Ober
- Emergency County Hospital Cluj Napoca, Cluj-Napoca, Romania
| | | | - Mihail Spinu
- Internal Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Maria Olinic
- Internal Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Emergency County Hospital Cluj Napoca, Cluj-Napoca, Romania
| | - Dan Tataru
- Internal Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Emergency County Hospital Cluj Napoca, Cluj-Napoca, Romania
| | - Dan-Mircea Olinic
- Internal Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Emergency County Hospital Cluj Napoca, Cluj-Napoca, Romania
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25
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Mao L, Yin R, Yang L, Zhao D. Role of advanced glycation end products on vascular smooth muscle cells under diabetic atherosclerosis. Front Endocrinol (Lausanne) 2022; 13:983723. [PMID: 36120471 PMCID: PMC9470882 DOI: 10.3389/fendo.2022.983723] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/11/2022] [Indexed: 11/30/2022] Open
Abstract
Atherosclerosis (AS) is a chronic inflammatory disease and leading cause of cardiovascular diseases. The progression of AS is a multi-step process leading to high morbidity and mortality. Hyperglycemia, dyslipidemia, advanced glycation end products (AGEs), inflammation and insulin resistance which strictly involved in diabetes are closely related to the pathogenesis of AS. A growing number of studies have linked AGEs to AS. As one of the risk factors of cardiac metabolic diseases, dysfunction of VSMCs plays an important role in AS pathogenesis. AGEs are increased in diabetes, participate in the occurrence and progression of AS through multiple molecular mechanisms of vascular cell injury. As the main functional cells of vascular, vascular smooth muscle cells (VSMCs) play different roles in each stage of atherosclerotic lesions. The interaction between AGEs and receptor for AGEs (RAGE) accelerates AS by affecting the proliferation and migration of VSMCs. In addition, increasing researches have reported that AGEs promote osteogenic transformation and macrophage-like transformation of VSMCs, and affect the progression of AS through other aspects such as autophagy and cell cycle. In this review, we summarize the effect of AGEs on VSMCs in atherosclerotic plaque development and progression. We also discuss the AGEs that link AS and diabetes mellitus, including oxidative stress, inflammation, RAGE ligands, small noncoding RNAs.
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Affiliation(s)
| | | | | | - Dong Zhao
- *Correspondence: Longyan Yang, ; Dong Zhao,
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26
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Trikouraki A, Yova D, Pouliakis A, Spathis A, Moulakakis KG, Matsopoulos G. Serum Biomarkers and Classification and Regression Trees Can Discriminate Symptomatic from Asymptomatic Carotid Artery Disease Patients. Artery Res 2021. [DOI: 10.1007/s44200-021-00004-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Abstract
Objective
To assess biomarkers between symptomatic and asymptomatic patients, and to construct a classification and regression tree (CART) algorithm for their discrimination.
Patients and Methods
136 patients were enrolled. They were symptomatic (high risk) (N = 82, stenosis degree ≥ 50%, proven to be responsible for ischemic stroke the last six months) and asymptomatic (low risk) (N = 54, stenosis degree ≤ 50%). Levels of fibrinogen, matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), soluble intercellular adhesion molecule (SiCAM), soluble vascular cell adhesion molecule (SvCAM), adiponectin and insulin were measured on a Luminex 3D platform and their differences were evaluated; subsequently, a CART model was created and evaluated.
Results
All measured biomarkers, except adiponectin, had significantly higher levels in symptomatic patients. The constructed CART prognostic model had 97.6% discrimination accuracy on symptomatic patients and 79.6% on asymptomatic, while the overall accuracy was 90.4%. Moreover, the population was split into training and test sets for CART validation.
Conclusion
Significant differences were found in the biomarkers between symptomatic and asymptomatic patients. The CART model proved to be a simple decision-making algorithm linked with risk probabilities and provided evidence to identify and, therefore, treat patients being at high risk for cardiovascular disease.
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Checkouri E, Blanchard V, Meilhac O. Macrophages in Atherosclerosis, First or Second Row Players? Biomedicines 2021; 9:biomedicines9091214. [PMID: 34572399 PMCID: PMC8465019 DOI: 10.3390/biomedicines9091214] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/08/2021] [Accepted: 09/11/2021] [Indexed: 12/24/2022] Open
Abstract
Macrophages represent a cell type that has been widely described in the context of atherosclerosis since the earliest studies in the 17th century. Their role has long been considered to be preponderant in the onset and aggravation of atherosclerosis, in particular by participating in the establishment of a chronic inflammatory state by the release of pro-inflammatory cytokines and by uncontrolled engorgement of lipids resulting in the formation of foam cells and later of the necrotic core. However, recent evidence from mouse models using an elegant technique of tracing vascular smooth muscle cells (VSMCs) during plaque development revealed that resident VSMCs display impressive plastic properties in response to an arterial injury, allowing them to switch into different cell types within the plaque, including mesenchymal-like cells, macrophage-like cells and osteochondrogenic-like cells. In this review, we oppose the arguments in favor or against the influence of macrophages versus VSMCs in all stages of atherosclerosis including pre-atherosclerosis, formation of lipid-rich foam cells, development of the necrotic core and the fibrous cap as well as calcification and rupture of the plaque. We also analyze the relevance of animal models for the investigation of the pathophysiological mechanisms of atherosclerosis in humans, and discuss potential therapeutic strategies targeting either VSMCs or macrophage to prevent the development of cardiovascular events. Overall, although major findings have been made from animal models, efforts are still needed to better understand and therefore prevent the development of atherosclerotic plaques in humans.
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Affiliation(s)
- Eloïse Checkouri
- INSERM, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Université de La Réunion, 97400 Sainte-Clotilde, France; (E.C.); (V.B.)
- Habemus Papam, Food Industry, 97470 Saint-Benoit, France
| | - Valentin Blanchard
- INSERM, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Université de La Réunion, 97400 Sainte-Clotilde, France; (E.C.); (V.B.)
- Departments of Medicine, Centre for Heart Lung Innovation, Providence Healthcare Research Institute, St Paul’s Hospital, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Olivier Meilhac
- INSERM, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Université de La Réunion, 97400 Sainte-Clotilde, France; (E.C.); (V.B.)
- CHU de La Réunion, INSERM, CIC1410, 97500 Saint-Pierre, France
- Correspondence: ; Tel.: +33-262-93-8811
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28
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Cui X, Xing R, Tian Y, Wang M, Sun Y, Xu Y, Yang Y, Zhao Y, Xie L, Xiao Y, Li D, Zheng B, Liu M, Chen H. The G2A Receptor Deficiency Aggravates Atherosclerosis in Rats by Regulating Macrophages and Lipid Metabolism. Front Physiol 2021; 12:659211. [PMID: 34381373 PMCID: PMC8351205 DOI: 10.3389/fphys.2021.659211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 04/13/2021] [Indexed: 11/16/2022] Open
Abstract
The orphan G protein-coupled receptor G2A has been linked to atherosclerosis development. However, available data from mouse models are controversial. Rat G2A receptor bears more similarities with its human homolog. We proposed that the atherosclerosis model established from Ldlr–/– rat, which has been reported to share more similar phenotypes with the human disease, may help to further understand this lipid receptor. G2A deletion was found markedly aggravated in the lipid disorder in the rat model, which has not been reported in mouse studies. Examination of aortas revealed exacerbated atherosclerotic plaques in G2A deficient rats, together with increased oxidative stress and macrophage accumulation. In addition, consistently promoted migration and apoptosis were noticed in G2A deficient macrophages, even in macrophages from G2A single knockout rats. Further analysis found significantly declined phosphorylation of PI3 kinase (PI3K) and AKT, together with reduced downstream genes Bcl2 and Bcl-xl, suggesting possible involvement of PI3K/AKT pathway in G2A regulation to macrophage apoptosis. These data indicate that G2A modulates atherosclerosis by regulating lipid metabolism and macrophage migration and apoptosis. Our study provides a new understanding of the role of G2A in atherosclerosis, supporting it as a potential therapeutic target.
