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Grodecki K, Geers J, Kwiecinski J, Lin A, Slipczuk L, Slomka PJ, Dweck MR, Nerlekar N, Williams MC, Berman D, Marwick T, Newby DE, Dey D. Phenotyping atherosclerotic plaque and perivascular adipose tissue: signalling pathways and clinical biomarkers in atherosclerosis. Nat Rev Cardiol 2025; 22:443-455. [PMID: 39743563 DOI: 10.1038/s41569-024-01110-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/20/2024] [Indexed: 01/04/2025]
Abstract
Computed tomography coronary angiography provides a non-invasive evaluation of coronary artery disease that includes phenotyping of atherosclerotic plaques and the surrounding perivascular adipose tissue (PVAT). Image analysis techniques have been developed to quantify atherosclerotic plaque burden and morphology as well as the associated PVAT attenuation, and emerging radiomic approaches can add further contextual information. PVAT attenuation might provide a novel measure of vascular health that could be indicative of the pathogenetic processes implicated in atherosclerosis such as inflammation, fibrosis or increased vascularity. Bidirectional signalling between the coronary artery and adjacent PVAT has been hypothesized to contribute to coronary artery disease progression and provide a potential novel measure of the risk of future cardiovascular events. However, despite the development of more advanced radiomic and artificial intelligence-based algorithms, studies involving large datasets suggest that the measurement of PVAT attenuation contributes only modest additional predictive discrimination to standard cardiovascular risk scores. In this Review, we explore the pathobiology of coronary atherosclerotic plaques and PVAT, describe their phenotyping with computed tomography coronary angiography, and discuss potential future applications in clinical risk prediction and patient management.
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Affiliation(s)
- Kajetan Grodecki
- Department of Biomedical Sciences, and Department of Medicine, Cedars-Sinai Medical Center, Biomedical Imaging Research Institute, Los Angeles, CA, USA
- 1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Jolien Geers
- Department of Biomedical Sciences, and Department of Medicine, Cedars-Sinai Medical Center, Biomedical Imaging Research Institute, Los Angeles, CA, USA
- Department of Cardiology, Centrum Voor Hart- en Vaatziekten (CHVZ), Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Jacek Kwiecinski
- Department of Interventional Cardiology and Angiology, National Institute of Cardiology, Warsaw, Poland
| | - Andrew Lin
- Monash Victorian Heart Institute and Monash Health Heart, Monash University, Victorian Heart Hospital, Melbourne, Victoria, Australia
| | - Leandro Slipczuk
- Division of Cardiology, Montefiore Healthcare Network/Albert Einstein College of Medicine, New York, NY, USA
| | - Piotr J Slomka
- Department of Biomedical Sciences, and Department of Medicine, Cedars-Sinai Medical Center, Biomedical Imaging Research Institute, Los Angeles, CA, USA
| | - Marc R Dweck
- British Heart Foundation Centre of Research Excellence, University of Edinburgh, Edinburgh, UK
| | - Nitesh Nerlekar
- Monash Victorian Heart Institute and Monash Health Heart, Monash University, Victorian Heart Hospital, Melbourne, Victoria, Australia
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Michelle C Williams
- British Heart Foundation Centre of Research Excellence, University of Edinburgh, Edinburgh, UK
| | - Daniel Berman
- Department of Biomedical Sciences, and Department of Medicine, Cedars-Sinai Medical Center, Biomedical Imaging Research Institute, Los Angeles, CA, USA
| | - Thomas Marwick
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - David E Newby
- British Heart Foundation Centre of Research Excellence, University of Edinburgh, Edinburgh, UK
| | - Damini Dey
- Department of Biomedical Sciences, and Department of Medicine, Cedars-Sinai Medical Center, Biomedical Imaging Research Institute, Los Angeles, CA, USA.
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Ruiz JI, Zhao B, Palaskas N, Deswal A, Zhao H, McQuade J, Suarez-Almazor ME. Major Adverse Cardiovascular Events in Patients with Melanoma Receiving Immune Checkpoint Inhibitors. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2025; 8:1-9. [PMID: 40224298 PMCID: PMC11987079 DOI: 10.36401/jipo-24-31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 02/01/2024] [Accepted: 02/20/2025] [Indexed: 04/15/2025]
Abstract
Introduction Immune checkpoint inhibitors (ICIs) might increase the risk of major adverse cardiovascular events (MACEs). This study aimed to evaluate the risk of MACE in patients with melanoma after ICI initiation. Methods We conducted a before-after cohort study using claims data from Optum's deidentified Clinformatics Data Mart Database. We included adult patients with melanoma who received any approved ICI between 2011 and 2021 with a minimum of 12 months of observable data before ICI. The main outcome was time to first MACE (myocardial infarction, coronary revascularization, stroke, heart failure hospitalization) and rate of MACE before and after ICI, ascertained using International Classification of Diseases, 9th/10th Revision diagnostic codes. Hazard ratio (HR) and incidence rate ratio (IRR) were calculated. Results We identified 4024 patients with ICI-treated melanoma. Mean age was 67.4 years (SD 14.1), 36% were women; 3066 (76.2%) received monotherapy and 958 (23.8%) combination immunotherapy. A total of 160 (4%) patients had a MACE before ICI and 224 (5.6%) after ICI (HR, 1.76; 95% CI, 1.47-2.12). MACE rate in the year before ICI was 56.16 per 1000 person-years compared with 80.91 per 1000 person-years the year after ICI (IRR, 1.44; 95% CI, 1.21-1.72). Ten cases of myocarditis were observed after ICI, 50% of them had a MACE. Risk factors associated with MACE after ICI were prior MACE, other cardiovascular conditions, hypertension, and older age. Glucocorticoid use was not associated with MACE. Conclusion Our results suggest that ICI might increase the risk of MACE in patients with melanoma during the first year after ICI.
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Affiliation(s)
- Juan I. Ruiz
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bo Zhao
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nicolas Palaskas
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anita Deswal
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hui Zhao
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jennifer McQuade
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Maria E. Suarez-Almazor
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Lee SB, Hong KW, Park B, Jung DH. Impact of genetic markers related to hyper-HDL cholesterol on the prevalence of myocardial infarction: a KoGES study. J Lipid Res 2025; 66:100777. [PMID: 40089108 PMCID: PMC12004384 DOI: 10.1016/j.jlr.2025.100777] [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: 12/25/2024] [Revised: 03/10/2025] [Accepted: 03/12/2025] [Indexed: 03/17/2025] Open
Abstract
Recent studies have shown that hyper-high-density lipoprotein cholesterol (HDL-C) is associated with cardiovascular disease risk and all-cause mortality, a phenomenon known as the HDL-C paradox. Several genes have been reported to show relationships between increased HDL-C and myocardial infarction (MI) risk. We investigated the genetic predisposition of lipid metabolism influencing MI. The study dataset was from the Korean Genome and Epidemiology cohort obtained from the National Biobank of Korea, with an initial population of 68,806 individuals. We categorized samples based on HDL-C levels into hypo-HDL-C (n = 25,884), normal-HDL-C (n = 41,117), and hyper-HDL-C groups (n = 1,805). We conducted genome-wide association studies for each group and the total sample. Significant associations were defined using genome-wide significant level and suggestive level. The lead SNP of each locus was selected for further interpretation. This analysis included 2,014 (2.6%) MI patients. Using multivariable logistic regression, we evaluated the association of 7,877 SNPs in nine loci. We identified six SNPs significantly related to both hypo- and hyper-HDL groups, one SNP associated with hyper-HDL, and six SNPs associated with hypo-HDL group. Additionally, we found three SNPs associated with MI prevalence in the hyper-HDL group, including one significant SNP and two suggestive SNPs. Contrary to the traditional view of HDL-C as protective, this study identified genetic variants that increase MI risk by more than six-fold. These SNPs could play a role as important markers for detecting MI in hyper-HDL cholesterol group.
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Affiliation(s)
- Sung-Bum Lee
- Department of Family Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea
| | - Kyung-Won Hong
- Institute of Advanced Technology, THERAGEN HEALTH Co., Ltd., Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Byoungjin Park
- Department of Family Medicine, Yongin Severance Hospital, Yongin-si, Republic of Korea
| | - Dong-Hyuk Jung
- Department of Family Medicine, Yongin Severance Hospital, Yongin-si, Republic of Korea.
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Suur BE, Karadimou G, Willems CJJM, Bergman O, Lengquist M, Kronqvist M, Baumgartner R, Malin S, Gisterå A, Hansson GK, Mälarstig A, Hedin U, Ketelhuth DFJ, Matic L. PCSK6 ablation in blood circulating cells increases atherosclerotic burden, but improves plaque stability by activating Th17-smooth muscle cell modulatory axis. Vascul Pharmacol 2025; 159:107490. [PMID: 40097084 DOI: 10.1016/j.vph.2025.107490] [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: 12/28/2024] [Revised: 03/02/2025] [Accepted: 03/14/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Proprotein convertase subtilisins/kexins (PCSKs) have been implicated in cancers and cardiovascular disease. We have shown that PCSK6 is a key protease regulating smooth muscle cell (SMC)-mediated vascular remodeling, but also that it can be expressed by T cells and macrophages in atherosclerotic plaques. Whether PCSK6 regulates innate and adaptive immune responses in the context of vascular inflammation is still unknown. METHODS In this study, detailed immunophenotyping of constitutive Pcsk6-/- mice was performed. Bone marrow transplantation into high-cholesterol diet fed Ldlr-/- mice was used to investigate PCSK6-mediated immune effects in atherogenesis and plaque stability. RESULTS Compared to controls, Pcsk6-/- mice showed higher plasma levels of the chemoattractants CCL2 and CCCL3, and Th17 cytokines IL-17 A and IL-17F. Pcsk6 ablation led to increased naïve and effector-memory CD4+ and CD8+ cell numbers in the spleen, and increased release of IL-17 A, IFN-γ and IL-10 as well as proliferation by spleenocytes in vitro. Lack of Pcsk6 also affected innate immunity as macrophages from Pcsk6-/- mice secreted more cytokines, including TNF-α, CCL2, IL-6 and IL-10 upon LPS stimulation in vitro, and were more prone to oxLDL uptake. In line with a pro-inflammatory phenotype, Pcsk6-/-➔Ldlr-/- transplanted mice presented a higher atherosclerotic plaque burden compared to Ldlr-/- receiving control bone marrow. Although larger, Pcsk6-/-➔Ldlr-/- plaques showed increased stability features, including collagen deposition and SMC presence coinciding with significantly increased local levels of the fibrogenic cytokine IL-17. CONCLUSIONS Global Pcsk6 ablation leads to the activation of both adaptive and innate immune systems. Interestingly, Pcsk6-/- ablation in bone marrow of hyperlipidemic mice revealed its dual role in atherogenesis, activating a Th17-SMC modulatory axis that promotes plaque stability, despite increased atherosclerotic burden.
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Affiliation(s)
- Bianca E Suur
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Glykeria Karadimou
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden
| | - Colin J J M Willems
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden
| | - Otto Bergman
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden; Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Mariette Lengquist
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden
| | - Malin Kronqvist
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden
| | - Roland Baumgartner
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Stephen Malin
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Anton Gisterå
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Göran K Hansson
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Anders Mälarstig
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Ulf Hedin
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden
| | - Daniel F J Ketelhuth
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden; Department of Molecular Medicine, University of Southern Denmark, Denmark
| | - Ljubica Matic
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden.
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Jin P, Zhang S, Yang L, Zeng Y, Li Y, Tang R. Analysis and validation of biomarkers and immune cell infiltration profiles in unstable coronary atherosclerotic plaques using bioinformatics and machine learning. Front Cardiovasc Med 2025; 12:1451255. [PMID: 40027512 PMCID: PMC11868056 DOI: 10.3389/fcvm.2025.1451255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 01/28/2025] [Indexed: 03/05/2025] Open
Abstract
Introduction Decreased stability of coronary atherosclerotic plaques correlates with a heightened risk of acute coronary syndrome (ACS). Thus, early diagnosis and treatment of unstable plaques are imperative in averting adverse cardiovascular events. This study aims to identify diagnostic biomarkers for unstable coronary atherosclerotic plaques and investigate the role of immune cell infiltration in their formation. Methods The datasets GSE163154 and GSE111782, obtained from the gene expression omnibus (GEO) database, were amalgamated for bioinformatics analysis, using the dataset GSE43292 as a test set. Sequentially, we performed principal component analysis (PCA), differential gene expression analysis, enrichment analysis, weighted gene co-expression network analysis (WGCNA), utilized a machine learning algorithm to screen key genes, conducted receiver operating characteristic (ROC) curve analysis and nomogram model to assess biomarker diagnostic efficacy, validated the biomarkers, and analyzed immune cell infiltration. Results In conclusion, enrichment analyses demonstrate that genes are significantly enriched in inflammatory and immune-related pathways. We identified HSPA2 and GEM as key genes and validated them experimentally. Significant differences existed in immune cell infiltration between subgroups. Additionally, HSPA2 and GEM showed significant associations with a wide range of immune cells. Discussion HSPA2 and GEM can function as diagnostic biomarkers for unstable coronary atherosclerotic plaques. In combination with immune cell infiltration analyses, our study provides new insights into the future study of unstable plaque occurrence and molecular mechanisms.
