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1
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Wang H, Tang R, Pan Q, Yin Q, Feng J, Deng L. Mitochondria dysfunction: A trigger for cardiovascular diseases in systemic lupus erythematosus. Int Immunopharmacol 2025; 144:113722. [PMID: 39622131 DOI: 10.1016/j.intimp.2024.113722] [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: 09/20/2024] [Revised: 11/09/2024] [Accepted: 11/25/2024] [Indexed: 12/15/2024]
Abstract
Cardiovascular disease (CVD), including pericarditis, myocarditis, sudden cardiac death, coronary heart disease, and stroke, are leading contributors to morbidity and mortality in systemic lupus erythematosus (SLE) patients. Emerging evidence highlights mitochondrial dysfunction as a key driver of cardiovascular pathology in SLE, with impaired oxidative phosphorylation, altered membrane potential, and disrupted metabolic processes promoting oxidative stress, inflammatory activation, and endothelial dysfunction. This review critically examines mitochondrial contributions to CVD in SLE, comparing these mechanisms with those in non-SLE CVD to highlight SLE-specific mitochondrial vulnerabilities. Furthermore, we discuss preclinical and clinical findings supporting mitochondrial pathways as potential therapeutic targets, aiming to bridge gaps in current understanding and outline future research directions. By synthesizing current knowledge of mitochondrial dysregulation, this review proposes therapeutic strategies to improve cardiovascular outcomes and advance patient care in SLE.
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Affiliation(s)
- Haitao Wang
- The School of Clinical Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| | - Rui Tang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| | - Qinyu Pan
- The School of Clinical Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| | - Qiuyan Yin
- The School of Clinical Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
| | - Li Deng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China; Department of Rheumatology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
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2
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Kwak H, Lee E, Karki R. DNA sensors in metabolic and cardiovascular diseases: Molecular mechanisms and therapeutic prospects. Immunol Rev 2025; 329:e13382. [PMID: 39158380 PMCID: PMC11744256 DOI: 10.1111/imr.13382] [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] [Indexed: 08/20/2024]
Abstract
DNA sensors generally initiate innate immune responses through the production of type I interferons. While extensively studied for host defense against invading pathogens, emerging evidence highlights the involvement of DNA sensors in metabolic and cardiovascular diseases. Elevated levels of modified, damaged, or ectopically localized self-DNA and non-self-DNA have been observed in patients and animal models with obesity, diabetes, fatty liver disease, and cardiovascular disease. The accumulation of cytosolic DNA aberrantly activates DNA signaling pathways, driving the pathological progression of these disorders. This review highlights the roles of specific DNA sensors, such as cyclic AMP-GMP synthase and stimulator of interferon genes (cGAS-STING), absent in melanoma 2 (AIM2), toll-like receptor 9 (TLR9), interferon gamma-inducible protein 16 (IFI16), DNA-dependent protein kinase (DNA-PK), and DEAD-box helicase 41 (DDX41) in various metabolic disorders. We explore how DNA signaling pathways in both immune and non-immune cells contribute to the development of these diseases. Furthermore, we discuss the intricate interplay between metabolic stress and immune responses, offering insights into potential therapeutic targets for managing metabolic and cardiovascular disorders. Understanding the mechanisms of DNA sensor signaling in these contexts provides a foundation for developing novel interventions aimed at mitigating the impact of these pervasive health issues.
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Affiliation(s)
- Hyosang Kwak
- Department of Biological Sciences, College of Natural ScienceSeoul National UniversitySeoulSouth Korea
| | - Ein Lee
- Department of Biomedical Sciences, College of MedicineSeoul National UniversitySeoulSouth Korea
| | - Rajendra Karki
- Department of Biological Sciences, College of Natural ScienceSeoul National UniversitySeoulSouth Korea
- Nexus Institute of Research and Innovation (NIRI)KathmanduNepal
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3
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Porsch F, Binder CJ. Autoimmune diseases and atherosclerotic cardiovascular disease. Nat Rev Cardiol 2024; 21:780-807. [PMID: 38937626 DOI: 10.1038/s41569-024-01045-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/28/2024] [Indexed: 06/29/2024]
Abstract
Autoimmune diseases are associated with a dramatically increased risk of atherosclerotic cardiovascular disease and its clinical manifestations. The increased risk is consistent with the notion that atherogenesis is modulated by both protective and disease-promoting immune mechanisms. Notably, traditional cardiovascular risk factors such as dyslipidaemia and hypertension alone do not explain the increased risk of cardiovascular disease associated with autoimmune diseases. Several mechanisms have been implicated in mediating the autoimmunity-associated cardiovascular risk, either directly or by modulating the effect of other risk factors in a complex interplay. Aberrant leukocyte function and pro-inflammatory cytokines are central to both disease entities, resulting in vascular dysfunction, impaired resolution of inflammation and promotion of chronic inflammation. Similarly, loss of tolerance to self-antigens and the generation of autoantibodies are key features of autoimmunity but are also implicated in the maladaptive inflammatory response during atherosclerotic cardiovascular disease. Therefore, immunomodulatory therapies are potential efficacious interventions to directly reduce the risk of cardiovascular disease, and biomarkers of autoimmune disease activity could be relevant tools to stratify patients with autoimmunity according to their cardiovascular risk. In this Review, we discuss the pathophysiological aspects of the increased cardiovascular risk associated with autoimmunity and highlight the many open questions that need to be answered to develop novel therapies that specifically address this unmet clinical need.