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Affiliation(s)
- Xueqin Cui
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Roumei Xing
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Yue Tian
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Man Wang
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Yue Sun
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Yongqian Xu
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Yiqing Yang
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Yongliang Zhao
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Ling Xie
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Yufang Xiao
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Dali Li
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Biao Zheng
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China.,Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, United States
| | - Mingyao Liu
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Huaqing Chen
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
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Takahashi L, Ishigami T, Tomiyama H, Kato Y, Kikuchi H, Tasaki K, Yamashita J, Inoue S, Taguri M, Nagao T, Chikamori T, Ishikawa Y, Yokoyama U. Increased Plasma Levels of Myosin Heavy Chain 11 Is Associated with Atherosclerosis. J Clin Med 2021; 10:jcm10143155. [PMID: 34300321 PMCID: PMC8304775 DOI: 10.3390/jcm10143155] [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: 06/10/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 11/16/2022] Open
Abstract
Many studies have revealed numerous potential biomarkers for atherosclerosis, but tissue-specific biomarkers are still needed. Recent lineage-tracing studies revealed that smooth muscle cells (SMCs) contribute substantially to plaque formation, and the loss of SMCs causes plaque vulnerability. We investigated the association of SMC-specific myosin heavy chain 11 (myosin-11) with atherosclerosis. Forty-five patients with atherosclerosis and 34 control subjects were recruited into our study. In the atherosclerosis patients, 35 patients had either coronary artery disease (CAD) or peripheral artery disease (PAD), and 10 had both CAD and PAD. Coronary arteries isolated from five patients were subjected to histological study. Circulating myosin-11 levels were higher in the CAD or PAD group than in controls. The area under the receiver operating characteristic curve of myosin-11 was 0.954. Circulating myosin-11 levels in the CAD and PAD group were higher than in the CAD or PAD group, while high-sensitivity C-reactive protein concentrations did not differ between these groups. Multinomial logistic regression analyses showed a significant association of myosin-11 levels with the presence of multiple atherosclerotic regions. Myosin-11 was expressed in the medial layer of human atherosclerotic lesions where apoptosis elevated. Circulating myosin-11 levels may be useful for detecting spatial expansion of atherosclerotic regions.
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Affiliation(s)
- Lisa Takahashi
- Department of Cardiology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; (L.T.); (H.T.); (J.Y.); (T.C.)
- Department of Physiology, Tokyo Medical University, 6-6-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan;
| | - Tomoaki Ishigami
- Department of Cardio-Renal Medicine and Medical Science, Yokohama City University, 3-9 Fukuura, Yokohama 236-0004, Japan;
| | - Hirofumi Tomiyama
- Department of Cardiology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; (L.T.); (H.T.); (J.Y.); (T.C.)
| | - Yuko Kato
- Department of Physiology, Tokyo Medical University, 6-6-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan;
| | - Hiroyuki Kikuchi
- Department of Preventive Medicine and Public Health, Tokyo Medical University, 6-6-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan; (H.K.); (S.I.)
| | - Koichiro Tasaki
- Department of Pathology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; (K.T.); (T.N.)
| | - Jun Yamashita
- Department of Cardiology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; (L.T.); (H.T.); (J.Y.); (T.C.)
| | - Shigeru Inoue
- Department of Preventive Medicine and Public Health, Tokyo Medical University, 6-6-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan; (H.K.); (S.I.)
| | - Masataka Taguri
- Department of Data Science, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan;
| | - Toshitaka Nagao
- Department of Pathology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; (K.T.); (T.N.)
| | - Taishiro Chikamori
- Department of Cardiology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; (L.T.); (H.T.); (J.Y.); (T.C.)
| | - Yoshihiro Ishikawa
- Cardiovascular Research Institute, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan;
| | - Utako Yokoyama
- Department of Physiology, Tokyo Medical University, 6-6-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan;
- Cardiovascular Research Institute, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan;
- Correspondence: ; Tel.: +81-03-351-6141
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30
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Tuominen H, Taina M, Puranen M, Onatsu J, Huumonen S, Vanninen R. Serum High-Sensitive C-reactive Protein May Reflect Periodontitis in Patients With Stroke. In Vivo 2021; 34:2829-2835. [PMID: 32871821 DOI: 10.21873/invivo.12109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/02/2020] [Accepted: 06/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIM Chronic infectious diseases are believed to increase the risk of stroke. We aimed to evaluate the prevalence of periodontal disease and its association with systemic inflammatory processes in patients suffering an acute stroke/transient ischemic attack (TIA). PATIENTS AND METHODS Altogether 36 acute stroke/TIA patients underwent clinical, laboratory and radiological examinations. The level of systemic inflammation was analyzed both with routine measurements of plasma C-reactive protein (p-CRP) and serum high-sensitivity CRP (s-hsCRP) to analyze their associations with periodontitis. The diagnostic criteria for periodontitis included increased probing depth (>4 mm) measured from four different sites, bleeding on probing, and horizontal (>1 mm), vertical (>1 mm) or apical bone loss observed on orthopantomography. RESULTS Twenty-six (72.2%) patients were diagnosed with periodontitis. Only five of the patients with periodontitis (19.2%) had elevated p-CRP values whereas the majority, (17/26; 65.4%) had elevated s-hsCRP values (p<0.01). Absolute s-hsCRP values in patients with periodontitis (8.9±12.5 mg/l) were significantly higher than in patients without periodontitis (2.3±3.0 mg/l; p<0.05). Absolute p-CRP concentrations did not differ (2.3±5.8 vs. 2.4±5.1 mg/l; p=not significant). The total number of periodontitis findings was significantly associated with s-hsCRP values (r=1.83) but not with p-CRP values. Conversely, seventeen of the nineteen patients with elevated s-hsCRP (89.5%) indicative of systemic inflammation had periodontitis. CONCLUSION Periodontitis is a common finding among patients with acute stroke/TIA as over 80% of patients with cryptogenic stroke/TIA had periodontitis. S-hsCRP is a useful tool for detecting subclinical systemic inflammation.