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Affiliation(s)
- Pengyue Jin
- Department of Forensic Medicine, Faculty of Basic Medical Science, Chongqing Medical University, Chongqing, China
- Chongqing Engineering Research Center for Criminal Investigation Technology, Chongqing, China
- Chongqing Key Laboratory of Forensic Medicine, Chongqing, China
| | - Shangyu Zhang
- Department of Forensic Medicine, Faculty of Basic Medical Science, Chongqing Medical University, Chongqing, China
- Chongqing Engineering Research Center for Criminal Investigation Technology, Chongqing, China
- Chongqing Key Laboratory of Forensic Medicine, Chongqing, China
- Department of Anatomy, Faculty of Basic Medical Sciences, Sichuan College of Traditional Chinese Medicine, Mianyang, China
| | - Li Yang
- Department of Forensic Medicine, Faculty of Basic Medical Science, Chongqing Medical University, Chongqing, China
- Chongqing Engineering Research Center for Criminal Investigation Technology, Chongqing, China
- Chongqing Key Laboratory of Forensic Medicine, Chongqing, China
| | - Yujie Zeng
- Department of Forensic Medicine, Faculty of Basic Medical Science, Chongqing Medical University, Chongqing, China
- Chongqing Engineering Research Center for Criminal Investigation Technology, Chongqing, China
- Chongqing Key Laboratory of Forensic Medicine, Chongqing, China
| | - Yongguo Li
- Department of Forensic Medicine, Faculty of Basic Medical Science, Chongqing Medical University, Chongqing, China
- Chongqing Engineering Research Center for Criminal Investigation Technology, Chongqing, China
- Chongqing Key Laboratory of Forensic Medicine, Chongqing, China
| | - Renkuan Tang
- Department of Forensic Medicine, Faculty of Basic Medical Science, Chongqing Medical University, Chongqing, China
- Chongqing Engineering Research Center for Criminal Investigation Technology, Chongqing, China
- Chongqing Key Laboratory of Forensic Medicine, Chongqing, China
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Heusch G, Kleinbongard P. The spleen in ischaemic heart disease. Nat Rev Cardiol 2025:10.1038/s41569-024-01114-x. [PMID: 39743566 DOI: 10.1038/s41569-024-01114-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/27/2024] [Indexed: 01/04/2025]
Abstract
Ischaemic heart disease is a consequence of coronary atherosclerosis, and atherosclerosis is a systemic inflammatory disease. The spleen releases various immune cells in temporally distinct patterns. Neutrophils, monocytes, macrophages, B cells and T cells execute innate and adaptive immune processes in the coronary atherosclerotic plaque and in the ischaemic myocardium. Prolonged inflammation contributes to ischaemic heart failure. The spleen is also a target of neuromodulation through vagal, sympathetic and sensory nerve activation. Efferent vagal activation and subsequent activation of the noradrenergic splenic nerve activate β2-adrenergic receptors on splenic T cells, which release acetylcholine that ultimately results in attenuation of cytokine secretion from splenic macrophages. Coeliac vagal nerve activation increases splenic sympathetic nerve activity and drives the release of T cells, a process that depends on placental growth factor. Activation of the vagosplenic axis protects acutely from ischaemia-reperfusion injury during auricular tragus vagal stimulation and remote ischaemic conditioning. Splenectomy abrogates all these deleterious and beneficial actions on the cardiovascular system. The aggregate effect of splenectomy in humans is a long-term increase in mortality from ischaemic heart disease. The spleen has been appreciated as an important immune organ for inflammatory processes in atherosclerosis, myocardial infarction and heart failure, whereas its complex interaction with circulating blood factors and with the autonomic and somatic nervous systems, as well as its role in cardioprotection, have emerged only in the past decade. In this Review, we describe this newly identified cardioprotective function of the spleen and highlight the potential for translating the findings to patients with ischaemic heart disease.
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Affiliation(s)
- Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany.
| | - Petra Kleinbongard
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany
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Murray PE, Coffman JA, Garcia-Godoy F. Oral Pathogens' Substantial Burden on Cancer, Cardiovascular Diseases, Alzheimer's, Diabetes, and Other Systemic Diseases: A Public Health Crisis-A Comprehensive Review. Pathogens 2024; 13:1084. [PMID: 39770344 PMCID: PMC11677847 DOI: 10.3390/pathogens13121084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 11/28/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
This review synthesizes the findings from 252 studies to explore the relationship between the oral pathogens associated with periodontitis, dental caries, and systemic diseases. Individuals with oral diseases, such as periodontitis, are between 1.7 and 7.5 times (average 3.3 times) more likely to develop systemic diseases or suffer adverse pregnancy outcomes, underscoring the critical connection between dental and overall health. Oral conditions such as periodontitis and dental caries represent a significant health burden, affecting 26-47% of Americans. The most important oral pathogens, ranked by publication frequency, include the herpes virus, C. albicans, S. mutans, P. gingivalis, F. nucleatum, A. actinomycetemcomitans, P. intermedia, T. denticola, and T. forsythia. The systemic diseases and disorders linked to oral infections, ranked similarly, include cancer, respiratory, liver, bowel, fever, kidney, complications in pregnancy, cardiovascular bacteremia, diabetes, arthritis, autoimmune, bladder, dementia, lupus, and Alzheimer's diseases. Evidence supports the efficacy of dental and periodontal treatments in eliminating oral infections and reducing the severity of systemic diseases. The substantial burden that oral pathogens have on cancer, cardiovascular diseases, Alzheimer's, diabetes, and other systemic diseases poses a significant public health crisis.
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Affiliation(s)
| | - Jonathan A Coffman
- College of Pharmacy, American University of Health Sciences, Signal Hill, CA 90755, USA
| | - Franklin Garcia-Godoy
- College of Dentistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Lindner JR, Morello M. In Vivo Cardiovascular Molecular Imaging: Contributions to Precision Medicine and Drug Development. Circulation 2024; 150:1885-1897. [PMID: 39621762 DOI: 10.1161/circulationaha.124.066522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Conventional forms of noninvasive cardiovascular imaging that evaluate morphology, function, flow, and metabolism play a vital role in individual treatment decisions, often based on guidelines. Innovations in molecular imaging have enhanced our ability to spatially quantify the expression of a wider array of disease-related proteins, genes, or cell types, or the activity of specific pathogenic pathways. These techniques, which usually rely on design of targeted imaging probes, have already been used extensively in cancer medicine and have now become part of cardiovascular care in conditions such as amyloidosis and sarcoidosis. The recognition that common cardiovascular conditions are caused by a substantial diversity of pathobiologic pathways and the diversity of therapies available for use have rekindled interest in expanding the role of molecular imaging of tissue phenotype to improve precision in diagnosis and therapeutic decision-making. The intent of this article is to raise awareness and understanding of approaches to molecular or cellular imaging of phenotype with targeted probes, and their potential to promote the principles of precision medicine. Also addressed are the diverse roles of molecular imaging to improve precision and efficiency of new drug development at the stages of candidate identification, preclinical testing, and clinical trials.
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Affiliation(s)
- Jonathan R Lindner
- Cardiovascular Division and Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville
| | - Matteo Morello
- Cardiovascular Division and Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville
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Liang Y, Dong L, Yan J, Yang Y, Liu Y, Wu H, Shi X, Dai M. Paeonol attenuates atherosclerosis by regulating vascular smooth muscle cells apoptosis and modulating immune cells infiltration through reducing LTβR expression. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156196. [PMID: 39520955 DOI: 10.1016/j.phymed.2024.156196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 09/26/2024] [Accepted: 10/26/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Atherosclerosis is a chronic inflammatory disease with multicellular participation, and the decrease of plaque stability induces the occurrence of clinical adverse events. In order to update the clinical treatment strategy of atherosclerosis, it is necessary to clarify the mechanism of plaque stabilization, especially to explore the targets of vascular smooth muscle cells (VSMCs) apoptosis and immune cell infiltration. Paeonol (Pae), a major phenolic compound derived from the bark of Paeonia albiflora Andr., has been proved to have anti-inflammatory properties in atherosclerosis. However, the pharmacological mechanisms of Pae in improving atherosclerosis remain unclear, particularly with regard to the role of stabilizing vulnerable plaques. PURPOSE This study is aiming to elucidate the effect of Pae against atherosclerotic unstable plaque, and to further explore the potential mechanism of Pae in inhibiting VSMCs apoptosis and immune cell infiltration. METHODS A high-fat diet (HFD) induced atherosclerosis mice model was established in ApoE-/- mice, Pae in two different dosages and simvastatin (SIM) were than administrated for another 4 weeks. Atherosclerotic plaque formation and lipid accumulation were assessed with hematoxylin and eosin (H&E) staining and oil red O staining. Immunofluorescence were employed to examine the general condition of mice and the protective effect of Pae on plaque progression. Cell apoptosis was assessed via TUNNEL staining and flow cytometry. The mRNA and protein expressions in aorta tissue was detected by RT-PCR and western blotting. To investigate the effect of Pae on the regulation of the LTβR/NIK/caspase-3 pathway, VSMCs were extracted from the aorta of C57BL/6 J mice and treated with LTα1β2. RESULTS Here, we show that Pae significantly inhibited atherosclerosis progression and stabilized vulnerable plaques in ApoE-/- mice, in association with decreased T/B cell infiltration and VSMC apoptosis. Notably, the number of plaque-infiltrating T/B cells showed a linear positive correlation with apoptotic VSMCs, and VSMCs sensitive to apoptosis expressed LTβR, which might be activated by LTα1β2-expressing T/B cells. Moreover, the protein expression of LTβR in VSMCs was decreased in plaques after treatment of Pae. Mechanistically, Pae treatment inhibited LTα1β2 stimulated VSMCs apoptosis via LTβR/NIK/caspase-3 signaling pathway in vitro. Importantly, LTβR overexpression increased the VSMCs apoptosis and plaque instability in ApoE-/- mice, partially reversing the protective effect of Pae. CONCLUSION Inhibition of LTβR signaling represents a promising strategy that exerts therapeutic effects through the combined suppression of immune cell infiltration and VSMCs apoptosis, providing novel insights into the anti-atherosclerosis mechanisms of Pae.
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Affiliation(s)
- Yuning Liang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Lishun Dong
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Jinjin Yan
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Yulong Yang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Yarong Liu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Key Laboratory for Research and Development of Traditional Chinese Medicine, Hefei, 230012, China
| | - Hongfei Wu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Key Laboratory for Research and Development of Traditional Chinese Medicine, Hefei, 230012, China
| | - Xiaoyan Shi
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Key Laboratory for Research and Development of Traditional Chinese Medicine, Hefei, 230012, China.
| | - Min Dai
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Key Laboratory for Research and Development of Traditional Chinese Medicine, Hefei, 230012, China.
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Wu Y, Xu Y, Xu L. Pharmacological therapy targeting the immune response in atherosclerosis. Int Immunopharmacol 2024; 141:112974. [PMID: 39168023 DOI: 10.1016/j.intimp.2024.112974] [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: 06/12/2024] [Revised: 08/14/2024] [Accepted: 08/16/2024] [Indexed: 08/23/2024]
Abstract
Atherosclerosis (AS) is a chronic inflammatory disease characterized by the formation of atherosclerotic plaques that consist of numerous cells including smooth muscle cells, endothelial cells, immune cells, and foam cells. The most abundant innate and adaptive immune cells, including neutrophils, monocytes, macrophages, B cells, and T cells, play a pivotal role in the inflammatory response, lipoprotein metabolism, and foam cell formation to accelerate atherosclerotic plaque formation. In this review, we have discussed the underlying mechanisms of activated immune cells in promoting AS and reviewed published clinical trials for the treatment of AS by suppressing immune cell activation. We have also presented some crucial shortcomings of current clinical trials. Lastly, we have discussed the therapeutic potential of novel compounds, including herbal medicine and dietary food, in alleviating AS in animals. Despite these limitations, further clinical trials and experimental studies will enhance our understanding of the mechanisms modulated by immune cells and promote widespread drug use to treat AS by suppressing immune system-induced inflammation.
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Affiliation(s)
- Yirong Wu
- Department of Cardiology, Hangzhou First People's Hospital, 310006 Zhejiang, China
| | - Yizhou Xu
- Department of Cardiology, Hangzhou First People's Hospital, 310006 Zhejiang, China.
| | - Linhao Xu
- Department of Cardiology, Hangzhou First People's Hospital, 310006 Zhejiang, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Translational Medicine Research Center, Hangzhou First People's Hospital, Hangzhou 310006, Zhejiang, China.
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Maffia P, Mauro C, Case A, Kemper C. Canonical and non-canonical roles of complement in atherosclerosis. Nat Rev Cardiol 2024; 21:743-761. [PMID: 38600367 DOI: 10.1038/s41569-024-01016-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/18/2024] [Indexed: 04/12/2024]
Abstract
Cardiovascular diseases are the leading cause of death globally, and atherosclerosis is the major contributor to the development and progression of cardiovascular diseases. Immune responses have a central role in the pathogenesis of atherosclerosis, with the complement system being an acknowledged contributor. Chronic activation of liver-derived and serum-circulating canonical complement sustains endothelial inflammation and innate immune cell activation, and deposition of complement activation fragments on inflamed endothelial cells is a hallmark of atherosclerotic plaques. However, increasing evidence indicates that liver-independent, cell-autonomous and non-canonical complement activities are underappreciated contributors to atherosclerosis. Furthermore, complement activation can also have atheroprotective properties. These specific detrimental or beneficial contributions of the complement system to the pathogenesis of atherosclerosis are dictated by the location of complement activation and engagement of its canonical versus non-canonical functions in a temporal fashion during atherosclerosis progression. In this Review, we summarize the classical and the emerging non-classical roles of the complement system in the pathogenesis of atherosclerosis and discuss potential strategies for therapeutic modulation of complement for the prevention and treatment of atherosclerotic cardiovascular disease.
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Affiliation(s)
- Pasquale Maffia
- School of Infection & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
- Africa-Europe Cluster of Research Excellence (CoRE) in Non-Communicable Diseases & Multimorbidity, African Research Universities Alliance (ARUA) & The Guild, Accra, Ghana
| | - Claudio Mauro
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Ayden Case
- Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
- Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Claudia Kemper
- Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.
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12
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Wang Y, Li Y, Lu Y, Li J. Biomimetic Nanoparticles for the Diagnosis and Therapy of Atherosclerosis. CHEM REC 2024; 24:e202400087. [PMID: 39148157 DOI: 10.1002/tcr.202400087] [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: 05/07/2024] [Revised: 06/23/2024] [Indexed: 08/17/2024]
Abstract
Atherosclerosis (AS) is a chronic inflammation of blood vessels, which often has no obvious symptoms in the early stage of the disease, but when atherosclerotic plaques are formed, they often cause lumen blockage, and even plaque rupture leads to thrombosis, that is the essential factor of cardiovascular events, for example myocardial infarction, cerebral infarction, and renal atrophy. Therefore, it is considerably significant for the early recognition and precise therapy of plaque. Biomimetic nanoparticles (BNPs), especially those coated with cell membranes, can retain the biological function of cell membranes or cells, which has led to extensive research and application in the diagnosis and treatment of AS in recent years. In this review, we summarized the roles of various key cells in AS progression, the construction of biomimetic nanoparticles based on these key cells as well as their applications in AS diagnosis and therapy. Furthermore, we give a challenge and prospect of biomimetic nanoparticles in AS, hoping to elevate their application quality and the possibility of clinical translation.