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Affiliation(s)
- Florentina Porsch
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Christoph J Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
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4
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Buch MH, Mallat Z, Dweck MR, Tarkin JM, O'Regan DP, Ferreira V, Youngstein T, Plein S. Current understanding and management of cardiovascular involvement in rheumatic immune-mediated inflammatory diseases. Nat Rev Rheumatol 2024; 20:614-634. [PMID: 39232242 DOI: 10.1038/s41584-024-01149-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2024] [Indexed: 09/06/2024]
Abstract
Immune-mediated inflammatory diseases (IMIDs) are a spectrum of disorders of overlapping immunopathogenesis, with a prevalence of up to 10% in Western populations and increasing incidence in developing countries. Although targeted treatments have revolutionized the management of rheumatic IMIDs, cardiovascular involvement confers an increased risk of mortality and remains clinically under-recognized. Cardiovascular pathology is diverse across rheumatic IMIDs, ranging from premature atherosclerotic cardiovascular disease (ASCVD) to inflammatory cardiomyopathy, which comprises myocardial microvascular dysfunction, vasculitis, myocarditis and pericarditis, and heart failure. Epidemiological and clinical data imply that rheumatic IMIDs and associated cardiovascular disease share common inflammatory mechanisms. This concept is strengthened by emergent trials that indicate improved cardiovascular outcomes with immune modulators in the general population with ASCVD. However, not all disease-modifying therapies that reduce inflammation in IMIDs such as rheumatoid arthritis demonstrate equally beneficial cardiovascular effects, and the evidence base for treatment of inflammatory cardiomyopathy in patients with rheumatic IMIDs is lacking. Specific diagnostic protocols for the early detection and monitoring of cardiovascular involvement in patients with IMIDs are emerging but are in need of ongoing development. This Review summarizes current concepts on the potentially targetable inflammatory mechanisms of cardiovascular pathology in rheumatic IMIDs and discusses how these concepts can be considered for the diagnosis and management of cardiovascular involvement across rheumatic IMIDs, with an emphasis on the potential of cardiovascular imaging for risk stratification, early detection and prognostication.
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Affiliation(s)
- Maya H Buch
- Centre for Musculoskeletal Research, Division of Musculoskeletal & Dermatological Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK.
- NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
| | - Ziad Mallat
- Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK
| | - Marc R Dweck
- Centre for Cardiovascular Science, Chancellors Building, Little France Crescent, University of Edinburgh, Edinburgh, UK
| | - Jason M Tarkin
- Section of Cardiorespiratory Medicine, Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK
| | - Declan P O'Regan
- MRC Laboratory of Medical Sciences, Imperial College London, London, UK
| | - Vanessa Ferreira
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Taryn Youngstein
- National Heart & Lung Institute, Imperial College London, London, UK
- Department of Rheumatology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Sven Plein
- Biomedical Imaging Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
- School of Biomedical Engineering and Imaging Sciences, Kings College London, London, UK
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5
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Nyárády BB, Dósa E, Kőhidai L, Pállinger É, Gubán R, Szőnyi Á, Kiss LZ, Bagyura Z. Associations between Various Inflammatory Markers and Carotid Findings in a Voluntary Asymptomatic Population Sample. Int J Mol Sci 2024; 25:9656. [PMID: 39273602 PMCID: PMC11394953 DOI: 10.3390/ijms25179656] [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: 07/31/2024] [Revised: 08/28/2024] [Accepted: 09/04/2024] [Indexed: 09/15/2024] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, and atherosclerosis is the key factor promoting its development. Carotid intima-media thickening and the presence of carotid plaques are important indices of cardiovascular risk. In addition, inflammation is a major and complex factor in the development of atherosclerosis. The relationships between carotid atherosclerosis and certain inflammatory markers have rarely been studied in healthy individuals. Therefore, we aimed to investigate the associations between subclinical carotid atherosclerosis and various inflammatory biomarkers in a large Caucasian population free of evident CVD. In addition to recording study participants' demographic characteristics, anthropometric characteristics, and atherosclerotic risk factors, laboratory tests were performed to measure levels of hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein, and inflammatory cytokines/chemokines, including interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, IL-33, interferon (IFN)-α2, IFN-γ, tumor necrosis factor-α, and monocyte chemoattractant protein (MCP)-1. This study included 264 asymptomatic individuals with a median age of 61.7 years (interquartile range, 54.5-67.5 years); 45.7% of participants were male. Participants were divided into two groups according to their carotid status: the normal carotid group, comprising 120 participants; and the pathological carotid group, comprising 144 participants. Compared with the normal carotid group, hypertension and diabetes mellitus were significantly more common and serum levels of HbA1c, IL-8, and MCP-1 were significantly higher in the pathological carotid group. Multivariate regression analysis revealed significant positive associations between pathological carotid findings and serum levels of IL-8 (highest tertile, OR: 2.4, p = 0.030) and MCP-1 (highest tertile, OR: 2.4, p = 0.040). Our results suggest that IL-8 and MCP-1 may serve as early indicators of subclinical atherosclerosis, thereby helping to identify individuals at increased risk of CVD before the onset of clinical symptoms.