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Affiliation(s)
- Hanna Tuominen
- The Institute of Dentistry, University of Eastern Finland, Kuopio, Finland
| | - Mikko Taina
- Unit of Radiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.,Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland
| | - Mirja Puranen
- Department of Pathology, Kuopio University Hospital, Kuopio, Finland.,Oral and Maxillofacial Department, Kuopio University Hospital, Kuopio, Finland
| | - Juha Onatsu
- NeuroCenter, Kuopio University Hospital, Kuopio, Finland
| | - Sisko Huumonen
- The Institute of Dentistry, University of Eastern Finland, Kuopio, Finland.,Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland
| | - Ritva Vanninen
- Unit of Radiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.,Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland
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31
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Terlecki M, Wojciechowska W, Dudek D, Siudak Z, Plens K, Guzik TJ, Drożdż T, Pęksa J, Bartuś S, Wojakowski W, Grygier M, Rajzer M. Impact of acute total occlusion of the culprit artery on outcome in NSTEMI based on the results of a large national registry. BMC Cardiovasc Disord 2021; 21:297. [PMID: 34126930 PMCID: PMC8204478 DOI: 10.1186/s12872-021-02099-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 05/31/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The impact of acute total occlusion (TO) of the culprit artery in non-ST-segment elevation myocardial infarction (NSTEMI) is not fully established. We aimed to evaluate the clinical and angiographic phenotype and outcome of NSTEMI patients with TO (NSTEMITO) compared to NSTEMI patients without TO (NSTEMINTO) and those with ST-segment elevation and TO (STEMITO). METHODS Demographic, clinical and procedure-related data of patients with acute myocardial infarction who underwent percutaneous coronary intervention (PCI) between 2014 and 2017 from the Polish National Registry were analysed. RESULTS We evaluated 131,729 patients: NSTEMINTO (n = 65,206), NSTEMITO (n = 16,209) and STEMITO (n = 50,314). The NSTEMITO group had intermediate results compared to the NSTEMINTO and STEMITO groups regarding mean age (68.78 ± 11.39 vs 65.98 ± 11.61 vs 64.86 ± 12.04 (years), p < 0.0001), Killip class IV on admission (1.69 vs 2.48 vs 5.03 (%), p < 0.0001), cardiac arrest before admission (2.19 vs 3.09 vs 6.02 (%), p < 0.0001) and death during PCI (0.43 vs 0.97 vs 1.76 (%), p < 0.0001)-for NSTEMINTO, NSTEMITO and STEMITO, respectively. However, we noticed that the NSTEMITO group had the longest time from pain to first medical contact (median 4.0 vs 5.0 vs 2.0 (hours), p < 0.0001) and the lowest frequency of TIMI flow grade 3 after PCI (88.61 vs 83.36 vs 95.57 (%), p < 0.0001) and that the left circumflex artery (LCx) was most often the culprit lesion (14.09 vs 35.86 vs 25.42 (%), p < 0.0001). CONCLUSIONS The NSTEMITO group clearly differed from the NSTEMINTO group. NSTEMITO appears to be an intermediate condition between NSTEMINTO and STEMITO, although NSTEMITO patients have the longest time delay to and the worst result of PCI, which can be explained by the location of the culprit lesion in the LCx.
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Affiliation(s)
- Michał Terlecki
- Jagiellonian University Medical College, 1st Department of Cardiology, Interventional Electrocardiology and Arterial Hypertension, Jakubowskiego St. 2, 30-688, Kraków, Poland
| | - Wiktoria Wojciechowska
- Jagiellonian University Medical College, 1st Department of Cardiology, Interventional Electrocardiology and Arterial Hypertension, Jakubowskiego St. 2, 30-688, Kraków, Poland
| | - Dariusz Dudek
- Jagiellonian University Medical College, 2nd Department of Cardiology, Kraków, Poland
| | - Zbigniew Siudak
- Faculty of Medicine and Health Sciences, Jan Kochanowski University, Kielce, Poland
| | | | - Tomasz J Guzik
- Jagiellonian University Medical College, Department of Internal and Agricultural Medicine, Kraków, Poland
| | - Tomasz Drożdż
- Jagiellonian University Medical College, 1st Department of Cardiology, Interventional Electrocardiology and Arterial Hypertension, Jakubowskiego St. 2, 30-688, Kraków, Poland
| | - Jan Pęksa
- Jagiellonian University Medical College, 1st Department of Cardiology, Interventional Electrocardiology and Arterial Hypertension, Jakubowskiego St. 2, 30-688, Kraków, Poland
| | - Stanisław Bartuś
- Jagiellonian University Medical College, 2nd Department of Cardiology, Kraków, Poland
| | - Wojciech Wojakowski
- Department of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, Poland
| | - Marek Grygier
- 1St Department of Cardiology, Poznan University of Medical Sciences, Poznan, Poland
| | - Marek Rajzer
- Jagiellonian University Medical College, 1st Department of Cardiology, Interventional Electrocardiology and Arterial Hypertension, Jakubowskiego St. 2, 30-688, Kraków, Poland.
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Nishida T, Hiro T, Takayama T, Sudo M, Haruta H, Fukamachi D, Hirayama A, Okumura Y. Clinical significance of microvessels detected by in vivo optical coherence tomography within human atherosclerotic coronary arterial intima: a study with multimodality intravascular imagings. Heart Vessels 2021; 36:756-765. [PMID: 33403471 DOI: 10.1007/s00380-020-01756-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 12/11/2020] [Indexed: 10/22/2022]
Abstract
The significance of microvessels within atherosclerotic plaques is not yet fully clarified. Associated with plaque vulnerability. The aim of this study is to examine tissue characteristics of plaque with microvessels detected by optical coherence tomography (OCT) by use of a commercially available color-coded intravascular ultrasound (IVUS) and coronary angioscopy (CAS). The subjects examined comprised of 44 patients with stable angina pectoris who underwent percutaneous coronary intervention. Microvessels were defined as a tiny tubule with a diameter of 50-300 µm detected over three or more frames in OCT. We compared the total volume of microvessels with tissue component such as fibrotic, lipidic, necrotic, and calcified volume and the number of yellow plaque. In IVUS analysis, % necrotic volume and % lipidic volume were significantly correlated and % fibrotic volume was inversely significantly correlated with the total volume of microvessel (r = 0.485, p = 0.0009; r = 0.401, p = 0.007; r = - 0.432, p = 0.003, respectively). The number of plaque with an angioscopic yellow grade of two or more was significantly correlated with the total volume of microvessel (r = 0.461, p = 0.002). The greater the luminal volume of microvessels, the more the percent content of necrotic/lipidic tissue volume within plaque and the more the number of yellow plaques. These data suggested that microvessels within coronary plaque might be related to plaque vulnerability.
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Affiliation(s)
- Toshihiko Nishida
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Takafumi Hiro
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
| | - Tadateru Takayama
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Mitsumasa Sudo
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Hironori Haruta
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Daisuke Fukamachi
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Atsushi Hirayama
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Yasuo Okumura
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan
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Giannopoulos S, Armstrong EJ. Clinical considerations after endovascular therapy of peripheral artery disease. Expert Rev Cardiovasc Ther 2021; 19:369-378. [PMID: 33870848 DOI: 10.1080/14779072.2021.1914590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Patients with peripheral artery disease (PAD) are at higher risk for all-cause mortality, driven by increased cardiovascular mortality rates. In this manuscript we review the literature on guideline-recommended therapies and discuss the major clinical considerations after endovascular therapy of PAD.Areas covered: Current guidelines recommend smoking cessation, aspirin, statin, and renin-angiotensin system inhibitors in order to reduce the risk of cardiovascular and limb-related adverse events. Nonetheless, studies have shown that patients with PAD are undertreated with these important medical therapies. Additionally, there is lack in evidence regarding the most optimal follow up imaging approach for early detection of disease recurrence and re-intervention among patients undergoing endovascular therapy for PAD. We also describe the benefits of supervised walking exercise for patients with PAD that undergo revascularization procedures and are fit for such interventions.Expert opinion: Adherence to guideline recommended medical therapy is crucial for improved outcomes in PAD management. Systematic assessment of risk-reduction interventions could help increase adherence to clinically beneficial interventions and improve the overall prognosis of patients with PAD undergoing revascularization procedures. Additionally, optimization of current follow up protocols is needed, with the optimal goal to develop standardized cost-effective algorithms regarding early detection of disease recurrence and re-intervention.