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Affiliation(s)
- Yan Wang
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou, 221004, China
| | - Yize Li
- School of Medical Imaging, Xuzhou Medical University, Xuzhou, 221004, China
| | - Yuqing Lu
- School of Medical Imaging, Xuzhou Medical University, Xuzhou, 221004, China
| | - Jingjing Li
- School of Medical Imaging, Xuzhou Medical University, Xuzhou, 221004, China
- Department of Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China
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13
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Jercălău CE, Andrei CL, Brezeanu LN, Darabont RO, Guberna S, Catană A, Lungu MD, Ceban O, Sinescu CJ. Lymphocyte-to-Red Blood Cell Ratio-The Guide Star of Acute Coronary Syndrome Prognosis. Healthcare (Basel) 2024; 12:1205. [PMID: 38921319 PMCID: PMC11203887 DOI: 10.3390/healthcare12121205] [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: 04/29/2024] [Revised: 06/09/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024] Open
Abstract
BACKGROUND Beneath the surface of the acute ST-elevation myocardial infarction (STEMI) iceberg lies a hidden peril, obscured by the well-known cardiovascular risk factors that tip the iceberg. Before delving into the potential time bomb these risk factors represent, it is crucial to recognize the obscured danger lurking under the surface. What secrets does the STEMI iceberg hold? To unveil these mysteries, a closer look at the pathophysiology of STEMI is imperative. Inflammation, the catalyst of the STEMI cascade, sets off a chain reaction within the cardiovascular system. Surprisingly, the intricate interplay between red blood cells (RBC) and lymphocytes remains largely unexplored in previous research. MATERIALS AND METHODS The study encompassed 163 patients diagnosed with STEMI. Utilizing linear and logistic regression, the lymphocyte-to-red blood cell ratio (LRR) was scrutinized as a potential predictive biomarker. RESULTS There was a statistically significant correlation between LRR and the prognosis of STEMI patients. Building upon this discovery, an innovative scoring system was proposed that integrates LRR as a crucial parameter. CONCLUSIONS Uncovering novel predictive markers for both immediate and delayed complications in STEMI is paramount. These markers have the potential to revolutionize treatment strategies by tailoring them to individual risk profiles, ultimately enhancing patient outcomes.
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Affiliation(s)
- Cosmina Elena Jercălău
- Department of Cardiology, “Bagdasar Arseni” Emergency Hospital, University of Medicine and Pharmacy “Carol Davila”, 011241 Bucharest, Romania; (R.O.D.); (A.C.); (C.J.S.)
| | - Cătălina Liliana Andrei
- Department of Cardiology, “Bagdasar Arseni” Emergency Hospital, University of Medicine and Pharmacy “Carol Davila”, 011241 Bucharest, Romania; (R.O.D.); (A.C.); (C.J.S.)
| | - Lavinia Nicoleta Brezeanu
- Department of Anaesthesia and Intensive Care, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Roxana Oana Darabont
- Department of Cardiology, “Bagdasar Arseni” Emergency Hospital, University of Medicine and Pharmacy “Carol Davila”, 011241 Bucharest, Romania; (R.O.D.); (A.C.); (C.J.S.)
| | - Suzana Guberna
- Department of Cardiology, Emergency Hospital “Bagdasar-Arseni”, 050474 Bucharest, Romania; (S.G.); (M.D.L.)
| | - Andreea Catană
- Department of Cardiology, “Bagdasar Arseni” Emergency Hospital, University of Medicine and Pharmacy “Carol Davila”, 011241 Bucharest, Romania; (R.O.D.); (A.C.); (C.J.S.)
| | - Maria Diana Lungu
- Department of Cardiology, Emergency Hospital “Bagdasar-Arseni”, 050474 Bucharest, Romania; (S.G.); (M.D.L.)
| | - Octavian Ceban
- Economic Cybernetics and Informatics Department, The Bucharest University of Economic Studies, 010374 Bucharest, Romania;
| | - Crina Julieta Sinescu
- Department of Cardiology, “Bagdasar Arseni” Emergency Hospital, University of Medicine and Pharmacy “Carol Davila”, 011241 Bucharest, Romania; (R.O.D.); (A.C.); (C.J.S.)
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14
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Obare LM, Bonami RH, Doran A, Wanjalla CN. B cells and atherosclerosis: A HIV perspective. J Cell Physiol 2024; 239:e31270. [PMID: 38651687 PMCID: PMC11209796 DOI: 10.1002/jcp.31270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 03/09/2024] [Accepted: 03/27/2024] [Indexed: 04/25/2024]
Abstract
Atherosclerosis remains a leading cause of cardiovascular disease (CVD) globally, with the complex interplay of inflammation and lipid metabolism at its core. Recent evidence suggests a role of B cells in the pathogenesis of atherosclerosis; however, this relationship remains poorly understood, particularly in the context of HIV. We review the multifaceted functions of B cells in atherosclerosis, with a specific focus on HIV. Unique to atherosclerosis is the pivotal role of natural antibodies, particularly those targeting oxidized epitopes abundant in modified lipoproteins and cellular debris. B cells can exert control over cellular immune responses within atherosclerotic arteries through antigen presentation, chemokine production, cytokine production, and cell-cell interactions, actively participating in local and systemic immune responses. We explore how HIV, characterized by chronic immune activation and dysregulation, influences B cells in the context of atherosclerosis, potentially exacerbating CVD risk in persons with HIV. By examining the proatherogenic and antiatherogenic properties of B cells, we aim to deepen our understanding of how B cells influence atherosclerotic plaque development, especially within the framework of HIV. This research provides a foundation for novel B cell-targeted interventions, with the potential to mitigate inflammation-driven cardiovascular events, offering new perspectives on CVD risk management in PLWH.
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Affiliation(s)
- Laventa M. Obare
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rachel H. Bonami
- Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Amanda Doran
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Celestine N. Wanjalla
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
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15
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Nguyen TK, Paone S, Baxter AA, Mayfosh AJ, Phan TK, Chan E, Peter K, Poon IKH, Thomas SR, Hulett MD. Heparanase promotes the onset and progression of atherosclerosis in apolipoprotein E gene knockout mice. Atherosclerosis 2024; 392:117519. [PMID: 38581737 DOI: 10.1016/j.atherosclerosis.2024.117519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 01/31/2024] [Accepted: 03/12/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND AND AIMS Atherosclerosis is the primary underlying cause of myocardial infarction and stroke, which are the major causes of death globally. Heparanase (Hpse) is a pro-inflammatory extracellular matrix degrading enzyme that has been implicated in atherogenesis. However, to date the precise roles of Hpse in atherosclerosis and its mechanisms of action are not well defined. This study aims to provide new insights into the contribution of Hpse in different stages of atherosclerosis in vivo. METHODS We generated Hpse gene-deficient mice on the atherosclerosis-prone apolipoprotein E gene knockout (ApoE-/-) background to investigate the impact of Hpse gene deficiency on the initiation and progression of atherosclerosis after 6 and 14 weeks high-fat diet feeding, respectively. Atherosclerotic lesion development, blood serum profiles, lesion composition and aortic immune cell populations were evaluated. RESULTS Hpse-deficient mice exhibited significantly reduced atherosclerotic lesion burden in the aortic sinus and aorta at both time-points, independent of changes in plasma cholesterol levels. A significant reduction in the necrotic core size and an increase in smooth muscle cell content were also observed in advanced atherosclerotic plaques of Hpse-deficient mice. Additionally, Hpse deficiency reduced circulating and aortic levels of VCAM-1 at the initiation and progression stages of disease and circulating MCP-1 levels in the initiation but not progression stage. Moreover, the aortic levels of total leukocytes and dendritic cells in Hpse-deficient ApoE-/- mice were significantly decreased compared to control ApoE-/-mice at both disease stages. CONCLUSIONS This study identifies Hpse as a key pro-inflammatory enzyme driving the initiation and progression of atherosclerosis and highlighting the potential of Hpse inhibitors as novel anti-inflammatory treatments for cardiovascular disease.
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Affiliation(s)
- Tien K Nguyen
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
| | - Stephanie Paone
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
| | - Amy A Baxter
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
| | - Alyce J Mayfosh
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
| | - Thanh Kha Phan
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
| | - Enoch Chan
- Department of Pathology, School of Biomedical Sciences, Faculty of Medicine & Health, University of New South Wales, Sydney, New South Wales, 2052, Australia
| | - Karlheinz Peter
- Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia
| | - Ivan K H Poon
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia
| | - Shane R Thomas
- Department of Pathology, School of Biomedical Sciences, Faculty of Medicine & Health, University of New South Wales, Sydney, New South Wales, 2052, Australia
| | - Mark D Hulett
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
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16
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Reilly NA, Sonnet F, Dekkers KF, Kwekkeboom JC, Sinke L, Hilt S, Suleiman HM, Hoeksema MA, Mei H, van Zwet EW, Everts B, Ioan-Facsinay A, Jukema JW, Heijmans BT. Oleic acid triggers metabolic rewiring of T cells poising them for T helper 9 differentiation. iScience 2024; 27:109496. [PMID: 38558932 PMCID: PMC10981094 DOI: 10.1016/j.isci.2024.109496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/29/2023] [Accepted: 03/09/2024] [Indexed: 04/04/2024] Open
Abstract
T cells are the most common immune cells in atherosclerotic plaques, and the function of T cells can be altered by fatty acids. Here, we show that pre-exposure of CD4+ T cells to oleic acid, an abundant fatty acid linked to cardiovascular events, upregulates core metabolic pathways and promotes differentiation into interleukin-9 (IL-9)-producing cells upon activation. RNA sequencing of non-activated T cells reveals that oleic acid upregulates genes encoding key enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis links these expression changes to the differentiation toward TH9 cells, a pro-atherogenic subset. Spectral flow cytometry shows that pre-exposure to oleic acid results in a skew toward IL-9+-producing T cells upon activation. Importantly, pharmacological inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, oleic acid may affect inflammatory diseases like atherosclerosis by rewiring T cell metabolism.
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Affiliation(s)
- Nathalie A. Reilly
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden, the Netherlands
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Friederike Sonnet
- Leiden University Center for Infectious Diseases (LUCID), Leiden, the Netherlands
| | - Koen F. Dekkers
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden, the Netherlands
| | | | - Lucy Sinke
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden, the Netherlands
| | - Stan Hilt
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden, the Netherlands
| | - Hayat M. Suleiman
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden, the Netherlands
| | - Marten A. Hoeksema
- Department of Medical Biochemistry, Amsterdam UMC, location University of Amsterdam, Amsterdam, the Netherlands
| | - Hailiang Mei
- Sequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden, the Netherlands
| | - Erik W. van Zwet
- Medical Statistics, Department of Biomedical Data Sciences, Leiden, the Netherlands
| | - Bart Everts
- Leiden University Center for Infectious Diseases (LUCID), Leiden, the Netherlands
| | - Andreea Ioan-Facsinay
- Department of Rheumatology Leiden University Medical Center, Leiden, the Netherlands
| | - J. Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
- Netherlands Heart Institute, Utrecht, the Netherlands
| | - Bastiaan T. Heijmans
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden, the Netherlands
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17
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Jercălău CE, Andrei CL, Darabont RO, Guberna S, Staicu AM, Rusu CT, Ceban O, Sinescu CJ. Blood Cell Ratios Unveiled: Predictive Markers of Myocardial Infarction Prognosis. Healthcare (Basel) 2024; 12:824. [PMID: 38667586 PMCID: PMC11049867 DOI: 10.3390/healthcare12080824] [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: 02/20/2024] [Revised: 04/03/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND Even if the management and treatment of patients with non-ST-elevation myocardial infarction (NSTEMI) have significantly evolved, it is still a burgeoning disease, an active volcano with very high rates of morbidity and mortality. Therefore, novel management and therapeutic strategies for this condition are urgently needed. Lately, theories related to the role of various blood cells in NSTEMI have emerged, with most of this research having so far been focused on correlating the ratios between various leukocyte types (neutrophil/lymphocyte ratio-NLR, neutrophil/monocyte ratio-NMR). But what about erythrocytes? Is there an interaction between these cells and leukocytes, and furthermore, can this relationship influence NSTEMI prognosis? Are they partners in crime? METHODS Through the present study, we sought, over a period of sixteen months, to evaluate the neutrophil/red blood cell ratio (NRR), monocyte/red blood cell ratio (MRR) and lymphocyte/red blood cell ratio (LRR), assessing their potential role as novel prognostic markers in patients with NSTEMI. RESULTS There was a statistically significant correlation between the NRR, LRR, MRR and the prognosis of NSTEMI patients. CONCLUSIONS These new predictive markers could represent the start of future innovative therapies that may influence crosstalk pathways and have greater benefits in terms of cardiac repair and the secondary prevention of NSTEMI.
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Affiliation(s)
- Cosmina Elena Jercălău
- Department of Cardiology, “Bagdasar Arseni” Emergency Hospital, University of Medicine and Pharmacy “Carol Davila”, 011241 Bucharest, Romania; (R.O.D.); (C.J.S.)
| | - Cătălina Liliana Andrei
- Department of Cardiology, “Bagdasar Arseni” Emergency Hospital, University of Medicine and Pharmacy “Carol Davila”, 011241 Bucharest, Romania; (R.O.D.); (C.J.S.)
| | - Roxana Oana Darabont
- Department of Cardiology, “Bagdasar Arseni” Emergency Hospital, University of Medicine and Pharmacy “Carol Davila”, 011241 Bucharest, Romania; (R.O.D.); (C.J.S.)
| | - Suzana Guberna
- Department of Cardiology, Emergency Hospital “Bagdasar-Arseni”, 050474 Bucharest, Romania; (S.G.); (A.M.S.)
| | - Arina Maria Staicu
- Department of Cardiology, Emergency Hospital “Bagdasar-Arseni”, 050474 Bucharest, Romania; (S.G.); (A.M.S.)
| | - Cătălin Teodor Rusu
- Department of Internal Medicine, “Coltea” Clinical Hospital, 030167 Bucharest, Romania;
| | - Octavian Ceban
- Economic Cybernetics and Informatics Department, The Bucharest University of Economic Studies, 010374 Bucharest, Romania;
| | - Crina Julieta Sinescu
- Department of Cardiology, “Bagdasar Arseni” Emergency Hospital, University of Medicine and Pharmacy “Carol Davila”, 011241 Bucharest, Romania; (R.O.D.); (C.J.S.)
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18
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Gallucci G, Turazza FM, Inno A, Canale ML, Silvestris N, Farì R, Navazio A, Pinto C, Tarantini L. Atherosclerosis and the Bidirectional Relationship between Cancer and Cardiovascular Disease: From Bench to Bedside-Part 1. Int J Mol Sci 2024; 25:4232. [PMID: 38673815 PMCID: PMC11049833 DOI: 10.3390/ijms25084232] [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: 03/17/2024] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Atherosclerosis, a complex metabolic-immune disease characterized by chronic inflammation driven by the buildup of lipid-rich plaques within arterial walls, has emerged as a pivotal factor in the intricate interplay between cancer and cardiovascular disease. This bidirectional relationship, marked by shared risk factors and pathophysiological mechanisms, underscores the need for a comprehensive understanding of how these two formidable health challenges intersect and influence each other. Cancer and its treatments can contribute to the progression of atherosclerosis, while atherosclerosis, with its inflammatory microenvironment, can exert profound effects on cancer development and outcomes. Both cancer and cardiovascular disease involve intricate interactions between general and personal exposomes. In this review, we aim to summarize the state of the art of translational data and try to show how oncologic studies on cardiotoxicity can broaden our knowledge of crucial pathways in cardiovascular biology and exert a positive impact on precision cardiology and cardio-oncology.