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Affiliation(s)
| | - Edit Dósa
- Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary
| | - László Kőhidai
- Department of Genetics, Cell and Immunobiology, Semmelweis University, 1089 Budapest, Hungary
| | - Éva Pállinger
- Department of Genetics, Cell and Immunobiology, Semmelweis University, 1089 Budapest, Hungary
| | - Renáta Gubán
- Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary
| | - Ádám Szőnyi
- Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary
| | - Loretta Zsuzsa Kiss
- Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary
- Institute for Clinical Data Management, Semmelweis University, 1085 Budapest, Hungary
| | - Zsolt Bagyura
- Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary
- Institute for Clinical Data Management, Semmelweis University, 1085 Budapest, Hungary
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6
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Gajagowni S, Hopkins S, Qadeer Y, Virani SS, Verdonschot JAJ, Coombs CC, Amos CI, Nead KT, Jaiswal S, Krittanawong C. Clonal hematopoiesis of indeterminate potential and cardiovascular disease: Pathogenesis, clinical presentation, and future directions. Prog Cardiovasc Dis 2024; 86:79-85. [PMID: 39278303 DOI: 10.1016/j.pcad.2024.09.001] [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: 09/11/2024] [Accepted: 09/11/2024] [Indexed: 09/18/2024]
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is a well-studied phenomenon in hematologic malignancies. With advancements in gene sampling and analysis and the use of large cohort studies, CHIP has recently been linked to cardiovascular disease (CVD). The relationship between CHIP and CVD appears to be bidirectional, with traditional risk factors for cardiovascular disease increasing the mutation burden in CHIP, and CHIP itself effecting the incidence or prognosis of a variety of CVD. The purpose of this review is to understand the epidemiology, risk factors, and pathogenesis of CHIP in the context of various CVD conditions.
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Affiliation(s)
- Saivaroon Gajagowni
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Steven Hopkins
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Yusuf Qadeer
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Salim S Virani
- Office of the Vice Provost (Research), The Aga Khan University, Karachi 74800, Pakistan; Section of Cardiology and Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Job A J Verdonschot
- Department of Cardiology, Maastricht University Medical Centre, Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), University Hospital Maastricht, P. Debyelaan 25, 6229, HX, Maastricht, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202, AZ, Maastricht, the Netherlands
| | - Catherine C Coombs
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, California, United States of America
| | - Christopher I Amos
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States of America
| | - Kevin T Nead
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, United States of America; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America
| | - Siddhartha Jaiswal
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Chayakrit Krittanawong
- Cardiology Division, NYU Langone Health and NYU School of Medicine, New York, NY, United States of America.
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Paul SK, Oshima M, Patil A, Sone M, Kato H, Maezawa Y, Kaneko H, Fukuyo M, Rahmutulla B, Ouchi Y, Tsujimura K, Nakanishi M, Kaneda A, Iwama A, Yokote K, Eto K, Takayama N. Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model. Nat Commun 2024; 15:4772. [PMID: 38858384 PMCID: PMC11164933 DOI: 10.1038/s41467-024-48663-w] [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: 05/07/2022] [Accepted: 05/07/2024] [Indexed: 06/12/2024] Open
Abstract
The underlying mechanisms of atherosclerosis, the second leading cause of death among Werner syndrome (WS) patients, are not fully understood. Here, we establish an in vitro co-culture system using macrophages (iMφs), vascular endothelial cells (iVECs), and vascular smooth muscle cells (iVSMCs) derived from induced pluripotent stem cells. In co-culture, WS-iMφs induces endothelial dysfunction in WS-iVECs and characteristics of the synthetic phenotype in WS-iVSMCs. Transcriptomics and open chromatin analysis reveal accelerated activation of type I interferon signaling and reduced chromatin accessibility of several transcriptional binding sites required for cellular homeostasis in WS-iMφs. Furthermore, the H3K9me3 levels show an inverse correlation with retrotransposable elements, and retrotransposable element-derived double-stranded RNA activates the DExH-box helicase 58 (DHX58)-dependent cytoplasmic RNA sensing pathway in WS-iMφs. Conversely, silencing type I interferon signaling in WS-iMφs rescues cell proliferation and suppresses cellular senescence and inflammation. These findings suggest that Mφ-specific inhibition of type I interferon signaling could be targeted to treat atherosclerosis in WS patients.