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Affiliation(s)
- Stefanos Giannopoulos
- Division of Cardiology, Rocky Mountain Regional VA Medical Center, University of Colorado, Denver, CO, USA
| | - Ehrin J Armstrong
- Division of Cardiology, Rocky Mountain Regional VA Medical Center, University of Colorado, Denver, CO, USA
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Sato W, Suto Y, Yamanaka T, Watanabe H. An advanced ultrasound application used to assess peripheral vascular diseases: superb microvascular imaging. J Echocardiogr 2021; 19:150-157. [PMID: 33856650 DOI: 10.1007/s12574-021-00527-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/02/2021] [Accepted: 03/31/2021] [Indexed: 11/29/2022]
Abstract
Over the past several years, a novel ultrasound imaging modality termed superb microvascular imaging (SMI) has enabled visualization of microvessels. SMI ultrasound studies of peripheral artery diseases have significantly extended our knowledge of tissue microcirculation and the arterial microenvironments of atherosclerotic lesions. We here present an overview of current knowledge on the utility of SMI assessment of vascular diseases and highlight certain peripheral microcirculation disorders for which SMI is particularly valuable. The evidence indicates that SMI can detect intraplaque neovascularization and usefully assess carotid plaque vulnerability; vascularization of the carotid arterial wall detected by SMI is a potential marker of disease activity in patients with Takayasu arteritis; SMI reveals the foot microcirculation and yields a quantitative vascular index (in line with the angiosome concept); and, SMI may serve as an auxiliary diagnostic modality for hereditary hemorrhagic telangiectasia and Raynaud syndrome. In general, microcirculatory evaluation by SMI is an attractive field for future research on therapeutic strategies for peripheral vascular diseases.
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Affiliation(s)
- Wakana Sato
- Department of Cardiovascular Medicine, Akita University Graduate School of Medicine, 1-1-1, Hondoh, Akita, 010-8543, Japan
| | - Yuta Suto
- Department of Cardiovascular Medicine, Akita University Graduate School of Medicine, 1-1-1, Hondoh, Akita, 010-8543, Japan
| | - Takayuki Yamanaka
- Department of Cardiovascular Medicine, Akita University Graduate School of Medicine, 1-1-1, Hondoh, Akita, 010-8543, Japan
| | - Hiroyuki Watanabe
- Department of Cardiovascular Medicine, Akita University Graduate School of Medicine, 1-1-1, Hondoh, Akita, 010-8543, Japan.
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35
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The Napkin-Ring Sign – the Story Behind Invasive Coronary Angiography. JOURNAL OF INTERDISCIPLINARY MEDICINE 2021. [DOI: 10.2478/jim-2021-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Coronary artery disease (CAD) represents one of the leading causes of morbidity and mortality across Europe. Most of the patients do not experience any warning sign before the coronary event develops, therefore screening this group of patients is essential to prevent major cardiac events. Coronary computed tomography angiography (CCTA) offers a noninvasive approach of the coronary arteries, providing information not only on the presence and severity of the coronary stenosis, but is also able to characterize the structure of the coronary wall. CCTA allows complex evaluation of the extension of CAD, and by assessing the structure of the atherosclerotic plaque, it can identify its degree of vulnerability. The napkin-ring sign (NRS) represents a ring-like attenuation of the non-calcified portion of the coronary lesion and has a high specificity (96–100%) for the identification of thin cap fibroatheroma (TCFA) or culprit lesion in acute coronary syndromes (ACS). It is also an independent predictor for ACS events and the strongest predictor for future ACS. Modern CCTA can provide submillimeter isotropic spatial resolution. Thus, CT attenuation-based tissue interpretation enables the assessment of total coronary plaque burden and individual plaque components, with a similar accuracy as intravascular ultrasoud-based investigations. This review aims to present the important role of CCTA as a potent screening tool for patients with CAD, and the current evidences in the detection and quantification of vulnerable plaques.
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Newman AAC, Serbulea V, Baylis RA, Shankman LS, Bradley X, Alencar GF, Owsiany K, Deaton RA, Karnewar S, Shamsuzzaman S, Salamon A, Reddy MS, Guo L, Finn A, Virmani R, Cherepanova OA, Owens GK. Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRβ and bioenergetic mechanisms. Nat Metab 2021; 3:166-181. [PMID: 33619382 PMCID: PMC7905710 DOI: 10.1038/s42255-020-00338-8] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 12/22/2020] [Indexed: 01/03/2023]
Abstract
Stable atherosclerotic plaques are characterized by a thick, extracellular matrix-rich fibrous cap populated by protective ACTA2+ myofibroblast (MF)-like cells, assumed to be almost exclusively derived from smooth muscle cells (SMCs). Herein, we show that in murine and human lesions, 20% to 40% of ACTA2+ fibrous cap cells, respectively, are derived from non-SMC sources, including endothelial cells (ECs) or macrophages that have undergone an endothelial-to-mesenchymal transition (EndoMT) or a macrophage-to-mesenchymal transition (MMT). In addition, we show that SMC-specific knockout of the Pdgfrb gene, which encodes platelet-derived growth factor receptor beta (PDGFRβ), in Apoe-/- mice fed a Western diet for 18 weeks resulted in brachiocephalic artery lesions nearly devoid of SMCs but with no changes in lesion size, remodelling or indices of stability, including the percentage of ACTA2+ fibrous cap cells. However, prolonged Western diet feeding of SMC Pdgfrb-knockout mice resulted in reduced indices of stability, indicating that EndoMT- and MMT-derived MFs cannot compensate indefinitely for loss of SMC-derived MFs. Using single-cell and bulk RNA-sequencing analyses of the brachiocephalic artery region and in vitro models, we provide evidence that SMC-to-MF transitions are induced by PDGF and transforming growth factor-β and dependent on aerobic glycolysis, while EndoMT is induced by interleukin-1β and transforming growth factor-β. Together, we provide evidence that the ACTA2+ fibrous cap originates from a tapestry of cell types, which transition to an MF-like state through distinct signalling pathways that are either dependent on or associated with extensive metabolic reprogramming.
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Affiliation(s)
- Alexandra A C Newman
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Cardiovascular Research Center, New York University Langone Medical Center, NY, New York, USA
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Vlad Serbulea
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Richard A Baylis
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Laura S Shankman
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Xenia Bradley
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Gabriel F Alencar
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Katherine Owsiany
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Rebecca A Deaton
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Santosh Karnewar
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Sohel Shamsuzzaman
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Anita Salamon
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Mahima S Reddy
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Liang Guo
- CVPath Institute, Gaithersburg, MD, USA
| | | | | | - Olga A Cherepanova
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Cardiovascular and Metabolic Sciences Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gary K Owens
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
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Vos A, de Jong PA, Verdoorn D, Mali WPTM, Bleys RLAW, Vink A. Histopathological characterization of intimal lesions and arterial wall calcification in the arteries of the leg of elderly cadavers. Clin Anat 2020; 34:835-841. [PMID: 33174629 PMCID: PMC8451780 DOI: 10.1002/ca.23701] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 11/06/2022]
Abstract
Introduction Although arteries of the leg have been studied in extensively diseased amputation specimens, little is known about the composition of vascular lesions present in the general population. The aim of this study was to describe the natural development of adaptive intimal thickening, atherosclerotic lesion development and vascular calcification in the leg of a general elderly population. Materials and Methods Two hundred and seventy postmortem samples from the popliteal and posterior tibial arteries of 14 elderly cadavers were studied histologically. Results Atherosclerotic lesions were more frequently observed in the popliteal (60%) than in the posterior tibial artery (34%; p < .0005). These atherosclerotic plaques were most often nonatheromatous (80% and 83% for popliteal and posterior tibial plaques, respectively). The atheroma's that were present were small (most <25% of plaque area). Atherosclerotic plaque calcification was observed more often in the popliteal (39%) than in the posterior tibial samples (17%; p < .0005). Medial arterial calcification was observed more often in the posterior tibial (62%) than in the popliteal samples (46%; p = .008). Plaque calcification and medial arterial calcification were not associated with lumen stenosis. Conclusions In the leg of elderly cadavers, the presence of atherosclerotic plaque and intimal calcification decreases from the proximal popliteal artery to the more distal posterior tibial artery and most atherosclerotic lesions are of the fibrous nonatheromatous type. In contrast, the presence and severity of medial calcification increases from proximal to distal.