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Affiliation(s)
| | - Fabio Maria Turazza
- Struttura Complessa di Cardiologia, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy;
| | - Alessandro Inno
- Oncologia Medica, IRCCS Ospedale Sacro Cuore Don Calabria, 37024 Negrar di Valpolicella, Italy;
| | - Maria Laura Canale
- Division of Cardiology, Azienda USL Toscana Nord-Ovest, Versilia Hospital, 55041 Lido di Camaiore, Italy;
| | - Nicola Silvestris
- Medical Oncology Unit, Department of Human Pathology “G.Barresi”, University of Messina, 98100 Messina, Italy;
| | - Roberto Farì
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41100 Modena, Italy
| | - Alessandro Navazio
- Cardiologia Ospedaliera, Department of Specialized Medicine, AUSL—IRCCS in Tecnologie Avanzate e Modelli Assistenziali in Oncologia, 42100 Reggio Emilia, Italy;
| | - Carmine Pinto
- Provincial Medical Oncology, Department of Oncology and Advanced Technologies, AUSL—IRCCS in Tecnologie Avanzate e Modelli Assistenziali in Oncologia, 42100 Reggio Emilia, Italy;
| | - Luigi Tarantini
- Cardiologia Ospedaliera, Department of Specialized Medicine, AUSL—IRCCS in Tecnologie Avanzate e Modelli Assistenziali in Oncologia, 42100 Reggio Emilia, Italy;
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19
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Pertiwi KR, Teunissen MBM, Krebbers G, Willems MC, Huisman L, Poelen C, van der Wal AC, de Boer OJ. Enrichment of type 1 innate lymphoid cells in the course of human atherosclerotic plaque development suggests contribution to atherogenesis. Front Immunol 2024; 15:1354617. [PMID: 38638438 PMCID: PMC11024276 DOI: 10.3389/fimmu.2024.1354617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 03/20/2024] [Indexed: 04/20/2024] Open
Abstract
Introduction Innate lymphoid cells (ILCs) have been implicated in multiple pathologic conditions, including atherogenesis, as documented in experimental mice studies, however, their role in atherosclerosis in humans remains unexplored. Methods Here, we identify ILCs and their dynamics in early, advanced, and complicated human carotid- and aortic atherosclerotic plaques, using a multiplex immunohistochemical quadruple-staining technique with prototypic transcription factors T-bet, GATA3, or RORgt for identification of the ILC1, ILC2 and ILC3 subsets, respectively, in combination with lineage markers CD3, CD20/ CD79a and CD56 to exclude other lymphoid cell types. ILC subsets were quantified, and to put this in perspective, their numbers were expressed as percentage of the total number of infiltrated lymphoid cells and related to the frequency of conventional T cells, B cells, NK cells, and NKT cells. Results All ILC subsets were present in every different stage of atherogenesis. ILC1s were the most abundant ILC subset, and their numbers significantly increased in the course of plaque development, but paradoxically, their relative frequency was reduced because of a higher increment of T cells and B cells. The numbers of ILC2s and ILC3s also gradually increased, but this trend did not achieve significance. T cell subsets always significantly outnumbered their ILC counterparts, except for the early lesions where the proportion of ILC1s was markedly higher, albeit not significant. Discussion The high abundance of ILC1s in the early stages and further significant enrichment in later stages, suggest they may participate in the initiation and development of atherogenesis, and thus, may represent a novel target to prevent or treat atherosclerosis.
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Affiliation(s)
- Kartika R. Pertiwi
- Department of Pathology, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
- Faculty of Medicine and Department of Biology Education, Faculty of Mathematics and Natural Science, Universitas Negeri Yogyakarta, Yogyakarta, Indonesia
| | - Marcel B. M. Teunissen
- Department of Dermatology, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Gabrielle Krebbers
- Department of Dermatology, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Martine C.M. Willems
- Department of Vascular Surgery, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
- Department of Vascular Surgery, Flevoziekenhuis, Almere, Netherlands
| | - Laurens Huisman
- Department of Vascular Surgery, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
- Department of Vascular Surgery, Flevoziekenhuis, Almere, Netherlands
| | - Cindy Poelen
- Department of Pathology, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Allard C. van der Wal
- Department of Pathology, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Onno J. de Boer
- Department of Pathology, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
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20
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Nakano R, Chogahara I, Ohira M, Imaoka K, Sato S, Bekki T, Sato K, Imaoka Y, Marlen D, Tanaka Y, Ohdan H. Atherosclerosis Deteriorates Liver Ischemia/Reperfusion Injury Via Interferon Regulatory Factor-1 Overexpression in a Murine Model. Transplant Proc 2024; 56:678-685. [PMID: 38433025 DOI: 10.1016/j.transproceed.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 02/04/2024] [Accepted: 02/13/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND Abdominal aortic calcification (AAC) is associated with cardiovascular-related mortality, along with an elevated risk of coronary, cerebrovascular, and cardiovascular events. Notably, AAC is strongly associated with poor overall and recurrence free survival posthepatectomy for hepatocellular carcinoma. Despite the acknowledged significance of atherosclerosis in systemic inflammation, its response to ischemia/reperfusion injury (IRI) remains poorly elucidated. In this study, we aimed to clarify the impact of atherosclerosis on the liver immune system using a warm IRI mouse model. METHODS Injury was induced in an atherosclerotic mouse model (ApoE-/-) or C57BL/6J wild-type (WT) mice through 70% clamping for 1 hour and analyzed after 6 hours of reperfusion. RESULTS Elevated serum levels of aspartate and alanine aminotransferase, along with histological assessment, indicated considerable damage in the livers of ApoE-/- mice than that in WT mice. This indicates a substantial contribution of atherosclerosis to IRI. Furthermore, T and natural killer (NK) cells in ApoE-/- mouse livers displayed a more inflammatory phenotype than those in WT mouse livers. Reverse transcription-polymerase chain reaction analysis revealed a significant upregulation of interleukin (IL)-15 and its transcriptional regulator, interferon regulatory factor-1 (IRF-1) in ApoE-/- mouse livers compared with that in WT mouse livers. CONCLUSIONS These findings suggest that in an atherosclerotic mouse model, atherosclerosis can mirror intrahepatic immunity, particularly activating liver NK and T cells through IL-15 production, thereby exacerbating hepatic damage. The upregulation of IL-15 expression is associated with IRF-1 overexpression.
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Affiliation(s)
- Ryosuke Nakano
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Ichiya Chogahara
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan; Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Minami-ku, Hiroshima, Japan.
| | - Kouki Imaoka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Saki Sato
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Tomoaki Bekki
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Koki Sato
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Yuki Imaoka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Doskali Marlen
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Yuka Tanaka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
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Xia Y, Gao D, Wang X, Liu B, Shan X, Sun Y, Ma D. Role of Treg cell subsets in cardiovascular disease pathogenesis and potential therapeutic targets. Front Immunol 2024; 15:1331609. [PMID: 38558816 PMCID: PMC10978666 DOI: 10.3389/fimmu.2024.1331609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 03/05/2024] [Indexed: 04/04/2024] Open
Abstract
In the genesis and progression of cardiovascular diseases involving both innate and adaptive immune responses, inflammation plays a pivotal and dual role. Studies in experimental animals indicate that certain immune responses are protective, while others exacerbate the disease. T-helper (Th) 1 cell immune responses are recognized as key drivers of inflammatory progression in cardiovascular diseases. Consequently, the CD4+CD25+FOXP3+ regulatory T cells (Tregs) are gaining increasing attention for their roles in inflammation and immune regulation. Given the critical role of Tregs in maintaining immune-inflammatory balance and homeostasis, abnormalities in their generation or function might lead to aberrant immune responses, thereby initiating pathological changes. Numerous preclinical studies and clinical trials have unveiled the central role of Tregs in cardiovascular diseases, such as atherosclerosis. Here, we review the roles and mechanisms of Treg subsets in cardiovascular conditions like atherosclerosis, hypertension, myocardial infarction and remodeling, myocarditis, dilated cardiomyopathy, and heart failure. While the precise molecular mechanisms of Tregs in cardiac protection remain elusive, therapeutic strategies targeting Tregs present a promising new direction for the prevention and treatment of cardiovascular diseases.
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Affiliation(s)
| | | | | | | | | | - Yunpeng Sun
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, China
| | - Dashi Ma
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, China
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22
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Piras L, Zuccanti M, Russo P, Riccio F, Agresti A, Lustri C, Dardani D, Ferrera A, Fiorentini V, Tocci G, Tini Melato G, Volpe M, Barbato E, Battistoni A. Association between Immune Checkpoint Inhibitors and Atherosclerotic Cardiovascular Disease Risk: Another Brick in the Wall. Int J Mol Sci 2024; 25:2502. [PMID: 38473748 PMCID: PMC10931678 DOI: 10.3390/ijms25052502] [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: 12/29/2023] [Revised: 02/11/2024] [Accepted: 02/15/2024] [Indexed: 03/14/2024] Open
Abstract
In recent years, immune checkpoint inhibitors have significantly changed the field of oncology, emerging as first-line treatment, either alone or in combination with other regimens, for numerous malignancies, improving overall survival and progression-free survival in these patients. However, immune checkpoint inhibitors might also cause severe or fatal immune-related adverse events, including adverse cardiovascular events. Initially, myocarditis was recognized as the main immune checkpoint inhibitor-related cardiac event, but our knowledge of other potential immune-related cardiovascular adverse events continues to broaden. Recently, preclinical and clinical data seem to support an association between immune checkpoint inhibitors and accelerated atherosclerosis as well as atherosclerotic cardiovascular events such as cardiac ischemic disease, stroke, and peripheral artery disease. In this review, by offering a comprehensive overview of the pivotal role of inflammation in atherosclerosis, we focus on the potential molecular pathways underlying the effects of immune checkpoint inhibitors on cardiovascular diseases. Moreover, we provide an overview of therapeutic strategies for cancer patients undergoing immunotherapy to prevent the development of cardiovascular diseases.
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Affiliation(s)
- Linda Piras
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Michela Zuccanti
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Paola Russo
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Francesca Riccio
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Antonio Agresti
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Camilla Lustri
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Domenico Dardani
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Armando Ferrera
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Vincenzo Fiorentini
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Giuliano Tocci
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Giacomo Tini Melato
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Massimo Volpe
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
- IRCCS San Raffaele, 00166 Rome, Italy
| | - Emanuele Barbato
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
| | - Allegra Battistoni
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (L.P.); (M.Z.); (P.R.); (F.R.); (A.A.); (C.L.); (D.D.); (A.F.); (V.F.); (G.T.); (G.T.M.); (M.V.); (E.B.)
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Domingo E, Marques P, Francisco V, Piqueras L, Sanz MJ. Targeting systemic inflammation in metabolic disorders. A therapeutic candidate for the prevention of cardiovascular diseases? Pharmacol Res 2024; 200:107058. [PMID: 38218355 DOI: 10.1016/j.phrs.2024.107058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 12/11/2023] [Accepted: 01/03/2024] [Indexed: 01/15/2024]
Abstract
Cardiovascular disease (CVD) remains the leading cause of death and disability worldwide. While many factors can contribute to CVD, atherosclerosis is the cardinal underlying pathology, and its development is associated with several metabolic risk factors including dyslipidemia and obesity. Recent studies have definitively demonstrated a link between low-grade systemic inflammation and two relevant metabolic abnormalities: hypercholesterolemia and obesity. Interestingly, both metabolic disorders are also associated with endothelial dysfunction/activation, a proinflammatory and prothrombotic phenotype of the endothelium that involves leukocyte infiltration into the arterial wall, one of the earliest stages of atherogenesis. This article reviews the current literature on the intricate relationship between hypercholesterolemia and obesity and the associated systemic inflammation and endothelial dysfunction, and discusses the effectiveness of present, emerging and in-development pharmacological therapies used to treat these metabolic disorders with a focus on their effects on the associated systemic inflammatory state and cardiovascular risk.
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Affiliation(s)
- Elena Domingo
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain
| | - Patrice Marques
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain
| | - Vera Francisco
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Valencia, Spain
| | - Laura Piqueras
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain; CIBERDEM, Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Carlos III Health Institute (ISCIII), Spain.
| | - Maria-Jesus Sanz
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain; CIBERDEM, Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Carlos III Health Institute (ISCIII), Spain.
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24
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Zhang YJ, Huang C, Zu XG, Liu JM, Li YJ. Use of Machine Learning for the Identification and Validation of Immunogenic Cell Death Biomarkers and Immunophenotypes in Coronary Artery Disease. J Inflamm Res 2024; 17:223-249. [PMID: 38229693 PMCID: PMC10790656 DOI: 10.2147/jir.s439315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/28/2023] [Indexed: 01/18/2024] Open
Abstract
Objective Immunogenic cell death (ICD) is part of the immune system's response to coronary artery disease (CAD). In this study, we bioinformatically evaluated the diagnostic and therapeutic utility of immunogenic cell death-related genes (IRGs) and their relationship with immune infiltration features in CAD. Methods We acquired the CAD-related datasets GSE12288, GSE71226, and GSE120521 from the Gene Expression Omnibus (GEO) database and the IRGs from the GeneCards database. After identifying the immune cell death-related differentially expressed genes (IRDEGs), we developed a risk model and detected immune subtypes in CAD. IRDEGs were identified using least absolute shrinkage and selection operator (LASSO) analysis. Using a nomogram, we confirmed that both the LASSO model and ICD signature genes had good diagnostic performance. Results There was a high degree of coincidence and immune representativeness between two CAD groups based on characteristic genes and hub genes. Hub genes were associated with the interaction of neuroactive ligands with receptors and cell adhesion receptors. The two groups differed in terms of adipogenesis, allograft rejection, and apoptosis, as well as the ICD signature and hub gene expression levels. The two CAD-ICD subtypes differed in terms of immune infiltration. Conclusion Quantitative real-time PCR (qRT-PCR) correlated CAD with the expression of OAS3, ITGAV, and PIBF1. The ICD signature genes are candidate biomarkers and reference standards for immune grouping in CAD and can be beneficial in precise immune-targeted therapy.