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Affiliation(s)
- Sudip Kumar Paul
- Department of Regenerative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Motohiko Oshima
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | | | - Masamitsu Sone
- Department of Regenerative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
- Hibernation Metabolism, Physiology and Development Group, Institute of Low Temperature Science, Hokkaido University, Sapporo, Japan
| | - Hisaya Kato
- Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshiro Maezawa
- Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiyori Kaneko
- Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masaki Fukuyo
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Bahityar Rahmutulla
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yasuo Ouchi
- Department of Regenerative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Kyoko Tsujimura
- Department of Regenerative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | | | - Atsushi Kaneda
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Atsushi Iwama
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Koutaro Yokote
- Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Koji Eto
- Department of Regenerative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
| | - Naoya Takayama
- Department of Regenerative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
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8
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Zhang T, Pang C, Xu M, Zhao Q, Hu Z, Jiang X, Guo M. The role of immune system in atherosclerosis: Molecular mechanisms, controversies, and future possibilities. Hum Immunol 2024; 85:110765. [PMID: 38369442 DOI: 10.1016/j.humimm.2024.110765] [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: 07/17/2023] [Revised: 02/06/2024] [Accepted: 02/08/2024] [Indexed: 02/20/2024]
Abstract
Numerous cardiovascular disorders have atherosclerosis as their pathological underpinning. Numerous studies have demonstrated that, with the aid of pattern recognition receptors, cytokines, and immunoglobulins, innate immunity, represented by monocytes/macrophages, and adaptive immunity, primarily T/B cells, play a critical role in controlling inflammation and abnormal lipid metabolism in atherosclerosis. Additionally, the finding of numerous complement components in atherosclerotic plaques suggests yet again how heavily the immune system controls atherosclerosis. Therefore, it is essential to have a thorough grasp of how the immune system contributes to atherosclerosis. The specific molecular mechanisms involved in the activation of immune cells and immune molecules in atherosclerosis, the controversy surrounding some immune cells in atherosclerosis, and the limitations of extrapolating from relevant animal models to humans were all carefully reviewed in this review from the three perspectives of innate immunity, adaptive immunity, and complement system. This could provide fresh possibilities for atherosclerosis research and treatment in the future.
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Affiliation(s)
- Tianle Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China
| | - Chenxu Pang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China
| | - Mengxin Xu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China
| | - Qianqian Zhao
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China
| | - Zhijie Hu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China
| | - Xijuan Jiang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
| | - Maojuan Guo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
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9
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Yennemadi AS, Jordan N, Diong S, Keane J, Leisching G. The Link Between Dysregulated Immunometabolism and Vascular Damage: Implications for the Development of Atherosclerosis in Systemic Lupus Erythematosus and Other Rheumatic Diseases. J Rheumatol 2024; 51:234-241. [PMID: 38224981 DOI: 10.3899/jrheum.2023-0833] [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] [Accepted: 11/30/2023] [Indexed: 01/17/2024]
Abstract
A bimodal pattern of mortality in systemic lupus erythematosus (SLE) exists. Early-stage deaths are predominantly caused by infection, whereas later-stage deaths are mainly caused by atherosclerotic disease. Further, although SLE-related mortality has reduced considerably in recent years, cardiovascular (CV) events remain one of the leading causes of death in people with SLE. Accelerated atherosclerosis in SLE is attributed to both an increase in traditional CV risk factors and the inflammatory effects of SLE itself. Many of these changes occur within the microenvironment of the vascular-immune interface, the site of atherosclerotic plaque development. Here, an intimate interaction between endothelial cells, vascular smooth muscle cells, and immune cells dictates physiological vs pathological responses to a chronic type 1 interferon environment. Low-density neutrophils (LDNs) have also been implicated in eliciting vasculature-damaging effects at such lesion sites. These changes are thought to be governed by dysfunctional metabolism of immune cells in this niche due at least in part to the chronic induction of type 1 interferons. Understanding these novel pathophysiological mechanisms and metabolic pathways may unveil potential innovative pharmacological targets and therapeutic opportunities for atherosclerosis, as well as shed light on the development of premature atherosclerosis in patients with SLE who develop CV events.
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Affiliation(s)
- Anjali S Yennemadi
- A.S. Yennemadi, MSc, J. Keane, MD, G. Leisching, PhD, TB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, School of Medicine, Trinity College Dublin, University of Dublin
| | - Natasha Jordan
- N. Jordan, PhD, Department of Rheumatology, St. James's Hospital
| | - Sophie Diong
- S. Diong, MD, Department of Dermatology, St. James's Hospital, Dublin, Ireland
| | - Joseph Keane
- A.S. Yennemadi, MSc, J. Keane, MD, G. Leisching, PhD, TB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, School of Medicine, Trinity College Dublin, University of Dublin
| | - Gina Leisching
- A.S. Yennemadi, MSc, J. Keane, MD, G. Leisching, PhD, TB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, School of Medicine, Trinity College Dublin, University of Dublin;
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10
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Wieland EB, Kempen LJ, Donners MM, Biessen EA, Goossens P. Macrophage heterogeneity in atherosclerosis: A matter of context. Eur J Immunol 2024; 54:e2350464. [PMID: 37943053 DOI: 10.1002/eji.202350464] [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: 05/22/2023] [Revised: 10/19/2023] [Accepted: 10/24/2023] [Indexed: 11/10/2023]
Abstract
During atherogenesis, plaque macrophages take up and process deposited lipids, trigger inflammation, and form necrotic cores. The traditional inflammatory/anti-inflammatory paradigm has proven insufficient in explaining their complex disease-driving mechanisms. Instead, we now appreciate that macrophages exhibit remarkable heterogeneity and functional specialization in various pathological contexts, including atherosclerosis. Technical advances for studying individual cells, especially single-cell RNA sequencing, indeed allowed to identify novel macrophage subsets in both murine and human atherosclerosis, highlighting the existence of diverse macrophage activation states throughout pathogenesis. In addition, recent studies highlighted the role of the local microenvironment in shaping the macrophages' phenotype and function. However, this remains largely undescribed in the context of atherosclerosis. In this review we explore the origins of macrophages and their functional specialization, shedding light on the diverse sources of macrophage accumulation in the atherosclerotic plaque. Next, we discuss the phenotypic diversity observed in both murine and human atherosclerosis, elucidating their distinct functions and spatial distribution within plaques. Finally, we highlight the importance of the local microenvironment in both phenotypic and functional specialization of macrophages in atherosclerosis and elaborate on the need for spatial multiomics approaches to provide a better understanding of the different macrophage subsets' roles in the pathogenesis of atherosclerosis.