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Affiliation(s)
- Annelotte Vos
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Pim A de Jong
- Department of Radiology, University Medical Center, Utrecht, The Netherlands
| | - Daphne Verdoorn
- Department of Anatomy, University Medical Center, Utrecht, The Netherlands
| | - Willem P T M Mali
- Department of Radiology, University Medical Center, Utrecht, The Netherlands
| | - Ronald L A W Bleys
- Department of Anatomy, University Medical Center, Utrecht, The Netherlands
| | - Aryan Vink
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
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Qian S, Ma T, Zhang N, Liu X, Zhao P, Li X, Chen D, Hu L, Chang L, Xu L, Deng X, Fan Y. Spatiotemporal transfer of nitric oxide in patient-specific atherosclerotic carotid artery bifurcations with MRI and computational fluid dynamics modeling. Comput Biol Med 2020; 125:104015. [DOI: 10.1016/j.compbiomed.2020.104015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/17/2020] [Accepted: 09/17/2020] [Indexed: 12/29/2022]
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Gallerand A, Stunault MI, Merlin J, Guinamard RR, Yvan-Charvet L, Ivanov S. Myeloid Cell Diversity and Impact of Metabolic Cues during Atherosclerosis. IMMUNOMETABOLISM 2020; 2:immunometab20200028. [PMID: 39649554 PMCID: PMC7617020 DOI: 10.20900/immunometab20200028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Myeloid cells are key contributors to tissue, immune and metabolic homeostasis and their alteration fuels inflammation and associated disorders such as atherosclerosis. Conversely, in a classical chicken-and-egg situation, systemic and local metabolism, together with receptor-mediated activation, regulate intracellular metabolism and reprogram myeloid cell functions. Those regulatory loops are notable during the development of atherosclerotic lesions. Therefore, understanding the intricate metabolic mechanisms regulating myeloid cell biology could lead to innovative approaches to prevent and treat cardiovascular diseases. In this review, we will attempt to summarize the different metabolic factors regulating myeloid cell homeostasis and contribution to atherosclerosis, the most frequent cardiovascular disease.
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Affiliation(s)
- Alexandre Gallerand
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
| | - Marion I. Stunault
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
| | - Johanna Merlin
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
| | - Rodolphe R. Guinamard
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
| | - Laurent Yvan-Charvet
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
| | - Stoyan Ivanov
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
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40
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Ignatyev IM, Gafurov MR, Krivosheeva NV. Criteria for Carotid Atherosclerotic Plaque Instability. Ann Vasc Surg 2020; 72:340-349. [PMID: 32927044 DOI: 10.1016/j.avsg.2020.08.145] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/14/2020] [Accepted: 08/16/2020] [Indexed: 11/18/2022]
Abstract
BACKGROUND The study aim is to determine the criteria for carotid atherosclerotic plaque instability with the use of an advanced ultrasound technology, immunohistochemical analysis, and electron paramagnetic resonance (EPR) and assess their correlations with histologic results. METHODS A total of 92 patients were included in the study and were examined by ultrasound duplex scanning and ultrasound elastography. Plaques harvested during carotid endarterectomy were obtained for histologic analysis, immunofluorescent assay, and EPR spectroscopic measurements. RESULTS Multivariate logistic regression analysis showed that plaques with an area >90 mm2 (odds ratio [OR], 4.05; 95% confidence interval [CI], 1.32-13.2; P = 0.006), plaque volume index > 0.6 cm3 (OR, 2.72; 95% CI, 1.05-9.58; P = 0.04), and juxtaluminal black area ≥8 mm2 (OR, 2.82; 95% CI, 1.22-6. 23; P = 0.02) were statistically significant independent predictors of histologically verified unstable plaques. Unstable plaques occurred in 94% of the patients with these indicators. Significant increases in the number of CD68+ and CD36+ cells (inflammatory markers) and CD31+ cells (neovasculogenesis markers) were revealed in unstable plaques by the immunohistochemical assay. EPR data analysis showed that divalent manganese could serve as a marker of plaque instability. CONCLUSIONS Additional ultrasound criteria, verified by histologic studies, significantly increased the information content for identifying patients with unstable plaques, which can be of great importance in stratifying the risk of ischemic stroke, especially in asymptomatic patients. The degree of calcification is not a mandatory criterion for plaque stabilization.
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Affiliation(s)
- Igor M Ignatyev
- Interregional Clinical and Diagnostic Centre, Kazan, Russia; Department of Cardiovascular and Endovascular Surgery, Kazan State Medical University, Kazan, Russia.
| | - Marat R Gafurov
- Institute of Physics of the Kazan (Volga Region) Federal University, Kazan, Russia
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Nagata M, Minami M, Yoshida K, Yang T, Yamamoto Y, Takayama N, Ikedo T, Hayashi K, Miyata T, Yokode M, Miyamoto S. Calcium-Binding Protein S100A4 Is Upregulated in Carotid Atherosclerotic Plaques and Contributes to Expansive Remodeling. J Am Heart Assoc 2020; 9:e016128. [PMID: 32914661 PMCID: PMC7726981 DOI: 10.1161/jaha.120.016128] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background Carotid plaques with expansive arterial remodeling are closely related to cerebral ischemic events. Although S100A4 (S100 calcium‐binding protein A4) is expressed in atherosclerotic lesions, its role in atherosclerotic plaque progression remains unknown. In this study, we examined the association between carotid arterial expansive remodeling and S100A4 expression. Methods and Results Preoperative high‐resolution magnetic resonance imaging was used to assess luminal stenosis and vascular remodeling in patients undergoing carotid endarterectomy. To examine murine carotid atherosclerosis, we induced experimental lesions by flow cessation in apolipoprotein E‐deficient mice fed a high‐fat diet. The role of S100A4 in plaque formation and smooth muscle cell proliferation was investigated in vivo and in vitro, respectively. Human carotid arterial expansive remodeling showed positive correlations with the expression of S100A4, MMP2, and MMP9. S100A4 mRNA levels were positively correlated with those of MMP2, MMP9, and MMP13. S100A4 was expressed in vascular smooth muscle cells (VSMCs) and VSMC‐derived foam cells in the plaque shoulder and marginal areas. S100A4 expression increased concomitantly with plaque formation in our animal model. Exogenous recombinant S100A4 protein enhanced the levels of Mmp2, Mmp9, and Mmp13 and the cell proliferation ability in VSMCs. A chemotaxis assay indicated that extracellular S100A4 functions as a chemoattractant for VSMCs. Conclusions S100A4 expression was elevated in human carotid plaques and showed a positive correlation with the degree of expansive remodeling. S100A4‐positive VSMC‐derived cells are considered to play an important role in carotid expansive remodeling.