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Affiliation(s)
- Yan-jiao Zhang
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
| | - Chao Huang
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of China
| | - Xiu-guang Zu
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
| | - Jin-ming Liu
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
| | - Yong-jun Li
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
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Zhao L, Ma D, Wang L, Su X, Feng L, Zhu L, Chen Y, Hao Y, Wang X, Feng J. Metabolic changes with the occurrence of atherosclerotic plaques and the effects of statins. Front Immunol 2023; 14:1301051. [PMID: 38143759 PMCID: PMC10739339 DOI: 10.3389/fimmu.2023.1301051] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/23/2023] [Indexed: 12/26/2023] Open
Abstract
Atherosclerosis is a common cardiovascular disease caused by the abnormal expression of multiple factors and genes influenced by both environmental and genetic factors. The primary manifestation of atherosclerosis is plaque formation, which occurs when inflammatory cells consume excess lipids, affecting their retention and modification within the arterial intima. This triggers endothelial cell (EC) activation, immune cell infiltration, vascular smooth muscle cell (VSMC) proliferation and migration, foam cell formation, lipid streaks, and fibrous plaque development. These processes can lead to vascular wall sclerosis, lumen stenosis, and thrombosis. Immune cells, ECs, and VSMCs in atherosclerotic plaques undergo significant metabolic changes and inflammatory responses. The interaction of cytokines and chemokines secreted by these cells leads to the onset, progression, and regression of atherosclerosis. The regulation of cell- or cytokine-based immune responses is a novel therapeutic approach for atherosclerosis. Statins are currently the primary pharmacological agents utilised for managing unstable plaques owing to their ability to enhance endothelial function, regulate VSMC proliferation and apoptosis by reducing cholesterol levels, and mitigate the expression and activity of inflammatory cytokines. In this review, we provide an overview of the metabolic changes associated with atherosclerosis, describe the effects of inflammatory responses on atherosclerotic plaques, and discuss the mechanisms through which statins contribute to plaque stabilisation. Additionally, we examine the role of statins in combination with other drugs in the management of atherosclerosis.
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Affiliation(s)
| | - Di Ma
- Bethune First Hospital, Jilin University, Changchun, China
| | - LiJuan Wang
- Bethune First Hospital, Jilin University, Changchun, China
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26
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Napiórkowska-Baran K, Schmidt O, Szymczak B, Lubański J, Doligalska A, Bartuzi Z. Molecular Linkage between Immune System Disorders and Atherosclerosis. Curr Issues Mol Biol 2023; 45:8780-8815. [PMID: 37998729 PMCID: PMC10670175 DOI: 10.3390/cimb45110552] [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: 09/26/2023] [Revised: 10/26/2023] [Accepted: 10/30/2023] [Indexed: 11/25/2023] Open
Abstract
A strong relationship exists between immune dysfunction and cardiovascular disease. Immune dysregulation can promote the development of cardiovascular diseases as well as exacerbate their course. The disorders may occur due to the presence of primary immune defects (currently known as inborn errors of immunity) and the more common secondary immune deficiencies. Secondary immune deficiencies can be caused by certain chronic conditions (such as diabetes, chronic kidney disease, obesity, autoimmune diseases, or cancer), nutritional deficiencies (including both lack of nutrients and bioactive non-nutrient compounds), and medical treatments and addictive substances. This article unravels the molecular linkage between the aforementioned immune system disorders and atherosclerosis.
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Affiliation(s)
- Katarzyna Napiórkowska-Baran
- Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Toruń, 85-067 Bydgoszcz, Poland;
| | - Oskar Schmidt
- Student Research Club of Clinical Immunology, Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Toruń, 85-067 Bydgoszcz, Poland; (O.S.); (B.S.); (J.L.); (A.D.)
| | - Bartłomiej Szymczak
- Student Research Club of Clinical Immunology, Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Toruń, 85-067 Bydgoszcz, Poland; (O.S.); (B.S.); (J.L.); (A.D.)
| | - Jakub Lubański
- Student Research Club of Clinical Immunology, Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Toruń, 85-067 Bydgoszcz, Poland; (O.S.); (B.S.); (J.L.); (A.D.)
| | - Agata Doligalska
- Student Research Club of Clinical Immunology, Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Toruń, 85-067 Bydgoszcz, Poland; (O.S.); (B.S.); (J.L.); (A.D.)
| | - Zbigniew Bartuzi
- Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Toruń, 85-067 Bydgoszcz, Poland;
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Doi T, Langsted A, Nordestgaard BG. Dual elevated remnant cholesterol and C-reactive protein in myocardial infarction, atherosclerotic cardiovascular disease, and mortality. Atherosclerosis 2023; 379:117141. [PMID: 37217436 DOI: 10.1016/j.atherosclerosis.2023.05.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 05/12/2023] [Accepted: 05/12/2023] [Indexed: 05/24/2023]
Abstract
BACKGROUND AND AIMS Elevated remnant cholesterol and low-grade inflammation each cause atherosclerotic cardiovascular disease (ASCVD); however, it is unknown whether joint elevation of both factors confers the highest risk. We tested the hypothesis that dual elevated remnant cholesterol and low-grade inflammation marked by elevated C-reactive protein is associated with the highest risk of myocardial infarction, ASCVD, and all-cause mortality. METHODS The Copenhagen General Population Study randomly recruited white Danish individuals aged 20-100 years in 2003-2015 and followed them for a median 9.5 years. ASCVD was cardiovascular mortality, myocardial infarction, stroke, and coronary revascularization. RESULTS In 103,221 individuals, we observed 2,454 (2.4%) myocardial infarctions, 5,437 (5.3%) ASCVD events, and 10,521 (10.2%) deaths. The hazard ratios increased with each of stepwise higher remnant cholesterol and stepwise higher C-reactive protein. In individuals with the highest tertile of both remnant cholesterol and C-reactive protein compared to individuals with the lowest tertile of both, the multivariable adjusted hazard ratios were 2.2 (95%CI:1.9-2.7) for myocardial infarction, 1.9 (1.7-2.2) for ASCVD, and 1.4 (1.3-1.5) for all-cause mortality. Corresponding values for only the highest tertile of remnant cholesterol were 1.6 (1.5-1.8), 1.4 (1.3-1.5), and 1.1 (1.0-1.1), and those for only the highest tertile of C-reactive protein were 1.7 (1.5-1.8), 1.6 (1.5-1.7), and 1.3 (1.3-1.4), respectively. There was no statistical evidence for interaction between elevated remnant cholesterol and elevated C-reactive protein on risk of myocardial infarction (p = 0.10), ASCVD (p = 0.40), or all-cause mortality (p = 0.74). CONCLUSIONS Dual elevated remnant cholesterol and C-reactive protein confers the highest risk of myocardial infarction, ASCVD, and all-cause mortality, that is, compared to either of these two factors individually.
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Affiliation(s)
- Takahito Doi
- Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev and Gentofte, Borgmester Ib Juuls Vej 73, 2730, Herlev, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, 2730, Herlev, Denmark; Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Anne Langsted
- Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev and Gentofte, Borgmester Ib Juuls Vej 73, 2730, Herlev, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, 2730, Herlev, Denmark; Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev and Gentofte, Borgmester Ib Juuls Vej 73, 2730, Herlev, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, 2730, Herlev, Denmark; Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
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Li Y, Wang J, Xie J. Biomimetic nanoparticles targeting atherosclerosis for diagnosis and therapy. SMART MEDICINE 2023; 2:e20230015. [PMID: 39188346 PMCID: PMC11236035 DOI: 10.1002/smmd.20230015] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 05/28/2023] [Indexed: 08/28/2024]
Abstract
Atherosclerosis is a typical chronic inflammatory vascular disease that seriously endangers human health. At present, oral lipid-lowering or anti-inflammatory drugs are clinically used to inhibit the development of atherosclerosis. However, traditional oral drug treatments have problems such as low utilization, slow response, and serious side effects. Traditional nanodrug delivery systems are difficult to interactively recognize by normal biological organisms, and it is difficult to target the delivery of drugs to target lesions. Therefore, building a biomimetic nanodrug delivery system with targeted drug delivery based on the pathological characteristics of atherosclerosis is the key to achieving efficient and safe treatment of atherosclerosis. In this review, various nanodrug delivery systems that can target atherosclerosis are summarized and discussed. In addition, the future prospects and challenges of its clinical translation are also discussed.
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Affiliation(s)
- Yuyu Li
- Department of CardiologyNational Cardiovascular Disease Regional Center for Anhuithe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Key Laboratory of Remodeling‐Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing Anzhen Hospital, Capital Medical UniversityBeijingChina
- Beijing Institute of Heart, Lung, and Blood Vessel DiseasesBeijing Anzhen Hospital Affiliated to Capital Medical UniversityBeijingChina
| | - Jifang Wang
- Department of CardiologyNational Cardiovascular Disease Regional Center for Anhuithe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Department of CardiologyDrum Tower HospitalMedical School of Nanjing UniversityNanjingChina
| | - Jun Xie
- Department of CardiologyNational Cardiovascular Disease Regional Center for Anhuithe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
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Pauli J, Reisenauer T, Winski G, Sachs N, Chernogubova E, Freytag H, Otto C, Reeps C, Eckstein HH, Scholz CJ, Maegdefessel L, Busch A. Apolipoprotein E (ApoE) Rescues the Contractile Smooth Muscle Cell Phenotype in Popliteal Artery Aneurysm Disease. Biomolecules 2023; 13:1074. [PMID: 37509110 PMCID: PMC10377618 DOI: 10.3390/biom13071074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 06/22/2023] [Accepted: 06/28/2023] [Indexed: 07/30/2023] Open
Abstract
Popliteal artery aneurysm (PAA) is the most frequent peripheral aneurysm, primarily seen in male smokers with a prevalence below 1%. This exploratory study aims to shed light on cellular mechanisms involved in PAA progression. Sixteen human PAA and eight non-aneurysmatic popliteal artery samples, partially from the same patients, were analyzed by immunohistochemistry, fluorescence imaging, Affymetrix mRNA expression profiling, qPCR and OLink proteomics, and compared to atherosclerotic (n = 6) and abdominal aortic aneurysm (AAA) tissue (n = 19). Additionally, primary cell culture of PAA-derived vascular smooth muscle cells (VSMC) was established for modulation and growth analysis. Compared to non-aneurysmatic popliteal arteries, VSMCs lose the contractile phenotype and the cell proliferation rate increases significantly in PAA. Array analysis identified APOE higher expressed in PAA samples, co-localizing with VSMCs. APOE stimulation of primary human PAA VSMCs significantly reduced cell proliferation. Accordingly, contractile VSMC markers were significantly upregulated. A single case of osseous mechanically induced PAA with a non-diseased VSMC profile emphasizes these findings. Carefully concluded, PAA pathogenesis shows similar features to AAA, yet the mechanisms involved might differ. APOE is specifically higher expressed in PAA tissue and could be involved in VSMC phenotype rescue.
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Affiliation(s)
- Jessica Pauli
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 10785 Berlin, Germany
| | - Tessa Reisenauer
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
| | - Greg Winski
- Molecular Vascular Medicine Group, Center for Molecular Medicine, Karolinska Institute, 17177 Stockholm, Sweden
- Perioperative Medicine and Intensive Care, Karolinska University Hospital, 17177 Stockholm, Sweden
| | - Nadja Sachs
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 10785 Berlin, Germany
| | - Ekaterina Chernogubova
- Molecular Vascular Medicine Group, Center for Molecular Medicine, Karolinska Institute, 17177 Stockholm, Sweden
| | - Hannah Freytag
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
| | - Christoph Otto
- Department of General, Visceral, Transplantation, Vascular & Pediatric Surgery, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Christian Reeps
- Division of Vascular and Endovascular Surgery, Department for Visceral, Thoracic and Vascular Surgery, Medical Faculty Carl Gustav Carus and University Hospital, Technische Universität Dresden, 01307 Dresden, Germany
| | - Hans-Henning Eckstein
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 10785 Berlin, Germany
| | | | - Lars Maegdefessel
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 10785 Berlin, Germany
- Molecular Vascular Medicine Group, Center for Molecular Medicine, Karolinska Institute, 17177 Stockholm, Sweden
| | - Albert Busch
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
- Division of Vascular and Endovascular Surgery, Department for Visceral, Thoracic and Vascular Surgery, Medical Faculty Carl Gustav Carus and University Hospital, Technische Universität Dresden, 01307 Dresden, Germany
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Reiche ME, Poels K, Bosmans LA, Vos WG, Van Tiel CM, Gijbels MJJ, Aarts SABM, Den Toom M, Beckers L, Weber C, Atzler D, Rensen PCN, Kooijman S, Lutgens E. Adipocytes control hematopoiesis and inflammation through CD40 signaling. Haematologica 2023; 108:1873-1885. [PMID: 36475519 PMCID: PMC10316249 DOI: 10.3324/haematol.2022.281482] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 11/30/2022] [Indexed: 08/18/2024] Open
Abstract
The co-stimulatory CD40-CD40L dyad plays an important role in chronic inflammatory diseases associated with aging. Although CD40 is mainly expressed by immune cells, CD40 is also present on adipocytes. We aimed to delineate the role of adipocyte CD40 in the aging hematopoietic system and evaluated the effects of adipocyte CD40 deficiency on cardiometabolic diseases. Adult adipocyte CD40-deficient mice (AdiCD40KO) mice had a decrease in bone marrow hematopoietic stem cells (Lin-Sca+cKit+, LSK) and common lymphoid progenitors, which was associated with increased bone marrow adiposity and T-cell activation, along with elevated plasma corticosterone levels, a phenotype that became more pronounced with age. Atherosclerotic AdiCD40koApoE-/- (CD40AKO) mice also displayed changes in the LSK population, showing increased myeloid and lymphoid multipotent progenitors, and augmented corticosterone levels. Increased T-cell activation could be observed in bone marrow, spleen, and adipose tissue, while the numbers of B cells were decreased. Although atherosclerosis was reduced in CD40AKO mice, plaques contained more activated T cells and larger necrotic cores. Analysis of peripheral adipose tissue in a diet-induced model of obesity revealed that obese AdiCD40KO mice had increased T-cell activation in adipose tissue and lymphoid organs, but decreased weight gain and improved insulin sensitivity, along with increased fat oxidation. In conclusion, adipocyte CD40 plays an important role in maintaining immune cell homeostasis in bone marrow during aging and chronic inflammatory diseases, particularly of the lymphoid populations. Although adipocyte CD40 deficiency reduces atherosclerosis burden and ameliorates diet-induced obesity, the accompanying T-cell activation may eventually aggravate cardiometabolic diseases.
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Affiliation(s)
- Myrthe E Reiche
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands; Department of Medical Cell Biology, Uppsala University, Uppsala
| | - Kikkie Poels
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Laura A Bosmans
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Winnie G Vos
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Claudia M Van Tiel
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Marion J J Gijbels
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Department of Biochemistry, Maastricht University, Maastricht
| | - Suzanne A B M Aarts
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Myrthe Den Toom
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Linda Beckers
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Christian Weber
- Cardiovascular Research Institute Maastricht (CARIM), Department of Biochemistry, Maastricht University, Maastricht, The Netherlands; Institute of Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, Munich, Germany; German Centre of Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich
| | - Dorothee Atzler
- Institute of Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, Munich, Germany; German Centre of Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität, Munich
| | - Patrick C N Rensen
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden
| | - Sander Kooijman
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden
| | - Esther Lutgens
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands; Institute of Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, Munich, Germany; German Centre of Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Cardiovascular Medicine, Experimental CardioVascular Immunology Laboratory, Mayo Clinic, Rochester, MN.