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Affiliation(s)
- Elias B Wieland
- Cardiovascular Research Institute Maastricht, Experimental Vascular Pathology, Department of Pathology, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Laura Jap Kempen
- Cardiovascular Research Institute Maastricht, Experimental Vascular Pathology, Department of Pathology, Maastricht University Medical Centre+, Maastricht, the Netherlands
- Laboratory of Immunology and Vaccinology, Faculty of Veterinary Medicine, FARAH, ULiège, Liège, Belgium
- Laboratory of Immunophysiology, GIGA Institute, Liege University, Liège, Belgium
| | - Marjo Mpc Donners
- Cardiovascular Research Institute Maastricht, Experimental Vascular Pathology, Department of Pathology, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Erik Al Biessen
- Cardiovascular Research Institute Maastricht, Experimental Vascular Pathology, Department of Pathology, Maastricht University Medical Centre+, Maastricht, the Netherlands
- Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany
| | - Pieter Goossens
- Cardiovascular Research Institute Maastricht, Experimental Vascular Pathology, Department of Pathology, Maastricht University Medical Centre+, Maastricht, the Netherlands
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11
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Ge P, Li H, Ya X, Xu Y, Ma L, He Q, Wang R, Liu Z, Zhang Q, Zhang Y, Wang W, Zhang D, Zhao J. Single-cell atlas reveals different immune environments between stable and vulnerable atherosclerotic plaques. Front Immunol 2023; 13:1085468. [PMID: 36741406 PMCID: PMC9889979 DOI: 10.3389/fimmu.2022.1085468] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/20/2022] [Indexed: 01/19/2023] Open
Abstract
Introduction Regardless of the degree of stenosis, vulnerable plaque is an important cause of ischemic stroke and thrombotic complications. The changes of the immune microenvironment within plaques seem to be an important factor affecting the characteristics of the plaque. However, the differences of immune microenvironment between stable and vulnerable plaques were remained unknown. Methods In this study, RNA-sequencing was performed on superficial temporal arteries from 5 traumatic patients and plaques from 3 atherosclerotic patients to preliminary identify the key immune response processes in plaques. Mass cytometry (CyTOF) technology was used to explore differences in immune composition between 9 vulnerable plaques and 12 stable plaques. Finally, immunofluorescence technique was used to validate our findings in the previous analysis. Results Our results showed that more CD86+CD68+ M1 pro-inflammatory macrophages were found in vulnerable plaques, while CD4+T memory cells were mainly found in stable plaques. In addition, a CD11c+ subset of CD4+T cells with higher IFN-r secretion was found within the vulnerable plaque. In two subsets of B cells, CD19+CD20-B cells in vulnerable plaques secreted more TNF-a and IL-6, while CD19-CD20+B cells expressed more PD-1 molecules. Conclusion In conclusion, our study suggested that M1-like macrophages are the major cell subset affecting plaque stability, while functional B cells may also contribute to plaque stability.