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Affiliation(s)
- Manabu Nagata
- Department of Neurosurgery Kyoto University Graduate School of Medicine Kyoto Japan.,Department of Clinical Innovative Medicine Kyoto University Graduate School of Medicine Kyoto Japan
| | - Manabu Minami
- Department of Clinical Innovative Medicine Kyoto University Graduate School of Medicine Kyoto Japan
| | - Kazumichi Yoshida
- Department of Neurosurgery Kyoto University Graduate School of Medicine Kyoto Japan
| | - Tao Yang
- Department of Neurosurgery Kyoto University Graduate School of Medicine Kyoto Japan.,Department of Clinical Innovative Medicine Kyoto University Graduate School of Medicine Kyoto Japan
| | - Yu Yamamoto
- Department of Neurosurgery Kyoto University Graduate School of Medicine Kyoto Japan.,Department of Clinical Innovative Medicine Kyoto University Graduate School of Medicine Kyoto Japan
| | - Naoki Takayama
- Department of Neurosurgery Kyoto University Graduate School of Medicine Kyoto Japan.,Department of Clinical Innovative Medicine Kyoto University Graduate School of Medicine Kyoto Japan
| | - Taichi Ikedo
- Department of Neurosurgery Kyoto University Graduate School of Medicine Kyoto Japan.,Department of Clinical Innovative Medicine Kyoto University Graduate School of Medicine Kyoto Japan
| | - Kosuke Hayashi
- Department of Neurosurgery Kyoto University Graduate School of Medicine Kyoto Japan.,Department of Clinical Innovative Medicine Kyoto University Graduate School of Medicine Kyoto Japan
| | - Takeshi Miyata
- Department of Neurosurgery Kyoto University Graduate School of Medicine Kyoto Japan.,Department of Clinical Innovative Medicine Kyoto University Graduate School of Medicine Kyoto Japan
| | - Masayuki Yokode
- Department of Clinical Innovative Medicine Kyoto University Graduate School of Medicine Kyoto Japan
| | - Susumu Miyamoto
- Department of Neurosurgery Kyoto University Graduate School of Medicine Kyoto Japan
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Bobetsis YA, Kotsikoris I, Liapis CD, Liasis N, Kakisis J, Kourlaba G, Lazari P, Antonopoulos CN, Deliargyris EN, Madianos PN. Association between periodontal disease and vulnerable plaque morphology in patients undergoing carotid endarterectomy. IJC HEART & VASCULATURE 2020; 30:100601. [PMID: 32802936 PMCID: PMC7419330 DOI: 10.1016/j.ijcha.2020.100601] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 07/20/2020] [Indexed: 01/23/2023]
Abstract
Periodontal disease is associated with echolucent plaques. Periodontal disease is associated with increased macrophages in plaques. Periodontal disease is associated with decreased smooth muscle cells in plaques. Periodontal disease is associated with plaque instability. Background Periodontal disease (PD) is a chronic inflammatory oral condition with potentially important systemic sequelae. We sought to determine whether the presence of PD in patients with severe carotid disease was associated with morphological features consistent with carotid plaque instability. Methods A total of 52 dentate patients hospitalized for carotid endarterectomy (CEA) had standardized assessments of their periodontal status, including measurements of probing pocket depth (PPD), clinical attachment level (CAL) and bleeding on probing (BoP). Carotid plaque morphology was assessed by ultrasound using the gray scale median (GSM) score and by immunohistochemistry using anti-CD68 and anti-alpha-actin antibodies, markers for macrophages and smooth muscle cells (SMCs) respectively. Results In total 30/52 patients (58%) had PD. Significant associations were noted between low GSM on ultrasound and each mm in PPD (p = 0.001), each mm in CAL (p = 0.002) and with a 10% increase in BoP (p = 0.009). Using the standardized PERIO definition the association remained robust (aOR = 10.4 [95% CI:2.3–46.3], p = .002). Significant associations were also observed with high macrophage accumulation and each individual PD measure (p < 0.01 for PPD, CAL and BoP) and with the PERIO definition (aOR = 15 [95% CI:1.8–127.8], p = .01). Similarly, low SMC density was also significantly associated with individual measures of PD (p < 0.05 for PPD, CAL and BoP), but not with the PERIO definition (aOR 3.4 [95% CI:0.9–12.8], p = .07). Conclusions The presence of PD was significantly associated with both ultrasound and immunohistochemistry features of carotid plaque instability in patients undergoing CEA.
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Affiliation(s)
- Yiorgos A Bobetsis
- Dept of Periodontology, School of Dentistry, National and Kapodistrian University of Athens, Greece
| | | | - Christos D Liapis
- Dept of Vascular Surgery, Medical School, National and Kapodistrian University of Athens, Greece.,Vascular & Endovascular Clinic, Athens Medical Center, Athens, Greece
| | - Nikolaos Liasis
- Dept of Vascular Diagnosis, Euromedic Greece, Athens, Greece
| | - John Kakisis
- Dept of Vascular Surgery, Medical School, National and Kapodistrian University of Athens, Greece
| | - Georgia Kourlaba
- 1 and 2 Dept of Pediatrics, Medical School, National and Kapodistrian University of Athens, Greece
| | - Paraskevi Lazari
- Dept of Pathology, Nikaia General Hospital, Piraeus, Greece.,Dept of Pathology, West Attica General Hospital, Athens, Greece
| | | | | | - Phoebus N Madianos
- Dept of Periodontology, School of Dentistry, National and Kapodistrian University of Athens, Greece
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Di Gregoli K, Somerville M, Bianco R, Thomas AC, Frankow A, Newby AC, George SJ, Jackson CL, Johnson JL. Galectin-3 Identifies a Subset of Macrophages With a Potential Beneficial Role in Atherosclerosis. Arterioscler Thromb Vasc Biol 2020; 40:1491-1509. [PMID: 32295421 PMCID: PMC7253188 DOI: 10.1161/atvbaha.120.314252] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Accepted: 04/06/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Galectin-3 (formerly known as Mac-2), encoded by the LGALS3 gene, is proposed to regulate macrophage adhesion, chemotaxis, and apoptosis. We investigated the role of galectin-3 in determining the inflammatory profile of macrophages and composition of atherosclerotic plaques. Approach and Results: We observed increased accumulation of galectin-3-negative macrophages within advanced human, rabbit, and mouse plaques compared with early lesions. Interestingly, statin treatment reduced galectin-3-negative macrophage accrual in advanced plaques within hypercholesterolemic (apolipoprotein E deficient) Apoe-/- mice. Accordingly, compared with Lgals3+/+:Apoe-/- mice, Lgals3-/-:Apoe-/- mice displayed altered plaque composition through increased macrophage:smooth muscle cell ratio, reduced collagen content, and increased necrotic core area, characteristics of advanced plaques in humans. Additionally, macrophages from Lgals3-/- mice exhibited increased invasive capacity in vitro and in vivo. Furthermore, loss of galectin-3 in vitro and in vivo was associated with increased expression of proinflammatory genes including MMP (matrix metalloproteinase)-12, CCL2 (chemokine [C-C motif] ligand 2), PTGS2 (prostaglandin-endoperoxide synthase 2), and IL (interleukin)-6, alongside reduced TGF (transforming growth factor)-β1 expression and consequent SMAD signaling. Moreover, we found that MMP12 cleaves macrophage cell-surface galectin-3 resulting in the appearance of a 22-kDa fragment, whereas plasma levels of galectin-3 were reduced in Mmp12-/-:Apoe-/- mice, highlighting a novel mechanism where MMP12-dependent cleavage of galectin-3 promotes proinflammatory macrophage polarization. Moreover, galectin-3-positive macrophages were more abundant within plaques of Mmp12-/-:Apoe-/- mice compared with Mmp12+/+:Apoe-/- animals. CONCLUSIONS This study reveals a prominent protective role for galectin-3 in regulating macrophage polarization and invasive capacity and, therefore, delaying plaque progression.