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31
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Gogulamudi VR, Islam MT, Durrant JR, Adeyemo AO, Trott DW, Hyuhn MH, Zhu W, Donato AJ, Walker AE, Lesniewski LA. Heterozygosity for ADP-ribosylation factor 6 suppresses the burden and severity of atherosclerosis. PLoS One 2023; 18:e0285253. [PMID: 37163513 PMCID: PMC10171652 DOI: 10.1371/journal.pone.0285253] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 04/18/2023] [Indexed: 05/12/2023] Open
Abstract
Atherosclerosis is the root cause of major cardiovascular diseases (CVD) such as myocardial infarction and stroke. ADP-ribosylation factor 6 (Arf6) is a ubiquitously expressed GTPase known to be involved in inflammation, vascular permeability and is sensitive to changes in shear stress. Here, using atheroprone, ApoE-/- mice, with a single allele deletion of Arf6 (HET) or wildtype Arf6 (WT), we demonstrate that reduction in Arf6 attenuates atherosclerotic plaque burden and severity. We found that plaque burden in the descending aorta was lower in HET compared to WT mice (p˂0.001) after the consumption of an atherogenic Paigen diet for 5 weeks. Likewise, luminal occlusion, necrotic core size, plaque grade, elastic lamina breaks, and matrix deposition were lower in the aortic root atheromas of HET compared to WT mice (all p≤0.05). We also induced advanced human-like complex atherosclerotic plaque in the left carotid artery using partial carotid ligation surgery and found that atheroma area, plaque grade, intimal necrosis, intraplaque hemorrhage, thrombosis, and calcification were lower in HET compared to WT mice (all p≤0.04). Our findings suggest that the atheroprotection afforded by Arf6 heterozygosity may result from reduced immune cell migration (all p≤0.005) as well as endothelial and vascular smooth muscle cell proliferation (both p≤0.001) but independent of changes in circulating lipids (all p≥0.40). These findings demonstrate a critical role for Arf6 in the development and severity of atherosclerosis and suggest that Arf6 inhibition can be explored as a novel therapeutic strategy for the treatment of atherosclerotic CVD.
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Affiliation(s)
- Venkateswara R. Gogulamudi
- Department of Internal Medicine, Division of Geriatrics, The University of Utah, Salt Lake City, Utah, United States of America
| | - Md Torikul Islam
- Department of Nutrition and Integrative Physiology, The University of Utah, Salt Lake City, Utah, United States of America
| | - Jessica R. Durrant
- Dallas Tissue Research, Farmers Branch, Texas, Dallas, United States of America
| | - Adelola O. Adeyemo
- Department of Internal Medicine, Division of Geriatrics, The University of Utah, Salt Lake City, Utah, United States of America
| | - Daniel W. Trott
- Department of Internal Medicine, Division of Geriatrics, The University of Utah, Salt Lake City, Utah, United States of America
- Department of Internal Medicine, Division of Cardiovascular Medicine, The University of Utah, Salt Lake City, Utah, United States of America
| | - Mi Ho Hyuhn
- Department of Internal Medicine, Division of Geriatrics, The University of Utah, Salt Lake City, Utah, United States of America
| | - Weiquan Zhu
- Department of Internal Medicine, Division of Cardiovascular Medicine, The University of Utah, Salt Lake City, Utah, United States of America
- Department of Pathology, The University of Utah, Salt Lake City, Utah, United States of America
- Program of Molecular Medicine, The University of Utah, Salt Lake City, Utah, United States of America
| | - Anthony J. Donato
- Department of Internal Medicine, Division of Geriatrics, The University of Utah, Salt Lake City, Utah, United States of America
- Department of Nutrition and Integrative Physiology, The University of Utah, Salt Lake City, Utah, United States of America
- Geriatric Research Education and Clinical Center, Veteran’s Affairs Medical Center-Salt Lake City, Salt Lake City, Utah, United States of America
- Department of Biochemistry, The University of Utah, Salt Lake City, Utah, United States of America
- Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, Utah, United States of America
| | - Ashley E. Walker
- Department of Internal Medicine, Division of Geriatrics, The University of Utah, Salt Lake City, Utah, United States of America
- Department of Human Physiology, The University of Oregon, Eugene, Oregon, United States of America
| | - Lisa A. Lesniewski
- Department of Internal Medicine, Division of Geriatrics, The University of Utah, Salt Lake City, Utah, United States of America
- Department of Nutrition and Integrative Physiology, The University of Utah, Salt Lake City, Utah, United States of America
- Geriatric Research Education and Clinical Center, Veteran’s Affairs Medical Center-Salt Lake City, Salt Lake City, Utah, United States of America
- Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, Utah, United States of America
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Kumric M, Urlic H, Bozic J, Vilovic M, Ticinovic Kurir T, Glavas D, Miric D, Zanchi J, Bradaric-Slujo A, Lozo M, Borovac JA. Emerging Therapies for the Treatment of Atherosclerotic Cardiovascular Disease: From Bench to Bedside. Int J Mol Sci 2023; 24:8062. [PMID: 37175766 PMCID: PMC10178593 DOI: 10.3390/ijms24098062] [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: 03/31/2023] [Revised: 04/18/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
Primarily a consequence of sedentary lifestyle, atherosclerosis has already reached pandemic proportions, and with every year the burden of it is only increasing. As low-density lipoprotein cholesterol (LDL-C) represents a crucial factor in atherosclerosis formation and progression, stringent lipid-lowering therapy could conceivably be the key to preventing the unfavorable outcomes that arise as a consequence of atherosclerosis. The use of statins in lipid-lowering is often burdened by adverse events or is insufficient to prevent cardiovascular events as a monotherapy. Therefore, in the present review, the authors aimed to discuss the underlying mechanisms of dyslipidemia and associated atherosclerotic cardiovascular disease (ASCVD) and preclinical and clinical trials of novel therapeutic approaches to its treatment, some of which are still in the early stages of development. Apart from novel therapies, a novel change in perspective is needed. Specifically, the critical objective in the future management of ASCVD is to embrace emerging evidence in the field of atherosclerosis, because clinicians are often burden by common practice and personal experience, both of which have so far been shown to be futile in the setting of atherosclerosis.
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Affiliation(s)
- Marko Kumric
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.)
| | - Hrvoje Urlic
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.)
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.)
| | - Marino Vilovic
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.)
| | - Tina Ticinovic Kurir
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.)
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Split, 21000 Split, Croatia
| | - Duska Glavas
- Cardiovascular Diseases Department, University Hospital of Split, 21000 Split, Croatia
| | - Dino Miric
- Cardiovascular Diseases Department, University Hospital of Split, 21000 Split, Croatia
| | - Jaksa Zanchi
- Cardiovascular Diseases Department, University Hospital of Split, 21000 Split, Croatia
| | - Anteo Bradaric-Slujo
- Cardiovascular Diseases Department, University Hospital of Split, 21000 Split, Croatia
| | - Mislav Lozo
- Cardiovascular Diseases Department, University Hospital of Split, 21000 Split, Croatia
| | - Josip A. Borovac
- Cardiovascular Diseases Department, University Hospital of Split, 21000 Split, Croatia
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Miceli G, Rizzo G, Basso MG, Cocciola E, Pennacchio AR, Pintus C, Tuttolomondo A. Artificial Intelligence in Symptomatic Carotid Plaque Detection: A Narrative Review. APPLIED SCIENCES 2023; 13:4321. [DOI: 10.3390/app13074321] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
Identifying atherosclerotic disease is the mainstay for the correct diagnosis of the large artery atherosclerosis ischemic stroke subtype and for choosing the right therapeutic strategy in acute ischemic stroke. Classification into symptomatic and asymptomatic plaque and estimation of the cardiovascular risk are essential to select patients eligible for pharmacological and/or surgical therapy in order to prevent future cerebral ischemic events. The difficulties in a “vulnerability” definition and the methodical issues concerning its detectability and quantification are still subjects of debate. Non-invasive imaging studies commonly used to detect arterial plaque are computed tomographic angiography, magnetic resonance imaging, and ultrasound. Characterization of a carotid plaque type using the abovementioned imaging modalities represents the basis for carotid atherosclerosis management. Classification into symptomatic and asymptomatic plaque and estimation of the cardiovascular risk are essential to select patients eligible for pharmacological and/or surgical therapy in order to prevent future cerebral ischemic events. In this setting, artificial intelligence (AI) can offer suggestive solutions for tissue characterization and classification concerning carotid artery plaque imaging by analyzing complex data and using automated algorithms to obtain a final output. The aim of this review is to provide overall knowledge about the role of AI models applied to non-invasive imaging studies for the detection of symptomatic and vulnerable carotid plaques.
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Affiliation(s)
- Giuseppe Miceli
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, Via del Vespro 129, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Giuliana Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, Via del Vespro 129, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Maria Grazia Basso
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, Via del Vespro 129, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Elena Cocciola
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, Via del Vespro 129, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Andrea Roberta Pennacchio
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, Via del Vespro 129, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Chiara Pintus
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, Via del Vespro 129, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, Via del Vespro 129, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90100 Palermo, Italy
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Staal AHJ, Cortenbach KRG, Gorris MAJ, van der Woude LL, Srinivas M, Heijmen RH, Geuzebroek GSC, Grewal N, Hebeda KM, de Vries IJM, DeRuiter MC, van Kimmenade RRJ. Adventitial adaptive immune cells are associated with ascending aortic dilatation in patients with a bicuspid aortic valve. Front Cardiovasc Med 2023; 10:1127685. [PMID: 37057097 PMCID: PMC10086356 DOI: 10.3389/fcvm.2023.1127685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/14/2023] [Indexed: 03/30/2023] Open
Abstract
BackgroundBicuspid aortic valve (BAV) is associated with ascending aorta aneurysms and dissections. Presently, genetic factors and pathological flow patterns are considered responsible for aneurysm formation in BAV while the exact role of inflammatory processes remains unknown.MethodsIn order to objectify inflammation, we employ a highly sensitive, quantitative immunohistochemistry approach. Whole slides of dissected, dilated and non-dilated ascending aortas from BAV patients were quantitatively analyzed.ResultsDilated aortas show a 4-fold increase of lymphocytes and a 25-fold increase in B lymphocytes in the adventitia compared to non-dilated aortas. Tertiary lymphoid structures with B cell follicles and helper T cell expansion were identified in dilated and dissected aortas. Dilated aortas were associated with an increase in M1-like macrophages in the aorta media, in contrast the number of M2-like macrophages did not change significantly.ConclusionThis study finds unexpected large numbers of immune cells in dilating aortas of BAV patients. These findings raise the question whether immune cells in BAV aortopathy are innocent bystanders or contribute to the deterioration of the aortic wall.
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Affiliation(s)
- Alexander H. J. Staal
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Kimberley R. G. Cortenbach
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Mark A. J. Gorris
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
- Division of Immunotherapy, Oncode Institute, Radboud University Medical Center, Nijmegen, Netherlands
| | - Lieke L. van der Woude
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
- Division of Immunotherapy, Oncode Institute, Radboud University Medical Center, Nijmegen, Netherlands
- Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Mangala Srinivas
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
- Cell Biology and Immunology, Wageningen University and Research, Wageningen, Netherlands
| | - Robin H. Heijmen
- Department of Cardiothoracic Surgery, Radboud University Medical Center, Nijmegen, Netherlands
| | | | - Nimrat Grewal
- Department of Cardiothoracic Surgery, Leiden University Medical Center, Leiden, Netherlands
| | - Konnie M. Hebeda
- Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
| | - I. Jolanda M. de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Marco C. DeRuiter
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, Netherlands
| | - Roland R. J. van Kimmenade
- Department of Cardiology, Radboud University Medical Center, Nijmegen, Netherlands
- *Correspondence: Roland R. J. van Kimmenade,
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Senders ML, Calcagno C, Tawakol A, Nahrendorf M, Mulder WJM, Fayad ZA. PET/MR imaging of inflammation in atherosclerosis. Nat Biomed Eng 2023; 7:202-220. [PMID: 36522465 DOI: 10.1038/s41551-022-00970-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 10/25/2022] [Indexed: 12/23/2022]
Abstract
Myocardial infarction, stroke, mental disorders, neurodegenerative processes, autoimmune diseases, cancer and the human immunodeficiency virus impact the haematopoietic system, which through immunity and inflammation may aggravate pre-existing atherosclerosis. The interplay between the haematopoietic system and its modulation of atherosclerosis has been studied by imaging the cardiovascular system and the activation of haematopoietic organs via scanners integrating positron emission tomography and resonance imaging (PET/MRI). In this Perspective, we review the applicability of integrated whole-body PET/MRI for the study of immune-mediated phenomena associated with haematopoietic activity and cardiovascular disease, and discuss the translational opportunities and challenges of the technology.
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Affiliation(s)
- Max L Senders
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Claudia Calcagno
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ahmed Tawakol
- Cardiology Division and Cardiovascular Imaging Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Matthias Nahrendorf
- Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Willem J M Mulder
- Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
- Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
- Laboratory of Chemical Biology, Department of Biochemical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
| | - Zahi A Fayad
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Association of elevated neutrophil-to-lymphocyte ratio with increased intracranial aneurysm stability scores and aneurysm growth. J Stroke Cerebrovasc Dis 2023; 32:107052. [PMID: 36780759 DOI: 10.1016/j.jstrokecerebrovasdis.2023.107052] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 02/01/2023] [Accepted: 02/03/2023] [Indexed: 02/13/2023] Open
Abstract
BACKGROUND AND PURPOSE Inflammation involves in the progression of intracranial aneurysms (IAs). However, whether the neutrophil-to-lymphocyte ratio (NLR) as an inflammatory marker links to IAs stability is unidentified. This study was performed to assess the association of the NLR with IAs stability. METHODS We retrospectively reviewed the medical records of patients diagnosed with unruptured IAs from January 2014 to June 2018. According to the quartiles of the NLR, patients with unruptured IAs were categorized into four groups. We evaluated the association between the NLR and IAs stability scores and IAs growth. Multiple logistic regression models were used in the analysis. RESULTS A significant dose-response association was found between the NLR with IAs stability scores and IAs growth. After adjustment for potential confounders, an elevated NLR (fourth quartile) was associated with increased PHASES score (>5) (adjusted odds ratio [OR], 2.007; 95% confidence interval [CI], 1.361-2.960; p<0.001 [p for trend <0.001]), increased ELAPSS score (>15) (adjusted OR, 1.581; 95% CI, 1.074-2.328; p=0.020 [p for trend =0.001]), increased JAPAN 3-year rupture risk score (>5) (adjusted OR, 1.512; 95% CI, 1.033-2.215; p=0.034 [p for trend <0.001]), and IAs growth (adjusted OR, 16.759; 95% CI, 3.022-92.928; p=0.001 [p for trend <0.001]). CONCLUSION An elevated NLR was associated with increased IAs stability scores and IAs growth. The association between NLR and IAs stability need further investigate.