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Affiliation(s)
- Peicong Ge
- Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Hao Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Xiaolong Ya
- Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yiqiao Xu
- Capital Medical University, Beijing, China
| | - Long Ma
- Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Qiheng He
- Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Rong Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Zechen Liu
- Department of Biostatistics, Harvard School of Public Health, Huntington Avenue, Boston, MA, United States
| | - Qian Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yan Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Wenjing Wang
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China,*Correspondence: Wenjing Wang, ; Dong Zhang, ; Jizong Zhao,
| | - Dong Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China,China National Clinical Research Center for Neurological Diseases, Beijing, China,Department of Neurosurgery, Beijing Hospital, Beijing, China,*Correspondence: Wenjing Wang, ; Dong Zhang, ; Jizong Zhao,
| | - Jizong Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China,China National Clinical Research Center for Neurological Diseases, Beijing, China,*Correspondence: Wenjing Wang, ; Dong Zhang, ; Jizong Zhao,
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12
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Moore J, Lakshmanan S, Manubolu VS, Kinninger A, Stojan G, Goldman DW, Petri M, Budoff M, Karpouzas GA. Coronary plaque progression is greater in systemic lupus erythematosus than rheumatoid arthritis. Coron Artery Dis 2023; 34:52-58. [PMID: 36421035 DOI: 10.1097/mca.0000000000001205] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with a high incidence of cardiovascular disease. Coronary atherosclerosis, particularly total plaque and noncalcified plaque on coronary computed tomography angiography (CCTA) has been correlated with cardiovascular events. We compared baseline coronary plaque burden and progression by serial CCTA in SLE and RA patients. METHODS We prospectively evaluated 44 patients who underwent serial CCTA examinations to quantify coronary plaque progression, 22 SLE patients, and 22 age- and sex-matched RA patients. Semiautomated plaque software was used for quantitative plaque assessment. Linear regression examined the effect of SLE diagnosis (versus RA) on annualized change in natural log-transformed total normalized atheroma volume (ln-TAV norm ) for low-attenuation, fibrofatty, fibrous, total noncalcified, densely calcified, and total plaque. RESULTS No quantitative differences for any plaque types were observed at baseline between SLE and RA patients ( P = 0.330-0.990). After adjustment for baseline plaque and cardiovascular risk factors, the increase in ln-TAV norm was higher in SLE than RA patients for fibrous [Exp-β: 0.202 (0.398), P = 0.0003], total noncalcified [Exp-β: 0.179 (0.393), P = 0.0001], and total plaque volume [Exp-β: 0.154 (0.501), P = 0.0007], but not for low-attenuation, fibrofatty, or densely calcified plaque ( P = 0.103-0.489). Patients with SLE had 80% more fibrous, 82% more noncalcified, and 85% more total plaque increase than those with RA. CONCLUSION Coronary plaque volume was similar in RA and SLE at baseline. Progression was greater in SLE, which may explain the greater cardiovascular risk in this disease. Further research to evaluate screening and management strategies for cardiovascular disease in these high-risk patients is warranted.
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Affiliation(s)
- Jeff Moore
- Chronic Disease Clinical Research Center, The Lundquist Institute for Biomedical Innovation at the Harbor University of California Los Angeles Medical Center, Torrance
- School of Exercise and Nutritional Sciences, San Diego State University, San Diego, California
| | - Suvasini Lakshmanan
- Chronic Disease Clinical Research Center, The Lundquist Institute for Biomedical Innovation at the Harbor University of California Los Angeles Medical Center, Torrance
| | - Venkat Sanjay Manubolu
- Chronic Disease Clinical Research Center, The Lundquist Institute for Biomedical Innovation at the Harbor University of California Los Angeles Medical Center, Torrance
| | - April Kinninger
- Chronic Disease Clinical Research Center, The Lundquist Institute for Biomedical Innovation at the Harbor University of California Los Angeles Medical Center, Torrance
| | - George Stojan
- Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Daniel W Goldman
- Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Michelle Petri
- Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Matthew Budoff
- Chronic Disease Clinical Research Center, The Lundquist Institute for Biomedical Innovation at the Harbor University of California Los Angeles Medical Center, Torrance
| | - George A Karpouzas
- Chronic Disease Clinical Research Center, The Lundquist Institute for Biomedical Innovation at the Harbor University of California Los Angeles Medical Center, Torrance
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13
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Natarajan P. Genomic Aging, Clonal Hematopoiesis, and Cardiovascular Disease. Arterioscler Thromb Vasc Biol 2023; 43:3-14. [PMID: 36353993 PMCID: PMC9780188 DOI: 10.1161/atvbaha.122.318181] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 10/31/2022] [Indexed: 11/11/2022]
Abstract
Chronologic age is the dominant risk factor for coronary artery disease but the features of aging promoting coronary artery disease are poorly understood. Advances in human genetics and population-based genetic profiling of blood cells have uncovered the surprising role of age-related subclinical leukemogenic mutations in blood cells, termed "clonal hematopoiesis of indeterminate potential," in coronary artery disease. Such mutations typically occur in DNMT3A, TET2, ASXL1, and JAK2. Murine and human studies prioritize the role of key inflammatory pathways linking clonal hematopoiesis with coronary artery disease. Increasingly larger, longitudinal, multiomics analyses are enabling further dissection into mechanistic insights. These observations expand the genetic architecture of coronary artery disease, now linking hallmark features of hematologic neoplasia with a much more common cardiovascular condition. Implications of these studies include the prospect of novel precision medicine paradigms for coronary artery disease.