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Affiliation(s)
- Karina Di Gregoli
- From the Laboratory of Cardiovascular Pathology, Bristol Medical School, Faculty of Health Sciences, University of Bristol, England
| | - Michelle Somerville
- From the Laboratory of Cardiovascular Pathology, Bristol Medical School, Faculty of Health Sciences, University of Bristol, England
| | - Rosaria Bianco
- From the Laboratory of Cardiovascular Pathology, Bristol Medical School, Faculty of Health Sciences, University of Bristol, England
| | - Anita C. Thomas
- From the Laboratory of Cardiovascular Pathology, Bristol Medical School, Faculty of Health Sciences, University of Bristol, England
| | - Aleksandra Frankow
- From the Laboratory of Cardiovascular Pathology, Bristol Medical School, Faculty of Health Sciences, University of Bristol, England
| | - Andrew C. Newby
- From the Laboratory of Cardiovascular Pathology, Bristol Medical School, Faculty of Health Sciences, University of Bristol, England
| | - Sarah J. George
- From the Laboratory of Cardiovascular Pathology, Bristol Medical School, Faculty of Health Sciences, University of Bristol, England
| | - Christopher L. Jackson
- From the Laboratory of Cardiovascular Pathology, Bristol Medical School, Faculty of Health Sciences, University of Bristol, England
| | - Jason L. Johnson
- From the Laboratory of Cardiovascular Pathology, Bristol Medical School, Faculty of Health Sciences, University of Bristol, England
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Zhu W, Liu S. The role of human cytomegalovirus in atherosclerosis: a systematic review. Acta Biochim Biophys Sin (Shanghai) 2020; 52:339-353. [PMID: 32253424 DOI: 10.1093/abbs/gmaa005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/05/2019] [Accepted: 01/20/2020] [Indexed: 12/11/2022] Open
Abstract
Atherosclerosis is a progressive vascular disease with increasing morbidity and mortality year by year in modern society. Human cytomegalovirus (HCMV) infection is closely associated with the development of atherosclerosis. HCMV infection may accelerate graft atherosclerosis and the development of transplant vasculopathy in organ transplantation. However, our current understanding of HCMV-associated atherosclerosis remains limited and is mainly based on clinical observations. The underlying mechanism of the involvement of HCMV infection in atherogenesis remains unclear. Here, we summarized current knowledge regarding the multiple influences of HCMV on a diverse range of infected cells, including vascular endothelial cells, vascular smooth muscle cells, monocytes, macrophages, and T cells. In addition, we described potential HCMV-induced molecular mechanisms, such as oxidative stress, endoplasmic reticulum stress, autophagy, lipid metabolism, and miRNA regulation, which are involved in the development of HCMV-associated atherogenesis. Gaining an improved understanding of these mechanisms will facilitate the development of novel and effective therapeutic strategies for the treatment of HCMV-related cardiovascular disease.
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Affiliation(s)
- Wenbo Zhu
- Clinical Research Institute, First Affiliated Hospital, University of South China, Hengyang 421001, China
| | - Shuangquan Liu
- Clinical Laboratory, First Affiliated Hospital, University of South China, Hengyang 421001, China
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45
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Giannopoulos S, Armstrong EJ. Diabetes mellitus: an important risk factor for peripheral vascular disease. Expert Rev Cardiovasc Ther 2020; 18:131-137. [PMID: 32129693 DOI: 10.1080/14779072.2020.1736562] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Stefanos Giannopoulos
- Division of Cardiology, Rocky Mountain Regional VA Medical Center, University of Colorado, Denver, CO, USA
| | - Ehrin J Armstrong
- Division of Cardiology, Rocky Mountain Regional VA Medical Center, University of Colorado, Denver, CO, USA
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Xiong Q, Li H, Zhou L, Liang J, Zhang Z, Han Y, Jing Y, Hu Y, Shi Y, Xu T, Qian G, Yuan J. A sulfated polysaccharide from the edible flesh of Cipangopaludina chinensis inhibits angiogenesis to enhance atherosclerotic plaque stability. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.103800] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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47
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Higashi M, Yamada N, Imakita S, Yutani C, Ishibashi-Ueda H, Iihara K, Naito H. CT-pathologic correlation of non-calcified atherosclerotic arterial plaques: a study using carotid endarterectomy specimens. Br J Radiol 2020; 93:20190901. [PMID: 31999208 DOI: 10.1259/bjr.20190901] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE Pathologic features of atherosclerotic plaques on CT are not established. We compared CT values among pathologically confirmed plaque constituents and evaluated their ability to distinguish plaque constituents. METHODS 50 histopathological images of carotid endarterectomy samples from 10 males and 2 females (age 54-74 years, average 65.9 years) were examined. We compared pre-operative CT [pre-contrast (CT-P), early post-contrast phase (CT-E), delayed post-contrast phase (CT-D)] of lipid-rich necrotic core (NC) and fibrous tissue (F) plaque components with pathological images. The ability of features to differentiate plaque components using several discrimination techniques were compared. RESULTS CT values of NC and F were 36 ± 13, 45 ± 11 (mean ± standard deviation, Hounsfield unit, HU), 41 ± 17, 69 ± 18, and 44 ± 16, 70 ± 13 in CT-P (p < 0.01), CT-E (p < 0.0001), and CT-D (p < 0.0001), respectively. The threshold, sensitivity, and accuracy for distinguishing NC from F were 44 HU, 74%, and 68%; 55 HU, 85%, and 85%; and 63 HU, 92%, and 84% in CTP, CT-E, and CT-D, respectively. CT-P had lower accuracy than CT-E and CT-D (both p < 0.05), but CT-E and CT-D were similar. CT-E and CT-D yielded 90 and 91% sensitivity and accuracy, respectively in linear discrimination analysis. CONCLUSION In both pre- and post-contrast CT, CT values were lower in NC than F. Although values overlapped, using two-phase post-contrast CTs improved discrimination ability. ADVANCES IN KNOWLEDGE Our findings may help to establish computer-aided diagnosis of vulnerable atherosclerotic plaques in future.
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Affiliation(s)
- Masahiro Higashi
- Department of Radiology, National Hospital Organization Osaka National Hospital, Osaka, Japan.,Department of Radiology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Naoaki Yamada
- Department of Radiology, National Cerebral and Cardiovascular Center, Suita, Japan
| | | | - Chikao Yutani
- Department of Pathology, Amagasaki Central Hospital, Amagasaki, Japan.,Department of Pathology, Cardiovascular Center Osaka Gyoumeikan Hospital, Osaka, Japan
| | | | - Koji Iihara
- Department of Neurosurgery, Graduate School of Medical Science Kyushu University, Fukuoka, Japan
| | - Hiroaki Naito
- Department of Radiology, Nippon Life Hospital, Osaka, Japan
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Han T, Paramsothy P, Hong J, Isquith D, Xu D, Bai H, Neradilek M, Gill E, Zhao XQ. High-resolution MRI assessed carotid atherosclerotic plaque characteristics comparing men and women with elevated ApoB levels. Int J Cardiovasc Imaging 2020; 36:481-489. [PMID: 32020410 DOI: 10.1007/s10554-019-01600-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 04/06/2019] [Indexed: 01/14/2023]
Abstract
Previous studies demonstrated that men were more likely to have plaque rupture and are at greater risk for myocardial infarction and stroke than women. We evaluated differences in carotid plaque characteristics by MRI between men and women with mild-moderate atherosclerosis and elevated ApoB levels. One hundred eighty-two subjects (104 men and 78 women) with CAD or carotid stenosis (≥ 15% by ultrasound), ApoB ≥ 120 mg/dL and carotid MRI scan were included. Percent wall volume (%WV) was calculated as (wall volume/total vessel volume) × 100%. Three major plaque compositions, fibrous tissue (FT), calcification (CA) and lipid rich necrotic core (LRNC), were identified and quantified using published MRI criteria. Adventitial and plaque neovascularization as fractional plasma volume (Vp) and permeability as transfer constant (Ktrans) were analyzed using kinetic modeling. These characteristics were compared between men and women. Men, compared to women, were younger (54 ± 8 vs. 58 ± 8 years, p = 0.01), had higher rate of previous MI (46 vs. 26%, p = 0.005) but lower proportions of metabolic syndrome (37 vs. 59%, p = 0.003). After adjusting for between-gender differences, men were significantly more likely to have LRNC (OR 2.22, 95% CI 1.04-4.89, p = 0.04) and showed significantly larger %LRNC than women (diff = 4.3%, 95% CI 1.6-6.9%, p = 0.002), while %WV, FT, and CA were similar between men and women. There were no statistically significant differences in adventitial and plaque Vp or Ktrans. Men were significantly more likely to have LRNC and had larger LRNC than women. However, men and women showed relatively similar levels of adventitial and plaque neovascularization and permeability.Trial registration: NCT00715273 at ClinicalTrials.gov. Registered 15 July 2008, retrospectively registered.