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Sato Y, Tamura M, Yanagita M. Tertiary lymphoid tissues: a regional hub for kidney inflammation. Nephrol Dial Transplant 2023; 38:26-33. [PMID: 34245300 DOI: 10.1093/ndt/gfab212] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Indexed: 01/26/2023] Open
Abstract
Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues that develop at sites of chronic inflammation in nonlymphoid organs. As with lymph nodes, TLTs initiate adaptive immune responses and coordinate local tissue immunity. Although virtually ignored for decades, TLTs have recently received a great deal of attention for their ability to influence disease severity, prognosis and response to therapy in various diseases, including cancer, autoimmune disorders and infections. TLTs are also induced in kidneys of patients with chronic kidney diseases such as immunoglobulin A nephropathy and lupus nephritis. Nevertheless, TLTs in the kidney have not been extensively investigated and their mechanism of development, functions and clinical relevance remain unknown, mainly because of the absence of adequate murine kidney TLT models and limited availability of human kidney samples containing TLTs. We recently found that aged kidneys, but not young kidneys, exhibit multiple TLTs after injury. Interestingly, although they are a minor component of TLTs, resident fibroblasts in the kidneys diversify into several distinct phenotypes that play crucial roles in TLT formation. Furthermore, the potential of TLTs as a novel kidney injury/inflammation marker as well as a novel therapeutic target for kidney diseases is also suggested. In this review article we describe the current understanding of TLTs with a focus on age-dependent TLTs in the kidney and discuss their potential as a novel therapeutic target and kidney inflammation marker.
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Affiliation(s)
- Yuki Sato
- Medical Innovation Center, TMK Project, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masaru Tamura
- Technology and Development Team for Mouse Phenotype Analysis, Japan Mouse Clinic, RIKEN BioResource Research Center (BRC), Tsukuba, Japan
| | - Motoko Yanagita
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
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38
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Meng Q, Liu H, Liu J, Pang Y, Liu Q. Advances in immunotherapy modalities for atherosclerosis. Front Pharmacol 2023; 13:1079185. [PMID: 36703734 PMCID: PMC9871313 DOI: 10.3389/fphar.2022.1079185] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/22/2022] [Indexed: 01/12/2023] Open
Abstract
Cardiovascular disease (CVD) is one of the leading causes of death worldwide. Atherosclerosis is the pathological basis of atherosclerotic cardiovascular disease (ASCVD). Atherosclerosis is now understood to be a long-term immune-mediated inflammatory condition brought on by a complicated chain of factors, including endothelial dysfunction, lipid deposits in the artery wall, and monocyte-derived macrophage infiltration, in which both innate immunity and adaptive immunity play an indispensable role. Recent studies have shown that atherosclerosis can be alleviated by inducing a protective immune response through certain auto-antigens or exogenous antigens. Some clinical trials have also demonstrated that atherosclerotic is associated with the presence of immune cells and immune factors in the body. Therefore, immunotherapy is expected to be a new preventive and curative measure for atherosclerosis. In this review, we provide a summary overview of recent progress in the research of immune mechanisms of atherosclerosis and targeted therapeutic pathways.
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Affiliation(s)
- Qingwen Meng
- Department of Pharmacy, The First Affiliated Hospital of Hainan Medical University, Haikou, China,Deparment of Cardiovascular, The First Affiliated Hospital of Hainan Medical University, Haikou, China,Hainan Provincial Key Laboratory of Tropical Brain Research and Transformation, Hainan Medical University, Haikou, China
| | - Huajiang Liu
- Deparment of Cardiovascular, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Jinteng Liu
- School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Yangyang Pang
- School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Qibing Liu
- Department of Pharmacy, The First Affiliated Hospital of Hainan Medical University, Haikou, China,School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China,*Correspondence: Qibing Liu,
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Zhao Y, Zhang L, Liu L, Zhou X, Ding F, Yang Y, Du S, Wang H, Van Eck M, Wang J. Specific Loss of ABCA1 (ATP-Binding Cassette Transporter A1) Suppresses TCR (T-Cell Receptor) Signaling and Provides Protection Against Atherosclerosis. Arterioscler Thromb Vasc Biol 2022; 42:e311-e326. [PMID: 36252122 DOI: 10.1161/atvbaha.122.318226] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND ABCA1 (ATP-binding cassette transporter A1) mediates cholesterol efflux to apo AI to maintain cellular cholesterol homeostasis. The current study aims to investigate whether T-cell-specific deletion of ABCA1 modulates the phenotype/function of T cells and the development of atherosclerosis. METHODS Mice with T-cell-specific deletion of ABCA1 on low-density lipoprotein receptor knockout (Ldlr-/-) background (Abca1CD4-/CD4-Ldlr-/-) were generated by multiple steps of (cross)-breedings among Abca1flox/flox, CD4-Cre, and Ldlr-/- mice. RESULTS Deletions of ABCA1 greatly suppressed cholesterol efflux to apo AI but slightly reduced membrane lipid rafts on T cells probably due to the upregulation of ABCG1. Moreover, ABCA1 deficiency impaired TCR (T-cell receptor) signaling and inhibited the survival and proliferation of T cells as well as the formation of effector memory T cells. Despite the comparable levels of plasma total cholesterol after Western-type diet feeding, Abca1CD4-/CD4-Ldlr-/- mice showed significantly attenuated arterial accumulations of T cells and smaller atherosclerotic lesions than Abca1+/+Ldlr-/-controls, which were associated with reduced surface CCR5 (CC motif chemokine receptor 5) and CXCR3 (CXC motif chemokine receptor 3), decreased antiapoptotic Bcl-2 (B-cell lymphoma 2) and Bcl-xL (B-cell lymphoma extra-large), and hampered abilities to produce IL (interleukin)-2 and IFN (interferon)-γ by ABCA1-deficient T cells. CONCLUSIONS ABCA1 is essential for T-cell cholesterol homeostasis. Deletion of ABCA1 in T cells impairs TCR signaling, suppresses the survival, proliferation, differentiation, and function of T cells, thereby providing atheroprotection in vivo.
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Affiliation(s)
- Ying Zhao
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Lili Zhang
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Limin Liu
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Xuan Zhou
- Department of Immunology (X.Z.), Soochow Medical College of Soochow University, Suzhou, China
| | - Fangfang Ding
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Yan Yang
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Shiyu Du
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Hongmin Wang
- School of Biology & Basic Medical Sciences, and Institutes of Biology & Medical Sciences (H.W., J.W.), Soochow Medical College of Soochow University, Suzhou, China
| | - Miranda Van Eck
- Division of BioTherapeutics (M.V.E.), Leiden Academic Centre for Drug Research, Leiden University, the Netherlands.,Division of Systems Pharmacology and Pharmacy (M.V.E.), Leiden Academic Centre for Drug Research, Leiden University, the Netherlands.,Pharmacy Leiden, the Netherlands (M.V.E.)
| | - Jun Wang
- School of Biology & Basic Medical Sciences, and Institutes of Biology & Medical Sciences (H.W., J.W.), Soochow Medical College of Soochow University, Suzhou, China
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40
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Miceli G, Basso MG, Rizzo G, Pintus C, Tuttolomondo A. The Role of the Coagulation System in Peripheral Arterial Disease: Interactions with the Arterial Wall and Its Vascular Microenvironment and Implications for Rational Therapies. Int J Mol Sci 2022; 23:14914. [PMID: 36499242 PMCID: PMC9739112 DOI: 10.3390/ijms232314914] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/19/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022] Open
Abstract
Peripheral artery disease (PAD) is a clinical manifestation of atherosclerotic disease with a large-scale impact on the economy and global health. Despite the role played by platelets in the process of atherogenesis being well recognized, evidence has been increasing on the contribution of the coagulation system to the atherosclerosis formation and PAD development, with important repercussions for the therapeutic approach. Histopathological analysis and some clinical studies conducted on atherosclerotic plaques testify to the existence of different types of plaques. Likely, the role of coagulation in each specific type of plaque can be an important determinant in the histopathological composition of atherosclerosis and in its future stability. In this review, we analyze the molecular contribution of inflammation and the coagulation system on PAD pathogenesis, focusing on molecular similarities and differences between atherogenesis in PAD and coronary artery disease (CAD) and discussing the possible implications for current therapeutic strategies and future perspectives accounting for molecular inflammatory and coagulation targets. Understanding the role of cross-talking between coagulation and inflammation in atherosclerosis genesis and progression could help in choosing the right patients for future dual pathway inhibition strategies, where an antiplatelet agent is combined with an anticoagulant, whose role, despite pathophysiological premises and trials' results, is still under debate.
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Affiliation(s)
- Giuseppe Miceli
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Maria Grazia Basso
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Giuliana Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Chiara Pintus
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital Policlinico “P. Giaccone”, 90100 Palermo, Italy
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Monsour M, Gordon J, Lockard G, Alayli A, Elsayed B, Connolly J, Borlongan CV. Minor Changes for a Major Impact: A Review of Epigenetic Modifications in Cell-Based Therapies for Stroke. Int J Mol Sci 2022; 23:13106. [PMID: 36361891 PMCID: PMC9656972 DOI: 10.3390/ijms232113106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 08/16/2024] Open
Abstract
Epigenetic changes in stroke may revolutionize cell-based therapies aimed at reducing ischemic stroke risk and damage. Epigenetic changes are a novel therapeutic target due to their specificity and potential for reversal. Possible targets for epigenetic modification include DNA methylation and demethylation, post-translational histone modification, and the actions of non-coding RNAs such as microRNAs. Many of these epigenetic modifications have been reported to modulate atherosclerosis development and progression, ultimately contributing to stroke pathogenesis. Furthermore, epigenetics may play a major role in inflammatory responses following stroke. Stem cells for stroke have demonstrated safety in clinical trials for stroke and show therapeutic benefit in pre-clinical studies. The efficacy of these cell-based interventions may be amplified with adjunctive epigenetic modifications. This review advances the role of epigenetics in atherosclerosis and inflammation in the context of stroke, followed by a discussion on current stem cell studies modulating epigenetics to ameliorate stroke damage.
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Affiliation(s)
- Molly Monsour
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Jonah Gordon
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Gavin Lockard
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Adam Alayli
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Bassel Elsayed
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Jacob Connolly
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Cesar V. Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
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Wei N, Xu Y, Li Y, Shi J, Zhang X, You Y, Sun Q, Zhai H, Hu Y. A bibliometric analysis of T cell and atherosclerosis. Front Immunol 2022; 13:948314. [PMID: 36311729 PMCID: PMC9606647 DOI: 10.3389/fimmu.2022.948314] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 09/30/2022] [Indexed: 08/29/2023] Open
Abstract
Atherosclerosis (AS) is widespread and develops into circulatory system problems. T cells play an essential regulatory role in AS occurrence and development. So far, there is no bibliometric research on T cells and AS. To learn more about T cell and AS development, 4,381 records were retrieved from Web of Science™ Core Collection. Then, these records were scientometrically analyzed using CiteSpace and VOSviewer in terms of spatiotemporal distribution, author distribution, subject categories, topic distribution, references, and keywords. Our analysis provides basic information on research in the field, demonstrates that the field has stabilized over the past decade, and identifies potential partners for interested researchers. Current research hotspots in this field mainly include the inflammatory mechanism, immune mechanism, related diseases, and related cytokines of AS. B cell, mortality, inhibition, and monocyte represent the frontiers of research in this field, undergoing an explosive phase. We hope that this work will provide new ideas for advancing the scientific research and clinical application of T cell and AS.
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Affiliation(s)
- Namin Wei
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yan Xu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Ya’nan Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jingjing Shi
- Department of Cardiovascular Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuesong Zhang
- Department of Cardiovascular Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yaping You
- Department of Cardiovascular Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qianqian Sun
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Huaqiang Zhai
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yuanhui Hu
- Department of Cardiovascular Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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43
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Zhu G, Lai Y, Chen F, Qian J, Lin H, Yuan D, Yao T, Liu X. Exploration of the Crucial Genes and Molecular Mechanisms Mediating Atherosclerosis and Abnormal Endothelial Shear Stress. DISEASE MARKERS 2022; 2022:6306845. [PMID: 35990248 PMCID: PMC9391161 DOI: 10.1155/2022/6306845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 07/12/2022] [Accepted: 07/18/2022] [Indexed: 11/29/2022]
Abstract
Background Abnormal endothelial shear stress (ESS) is a significant risk factor for atherosclerosis (AS); however, the genes and pathways between ESS and AS are poorly understood. Here, we screened hub genes and potential regulatory targets linked to the progression of AS induced by abnormal ESS. Methods The microarray data of ESS and AS were downloaded from the Gene Expression Omnibus (GEO) database. The coexpression modules related to shear stress and AS were identified with weighted gene coexpression network analysis (WGCNA). Coexpression genes in modules obtained from GSE28829 and GSE160611 were considered as SET1. The results were validated in validation set by differential gene analysis. The limma package in R was used to identify differentially expressed genes (DEGs). The common DEGs of GSE100927 and GSE103672 were regarded as SET2. Next, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was conducted. Protein-protein interaction (PPI) enrichment analysis was assembled, and hub genes were identified using MCODE and ClueGO in Cytoscape. ROC curve analyses were conducted to assess the ability of common hub genes to distinguish samples of atherosclerotic plaque from normal arterial. The expression of common hub gene was verified in ox-LDL-induced foam cells and GSE41571. Results We identified three gene modules (the blue, tan, and cyan modules) related to AS and three shear stress-related modules (the brown, red, and pink modules). A total of 129 genes in SET1 and 476 genes in SET2 were identified. CCRL2, LGALS9, and PLCB2 were identified as common hub genes and validated in the GSE100927, GSE28829, and GSE41571. ROC analysis indicates the expression of CCRL2, LGALS9, and PLCB2 could effectively distinguish the atherosclerotic plaque and normal arterial. The expression level of CCRL2, LGALS9, and PLCB2 increases with the accumulation of lipid increased. Conclusion We identified CCRL2, LGALS9, and PLCB2 as key genes associated with abnormal ESS and AS and may provide potential prevention and treatment target of AS induced by abnormal ESS.