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Affiliation(s)
- Pradeep Natarajan
- Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA
- Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA
- Department of Medicine, Harvard Medical School, Boston, MA
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14
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Chew NWS, Loong SSE, Foo R. Progress in molecular biology and translational science: Epigenetics in cardiovascular health and disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 197:105-134. [PMID: 37019589 DOI: 10.1016/bs.pmbts.2023.01.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Conrad Waddington's epigenetics landscape has provided a metaphorical framework for how cells progress from undifferentiated states to one of several discrete, distinct, differentiated cell fates. The understanding of epigenetics has evolved over time, with DNA methylation being the most studied epigenetic modification, followed by histone modifications and non-coding RNA. Cardiovascular diseases (CVD) are leading contributors to death worldwide, with the prevalence of CVDs increasing across the last couple of decades. Significant amount of resources being poured into researching key mechanisms and underpinnings of the various CVDs. These molecular studies looked at the genetics, epigenetics as well as the transcriptomics of various cardiovascular conditions, aiming to provide mechanistic insights. It has paved the way for therapeutics to be developed and in recent years, epi-drugs for the treatment of CVDs. This chapter aims to cover the various roles of epigenetics in the context of cardiovascular health and disease. The following will be examined in detail: the developments in basic experimental techniques used to study epigenetics, the role of epigenetics in various CVDs (hypertension, atrial fibrillation, atherosclerosis, and heart failure), and current advances in epi-therapeutics, providing a holistic view of the current concerted efforts in advancing the field of epigenetics in CVDs.
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Affiliation(s)
- Nicholas W S Chew
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore.
| | - Shaun S E Loong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Roger Foo
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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15
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Willemsen L, Prange KH, Neele AE, van Roomen CP, Gijbels M, Griffith GR, Toom MD, Beckers L, Siebeler R, Spann NJ, Chen HJ, Bosmans LA, Gorbatenko A, van Wouw S, Zelcer N, Jacobs H, van Leeuwen F, de Winther MP. DOT1L regulates lipid biosynthesis and inflammatory responses in macrophages and promotes atherosclerotic plaque stability. Cell Rep 2022; 41:111703. [DOI: 10.1016/j.celrep.2022.111703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 08/29/2022] [Accepted: 11/01/2022] [Indexed: 11/23/2022] Open
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16
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Vellasamy DM, Lee SJ, Goh KW, Goh BH, Tang YQ, Ming LC, Yap WH. Targeting Immune Senescence in Atherosclerosis. Int J Mol Sci 2022; 23:13059. [PMID: 36361845 PMCID: PMC9658319 DOI: 10.3390/ijms232113059] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/07/2022] [Accepted: 10/10/2022] [Indexed: 10/29/2023] Open
Abstract
Atherosclerosis is one of the main underlying causes of cardiovascular diseases (CVD). It is associated with chronic inflammation and intimal thickening as well as the involvement of multiple cell types including immune cells. The engagement of innate or adaptive immune response has either athero-protective or atherogenic properties in exacerbating or alleviating atherosclerosis. In atherosclerosis, the mechanism of action of immune cells, particularly monocytes, macrophages, dendritic cells, and B- and T-lymphocytes have been discussed. Immuno-senescence is associated with aging, viral infections, genetic predispositions, and hyperlipidemia, which contribute to atherosclerosis. Immune senescent cells secrete SASP that delays or accelerates atherosclerosis plaque growth and associated pathologies such as aneurysms and coronary artery disease. Senescent cells undergo cell cycle arrest, morphological changes, and phenotypic changes in terms of their abundances and secretome profile including cytokines, chemokines, matrix metalloproteases (MMPs) and Toll-like receptors (TLRs) expressions. The senescence markers are used in therapeutics and currently, senolytics represent one of the emerging treatments where specific targets and clearance of senescent cells are being considered as therapy targets for the prevention or treatment of atherosclerosis.
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Affiliation(s)
- Danusha Michelle Vellasamy
- School of Biosciences, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
| | - Sin-Jye Lee
- School of Biosciences, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
| | - Khang Wen Goh
- Faculty of Data Science and Information Technology, INTI International University, Nilai 71800, Malaysia
| | - Bey-Hing Goh
- Biofunctional Molecule Exploratory (BMEX) Research Group, School of Pharmacy, Monash University Malaysia, Bandar Sunway 47500, Malaysia
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
| | - Yin-Quan Tang
- School of Biosciences, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
- Centre for Drug Discovery and Molecular Pharmacology, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
| | - Long Chiau Ming
- PAP Rashidah Sa’adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Gadong BE1410, Brunei
| | - Wei Hsum Yap
- School of Biosciences, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
- Centre for Drug Discovery and Molecular Pharmacology, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
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17
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Nishimoto S, Sata M, Fukuda D. Expanding role of deoxyribonucleic acid-sensing mechanism in the development of lifestyle-related diseases. Front Cardiovasc Med 2022; 9:881181. [PMID: 36176986 PMCID: PMC9513035 DOI: 10.3389/fcvm.2022.881181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 08/15/2022] [Indexed: 11/14/2022] Open
Abstract
In lifestyle-related diseases, such as cardiovascular, metabolic, respiratory, and kidney diseases, chronic inflammation plays a causal role in their pathogenesis; however, underlying mechanisms of sterile chronic inflammation are not well-understood. Previous studies have confirmed the damage of cells in these organs in the presence of various risk factors such as diabetes, dyslipidemia, and cigarette smoking, releasing various endogenous ligands for pattern recognition receptors. These studies suggested that nucleic acids released from damaged tissues accumulate in these tissues, acting as an endogenous ligand. Undamaged DNA is an integral factor for the sustenance of life, whereas, DNA fragments, especially those from pathogens, are potent activators of the inflammatory response. Recent studies have indicated that inflammatory responses such as the production of type I interferon (IFN) induced by DNA-sensing mechanisms which contributes to self-defense system in innate immunity participates in the progression of inflammatory diseases by the recognition of nucleic acids derived from the host, including mitochondrial DNA (mtDNA). The body possesses several types of DNA sensors. Toll-like receptor 9 (TLR9) recognizes DNA fragments in the endosomes. In addition, the binding of DNA fragments in the cytosol activates cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS), resulting in the synthesis of the second messenger cyclic GMP-AMP (cGAMP). The binding of cGAMP to stimulator of interferon genes (STING) activates NF-κB and TBK-1 signaling and consequently the production of many inflammatory cytokines including IFNs. Numerous previous studies have demonstrated the role of DNA sensors in self-defense through the recognition of DNA fragments derived from pathogens. Beyond the canonical role of TLR9 and cGAS-STING, this review describes the role of these DNA-sensing mechanism in the inflammatory responses caused by endogenous DNA fragments, and in the pathogenesis of lifestyle-related diseases.