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Affiliation(s)
- Tianwen Han
- Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA, 98104, USA
| | - Pathmaja Paramsothy
- Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA, 98104, USA
| | - Jaekyoung Hong
- Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA, 98104, USA
| | - Daniel Isquith
- Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA, 98104, USA
| | - Dongxiang Xu
- Department of Radiology, University of Washington, Seattle, WA, 98109, USA
| | - Hua Bai
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, 100032, China
| | - Moni Neradilek
- The Mountain-Whisper-Light Statistics, Seattle, WA, 98112, USA
| | - Edward Gill
- Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA, 98104, USA
| | - Xue-Qiao Zhao
- Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA, 98104, USA. .,Harborview Medical Center, University of Washington, GEC-37, 325 9th Ave, Box 359720, Seattle, WA, 98104, USA.
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Coronary Artery Disease: From Mechanism to Clinical Practice. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1177:1-36. [PMID: 32246442 DOI: 10.1007/978-981-15-2517-9_1] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In most developed countries, coronary artery disease (CAD), mostly caused by atherosclerosis of coronary arteries, is one of the primary causes of death. From 1990s to 2000s, mortality caused by acute MI declined up to 50%. The incidence of CAD is related with age, gender, economic, etc. Atherosclerosis contains some highly correlative processes such as lipid disturbances, thrombosis, inflammation, vascular smooth cell activation, remodeling, platelet activation, endothelial dysfunction, oxidative stress, altered matrix metabolism, and genetic factors. Risk factors of CAD exist among many individuals of the general population, which includes hypertension, lipids and lipoproteins metabolism disturbances, diabetes mellitus, chronic kidney disease, age, genders, lifestyle, cigarette smoking, diet, obesity, and family history. Angina pectoris is caused by myocardial ischemia in the main expression of pain in the chest or adjoining area, which is usually a result of exertion and related to myocardial function disorder. Typical angina pectoris would last for minutes with gradual exacerbation. Rest, sit, or stop walking are the usual preference for patients with angina, and reaching the maximum intensity in seconds is uncommon. Rest or nitroglycerin usage can relieve typical angina pectoris within minutes. So far, a widely accepted angina pectoris severity grading system included CCS (Canadian Cardiovascular Society) classification, Califf score, and Goldman scale. Patients with ST-segment elevated myocardial infarction (STEMI) may have different symptoms and signs of both severe angina pectoris and various complications. The combination of rising usage of sensitive MI biomarkers and precise imaging techniques, including electrocardiograph (ECG), computed tomography, and cardiac magnetic resonance imaging, made the new MI criteria necessary. Complications of acute myocardial infarction include left ventricular dysfunction, cardiogenic shock, structural complications, arrhythmia, recurrent chest discomfort, recurrent ischemia and infarction, pericardial effusion, pericarditis, post-myocardial infarction syndrome, venous thrombosis pulmonary embolism, left ventricular aneurysm, left ventricular thrombus, and arterial embolism.
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Mantani PT, Dunér P, Ljungcrantz I, Nilsson J, Björkbacka H, Fredrikson GN. ILC2 transfers to apolipoprotein E deficient mice reduce the lipid content of atherosclerotic lesions. BMC Immunol 2019; 20:47. [PMID: 31823769 PMCID: PMC6905041 DOI: 10.1186/s12865-019-0330-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 12/02/2019] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Expansion of type 2 innate lymphoid cells (ILC2s) in hypercholesterolaemic mice protects against atherosclerosis while different ILC2 subsets have been described (natural, inflammatory) based on their suppression of tumorigenicity 2 (ST2) and killer-cell lectin like receptor G1 (KLRG1) expression. The aim of the current study is to characterize the interleukin 25 (IL25)-induced splenic ILC2 population (Lin-CD45+IL17RB+ICOS+IL7raintermediate) and address its direct role in experimental atherosclerosis by its adoptive transfer to hypercholesterolaemic apolipoprotein E deficient (apoE-/-) mice. RESULTS Immunomagnetically enriched, FACS-sorted ILC2s from the spleens of IL-25 treated apoE-/- mice were stained for KLRG1 and ST2 directly upon cell obtainment or in vitro cell expansion for flow cytometric analysis. IL25-induced splenic ILC2s express high levels of both KLRG1 and ST2. However, both markers are downregulated upon in vitro cell expansion. In vitro expanded splenic ILC2s were intraperitoneally transferred to apoE-/- recipients on high fat diet. ApoE-/- mice that received in vitro expanded splenic ILC2s had decreased lipid content in subvalvular heart and brachiocephalic artery (BCA) plaques accompanied by increased peritoneal B1 cells, activated eosinophils and alternatively activated macrophages (AAMs) as well as anti-phosphorylcholine (PC) immunoglobulin (Ig) M in plasma. CONCLUSIONS With the current data we designate the IL25-induced ILC2 population to decrease the lipid content of atherosclerotic lesions in apoE-/- mice and we directly link the induction of B1 cells and the atheroprotective anti-PC IgM antibodies with ILC2s.
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Affiliation(s)
- Polyxeni T Mantani
- Department of Clinical Sciences, Skåne University Hospital Malmö, CRC, Building 91:12, Jan Waldenströms gata 35, 20502, Malmö, Sweden. .,Lund University, Lund, Sweden.
| | - Pontus Dunér
- Department of Clinical Sciences, Skåne University Hospital Malmö, CRC, Building 91:12, Jan Waldenströms gata 35, 20502, Malmö, Sweden.,Lund University, Lund, Sweden
| | - Irena Ljungcrantz
- Department of Clinical Sciences, Skåne University Hospital Malmö, CRC, Building 91:12, Jan Waldenströms gata 35, 20502, Malmö, Sweden.,Lund University, Lund, Sweden
| | - Jan Nilsson
- Department of Clinical Sciences, Skåne University Hospital Malmö, CRC, Building 91:12, Jan Waldenströms gata 35, 20502, Malmö, Sweden.,Lund University, Lund, Sweden
| | - Harry Björkbacka
- Department of Clinical Sciences, Skåne University Hospital Malmö, CRC, Building 91:12, Jan Waldenströms gata 35, 20502, Malmö, Sweden.,Lund University, Lund, Sweden
| | - Gunilla Nordin Fredrikson
- Department of Clinical Sciences, Skåne University Hospital Malmö, CRC, Building 91:12, Jan Waldenströms gata 35, 20502, Malmö, Sweden. .,Lund University, Lund, Sweden.
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