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Affiliation(s)
- Guoqi Zhu
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yan Lai
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Fei Chen
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jun Qian
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hao Lin
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Deqiang Yuan
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tongqing Yao
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - XueBo Liu
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
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Bellini R, Bonacina F, Norata GD. Crosstalk between dendritic cells and T lymphocytes during atherogenesis: Focus on antigen presentation and break of tolerance. Front Cardiovasc Med 2022; 9:934314. [PMID: 35966516 PMCID: PMC9365967 DOI: 10.3389/fcvm.2022.934314] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/05/2022] [Indexed: 12/14/2022] Open
Abstract
Atherosclerosis is a chronic disease resulting from an impaired lipid and immune homeostasis, where the interaction between innate and adaptive immune cells leads to the promotion of atherosclerosis-associated immune-inflammatory response. Emerging evidence has suggested that this response presents similarities to the reactivity of effector immune cells toward self-epitopes, often as a consequence of a break of tolerance. In this context, dendritic cells, a heterogeneous population of antigen presenting cells, play a key role in instructing effector T cells to react against foreign antigens and T regulatory cells to maintain tolerance against self-antigens and/or to patrol for self-reactive effector T cells. Alterations in this delicate balance appears to contribute to atherogenesis. The aim of this review is to discuss different DC subsets, and their role in atherosclerosis as well as in T cell polarization. Moreover, we will discuss how loss of T cell tolerogenic phenotype participates to the immune-inflammatory response associated to atherosclerosis and how a better understanding of these mechanisms might result in designing immunomodulatory therapies targeting DC-T cell crosstalk for the treatment of atherosclerosis-related inflammation.
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Affiliation(s)
- Rossella Bellini
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Fabrizia Bonacina
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
- *Correspondence: Fabrizia Bonacina,
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
- Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy
- Giuseppe Danilo Norata,
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Wilhelmson AS, Johansson I, Fogelstrand L, Fagman JB, Arnal JF, Karlsson MCI, Tivesten Å. Deficiency of mature B cells does not alter the atherogenic response to castration in male mice. Sci Rep 2022; 12:12931. [PMID: 35902665 PMCID: PMC9334632 DOI: 10.1038/s41598-022-16846-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 07/18/2022] [Indexed: 11/09/2022] Open
Abstract
Testosterone deficiency in men is associated with increased atherosclerosis burden and increased cardiovascular risk. In male mice, testosterone deficiency induced by castration increases atherosclerosis as well as mature B cell numbers in spleen. As B cells are potentially pro-atherogenic, we hypothesized that there may be a link between these effects. To address whether mature B cell deficiency alter the atherogenic response to castration, we studied B cell-deficient μMT and genotype control male mice on an atherosclerosis-prone Apoe-/- background that were castrated or sham-operated pre-pubertally and fed a high-fat diet between 8 and 16 weeks of age to accelerate atherosclerosis development. Genotype did not affect the effects of castration on body weight or weights of fat depots and there were no differences in serum cholesterol levels across the four groups. Atherosclerosis assessed by quantification of lesion area in serial sections of the aortic root was significantly increased by castration and by the μMT mutation, with no significant interaction between genotype and surgery. In conclusion, castration evokes a similar atherogenic response in B cell-deficient μMT and control mice. These data suggest that atherogenesis following castration is unrelated to the effects of androgens on mature B cell numbers.
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Affiliation(s)
- Anna S Wilhelmson
- Wallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. .,The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. .,Biotech Research and Innovation Center (BRIC), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. .,Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Inger Johansson
- Wallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Linda Fogelstrand
- Wallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.,Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Johan Bourghardt Fagman
- Wallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.,Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Jean-Francois Arnal
- I2MC, Inserm U1048, CHU de Toulouse and Université de Toulouse, Toulouse, France
| | - Mikael C I Karlsson
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Åsa Tivesten
- Wallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
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Zhou Y, Wang S, Liang X, Heger Z, Xu M, Lu Q, Yu M, Adam V, Li N. Turning Hot into Cold: Immune Microenvironment Reshaping for Atherosclerosis Attenuation Based on pH-Responsive shSiglec-1 Delivery System. ACS NANO 2022; 16:10517-10533. [PMID: 35762565 DOI: 10.1021/acsnano.2c01778] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Current atherosclerosis treatment is based on a combination of cholesterol-lowering medication and low-fat diets; however, the clinical effect is unsatisfactory. It has been shown that the level of immune cell infiltration and pro-inflammatory factors in the atherosclerotic immune microenvironment (AIM) play important roles in the development and progression of atherosclerosis. Therefore, we hypothesized that reshaping "hot AIM" into "cold AIM" could attenuate atherosclerosis. For this purpose, we designed a pH-responsive and charge-reversible nanosystem, referred to as Au-PEI/shSiglec-1/PEI-acetylsalicylic acid (ASPA NPs) to effectively deliver shSiglec-1, which blocked the interactions between macrophages with CD8+ T/NKT cells, thus inhibiting immune cell infiltration. Further, we demonstrated that acetylsalicylic acid (ASA), detached from the pH-responsive PEI-ASA polymer, and inhibited lipid accumulation in macrophage, thereby decreasing the lipid antigen presentation. Additionally, reduced macrophage-produced inflammatory factors by ASA and low CD8+ T/NKT cell infiltration levels synergistically inhibit Th17 cell differentiation, thus further dramatically attenuating inflammation in AIM by decreasing the IL-17A production. Eventually, ASPA NPs efficiently reshaped AIM by inhibiting immune cell infiltration, lipid antigen presentation, and pro-inflammation, which provided a feasible therapeutic strategy for atherosclerosis immunotherapy.
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Affiliation(s)
- Yue Zhou
- Tianjin Key Laboratory of Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Siyu Wang
- Tianjin Key Laboratory of Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Xiaoyang Liang
- Tianjin Key Laboratory of Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Zbynek Heger
- Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-61300 Brno, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Purkynova 123, CZ-61200 Brno, Czech Republic
| | - Min Xu
- Tianjin Key Laboratory of Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Qiang Lu
- Tianjin Key Laboratory of Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Meng Yu
- School of Pharmaceutical Science Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China
| | - Vojtech Adam
- Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-61300 Brno, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Purkynova 123, CZ-61200 Brno, Czech Republic
| | - Nan Li
- Tianjin Key Laboratory of Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
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Stahr N, Galkina EV. Immune Response at the Crossroads of Atherosclerosis and Alzheimer's Disease. Front Cardiovasc Med 2022; 9:870144. [PMID: 35872901 PMCID: PMC9298512 DOI: 10.3389/fcvm.2022.870144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 06/02/2022] [Indexed: 11/30/2022] Open
Abstract
Alzheimer's disease (AD) and cardiovascular disease (CVD) are pathologies that are characterized by common signatures of vascular dysfunction and chronic inflammation that are accelerated with aging. Importantly, epidemiological studies report an independent interaction between AD and CVD and data suggest that chronic inflammation in CVD may accelerate AD development. Atherosclerosis affects most large to medium sized arteries including those supplying the cerebral circulation. Vascular dysfunction caused by atherosclerosis results in blood brain barrier breakdown, inflammation, an impaired clearance of amyloid-beta (Aβ), and finally ends with neurovascular dysfunction. Numerous data indicate that innate and adaptive immune responses shape atherogenesis and increasing evidence suggests an implication of the immune response in AD progression. Currently, mechanisms by which these two diseases are interconnected with each other are not well-defined. In this review, we discuss the recent advances in our understanding of the intertwined role of the immune response in atherosclerosis and AD and the implications of these findings for human health.
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Tatlisu MA, Atici A, Ozcan FB, Çelik M, Kirac E, Baycan OF, Caliskan M. A Associação de TWEAK com Calcificação da Artéria Coronária em Pacientes com Doença Renal Crônica. Arq Bras Cardiol 2022; 119:436-445. [PMID: 35703664 PMCID: PMC9438529 DOI: 10.36660/abc.20210599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 03/09/2022] [Indexed: 11/29/2022] Open
Abstract
Fundamento O receptor fraco indutor de apoptose semelhante a fator de necrose tumoral solúvel (sTWEAK) é um membro da superfamília de TNF que tem um papel crítico na proliferação e inflamação na circulação arterial. Objetivos Este estudo prospectivo tem o objetivo de mostrar a relação entre os níveis de sTWEAK e calcificação da artéria coronária (CAC) em pacientes com doença renal crônica (DRC). Métodos Este estudo prospectivo incluiu 139 pacientes consecutivos que passaram por angiografia coronariana por tomografia computadorizada, por qualquer motivo, para síndromes coronarianas agudas, de agosto de 2020 a fevereiro de 2021. Um total de 12 pacientes foi excluído do estudo devido aos critérios de exclusão. Os pacientes foram divididos em dois grupos com base em terem um escore CAC menor que 400 (n=84) ou um escore de 400 ou mais (n=43). A significância foi presumida em p-valor bilateral <0,05. Resultados À medida que o escore CAC aumentou, os níveis de sTWEAK diminuíram de forma estatisticamente significativa e detectou-se uma relação forte entre níveis de sTWEAK e escore CAC (r: -0,779, p<0,001). A análise ROC revelou que o nível de corte ideal de sTWEAK para prever o escore CAC de 400 era 761 pg/mL com uma sensibilidade de 71% e especificidade de 73% (AUC: 0,78; IC 95%: 0,70-0,85; p <0,001). Conclusões Embora os estudos em larga escala tenham demonstrado uma correlação positiva entre os níveis de TFGe e sTWEAK, alguns estudos detectaram que o aumento nos níveis de sTWEAK estão associados a mortalidade e gravidade do sistema da artéria coronária em pacientes com DRC. Nossos resultados comprovam nossa hipótese de que os níveis de sTWEAK mostram calcificação coronária em vez de outros tipos de placas ateroscleróticas.
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Chyu KY, Zhao X, Zhou J, Dimayuga PC, Lio NW, Cercek B, Trac NT, Chung EJ, Shah PK. Immunization using ApoB-100 peptide-linked nanoparticles reduces atherosclerosis. JCI Insight 2022; 7:149741. [PMID: 35536648 PMCID: PMC9220835 DOI: 10.1172/jci.insight.149741] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 04/26/2022] [Indexed: 11/30/2022] Open
Abstract
Active immunization with the apolipoprotein B-100 (ApoB-100) peptide P210 reduces experimental atherosclerosis. To advance this immunization strategy to future clinical testing, we explored the possibility of delivering P210 as an antigen using nanoparticles, given this approach has been used clinically. We first characterized the responses of T cells to P210 using PBMCs from patients with atherosclerotic cardiovascular disease (ASCVD). We then investigated the use of P210 in self-assembling peptide amphiphile micelles (P210-PAMs) as a vaccine formulation to reduce atherosclerosis in B6.129P2-Apoetm1Unc/J (ApoE–/–) mice and P210’s potential mechanisms of action. We also generated and characterized a humanized mouse model with chimeric HLA-A*02:01/Kb in ApoE–/– background to test the efficacy of P210-PAM immunization as a bridge to future clinical testing. P210 provoked T cell activation and memory response in PBMCs of patients with ASCVD. Dendritic cell uptake of P210-PAM and its costaining with MHC-I molecules supported its use as a vaccine formulation. In ApoE–/– mice, immunization with P210-PAMs dampened P210-specific CD4+ T cell proliferative response and CD8+ T cell cytolytic response, modulated macrophage phenotype, and significantly reduced aortic atherosclerosis. Potential clinical relevance of P210-PAM immunization was demonstrated by reduced atherosclerosis in the humanized ApoE–/– mouse model. Our data support experimental and translational use of P210-PAM as a potential vaccine candidate against human ASCVD.
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Affiliation(s)
- Kuang-Yuh Chyu
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Heart Institute, Los Angeles, United States of America
| | - Xiaoning Zhao
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Heart Institute, Los Angeles, United States of America
| | - Jianchang Zhou
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Heart Institute, Los Angeles, United States of America
| | - Paul C Dimayuga
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Heart Institute, Los Angeles, United States of America
| | - Nicole Wm Lio
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Heart Institute, Los Angeles, United States of America
| | - Bojan Cercek
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Heart Institute, Los Angeles, United States of America
| | - Noah T Trac
- Department of Biomedical Engineering, University of Southern California, Los Angeles, United States of America
| | - Eun Ji Chung
- Department of Biomedical Engineering, University of Southern California, Los Angeles, United States of America
| | - Prediman K Shah
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Heart Institute, Los Angeles, United States of America
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Yin Y, Xie Z, Chen D, Guo H, Han M, Zhu Z, Bi J. Integrated investigation of DNA methylation, gene expression and immune cell population revealed immune cell infiltration associated with atherosclerotic plaque formation. BMC Med Genomics 2022; 15:108. [PMID: 35534881 PMCID: PMC9082837 DOI: 10.1186/s12920-022-01259-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 05/03/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND The clinical consequences of atherosclerosis are significant source of morbidity and mortality throughout the world, while the molecular mechanisms of the pathogenesis of atherosclerosis are largely unknown. METHODS In this study, we integrated the DNA methylation and gene expression data in atherosclerotic plaque samples to decipher the underlying association between epigenetic and transcriptional regulation. Immune cell classification was performed on the basis of the expression pattern of detected genes. Finally, we selected ten genes with dysregulated methylation and expression levels for RT-qPCR validation. RESULTS Global DNA methylation profile showed obvious changes between normal aortic and atherosclerotic lesion tissues. We found that differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were highly associated with atherosclerosis by being enriched in atherosclerotic plaque formation-related pathways, including cell adhesion and extracellular matrix organization. Immune cell fraction analysis revealed that a large number of immune cells, especially macrophages, activated mast cells, NK cells, and Tfh cells, were specifically enriched in the plaque. DEGs associated with immune cell fraction change showed that they were mainly related to the level of macrophages, monocytes, resting NK cells, activated CD4 memory T cells, and gamma delta T cells. These genes were highly enriched in multiple pathways of atherosclerotic plaque formation, including blood vessel remodeling, collagen fiber organization, cell adhesion, collagen catalogic process, extractable matrix assembly, and platelet activation. We also validated the expression alteration of ten genes associated with infiltrating immune cells in atherosclerosis. CONCLUSIONS In conclusion, these findings provide new evidence for understanding the mechanisms of atherosclerotic plaque formation, and provide a new and valuable research direction based on immune cell infiltration.
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Affiliation(s)
- Yihong Yin
- Department of Neural Medicine, The Second Hospital of Shandong University, Shandong University, No. 247 Beiyuan Street, Jinan, 250033, China
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, China
| | - Zhaohong Xie
- Department of Neural Medicine, The Second Hospital of Shandong University, Shandong University, No. 247 Beiyuan Street, Jinan, 250033, China
| | - Dong Chen
- Center for Genome Analysis, Wuhan Ruixing Biotechnology Co. Ltd, Wuhan, 430075, China
| | - Hao Guo
- Center for Genome Analysis, Wuhan Ruixing Biotechnology Co. Ltd, Wuhan, 430075, China
| | - Min Han
- Department of Neural Medicine, The Second Hospital of Shandong University, Shandong University, No. 247 Beiyuan Street, Jinan, 250033, China
| | - Zhengyu Zhu
- Department of Neural Medicine, The Second Hospital of Shandong University, Shandong University, No. 247 Beiyuan Street, Jinan, 250033, China.
| | - Jianzhong Bi
- Department of Neural Medicine, The Second Hospital of Shandong University, Shandong University, No. 247 Beiyuan Street, Jinan, 250033, China.
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