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Affiliation(s)
- Sachiko Nishimoto
- Faculty of Clinical Nutrition and Dietetics, Konan Women’s University, Kobe, Japan
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masataka Sata
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Daiju Fukuda
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
- Department of Cardiovascular Medicine, Osaka Metropolitan University, Osaka, Japan
- *Correspondence: Daiju Fukuda, ,
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18
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Cobo I, Tanaka TN, Chandra Mangalhara K, Lana A, Yeang C, Han C, Schlachetzki J, Challcombe J, Fixsen BR, Sakai M, Li RZ, Fields H, Mokry M, Tsai RG, Bejar R, Prange K, de Winther M, Shadel GS, Glass CK. DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages. Immunity 2022; 55:1386-1401.e10. [PMID: 35931086 PMCID: PMC9718507 DOI: 10.1016/j.immuni.2022.06.022] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/29/2022] [Accepted: 06/28/2022] [Indexed: 12/15/2022]
Abstract
Deleterious somatic mutations in DNA methyltransferase 3 alpha (DNMT3A) and TET mehtylcytosine dioxygenase 2 (TET2) are associated with clonal expansion of hematopoietic cells and higher risk of cardiovascular disease (CVD). Here, we investigated roles of DNMT3A and TET2 in normal human monocyte-derived macrophages (MDM), in MDM isolated from individuals with DNMT3A or TET2 mutations, and in macrophages isolated from human atherosclerotic plaques. We found that loss of function of DNMT3A or TET2 resulted in a type I interferon response due to impaired mitochondrial DNA integrity and activation of cGAS signaling. DNMT3A and TET2 normally maintained mitochondrial DNA integrity by regulating the expression of transcription factor A mitochondria (TFAM) dependent on their interactions with RBPJ and ZNF143 at regulatory regions of the TFAM gene. These findings suggest that targeting the cGAS-type I IFN pathway may have therapeutic value in reducing risk of CVD in patients with DNMT3A or TET2 mutations.
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Affiliation(s)
- Isidoro Cobo
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Tiffany N Tanaka
- University of California San Diego, Moores Cancer Center, La Jolla, CA, USA
| | | | - Addison Lana
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Calvin Yeang
- University of California San Diego, Sulpizio Cardiovascular Center, La Jolla, CA, USA
| | - Claudia Han
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Johannes Schlachetzki
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Jean Challcombe
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Bethany R Fixsen
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Mashito Sakai
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan
| | - Rick Z Li
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Hannah Fields
- University of California San Diego, Moores Cancer Center, La Jolla, CA, USA
| | - Michal Mokry
- Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, 3584 EA Utrecht, the Netherlands
| | - Randy G Tsai
- University of California San Diego, Moores Cancer Center, La Jolla, CA, USA
| | - Rafael Bejar
- University of California San Diego, Moores Cancer Center, La Jolla, CA, USA
| | - Koen Prange
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Menno de Winther
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Christopher K Glass
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
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19
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Wang Y, Wang Q, Xu D. New insights into macrophage subsets in atherosclerosis. J Mol Med (Berl) 2022; 100:1239-1251. [PMID: 35930063 DOI: 10.1007/s00109-022-02224-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 05/27/2022] [Accepted: 06/15/2022] [Indexed: 12/11/2022]
Abstract
Macrophages in atherosclerotic patients are notably plastic and heterogeneous. Single-cell RNA sequencing (Sc RNA-seq) can provide information about all the RNAs in individual cells, and it is used to identify cell subpopulations in atherosclerosis (AS) and reveal the heterogeneity of these cells. Recently, some findings from Sc RNA-seq experiments have suggested the existence of multiple macrophage subsets in atherosclerotic plaque lesions, and these subsets exhibit significant differences in their gene expression levels and functions. These cells affect various aspects of plaque lesion development, stabilization, and regression, as well as plaque rupture. This article aims to review the content and results of current studies that used RNA-seq to explore the different types of macrophages in AS and the related molecular mechanisms as well as to identify the potential roles of these macrophage types in the pathogenesis of atherosclerotic plaques. Also, this review listed some new therapeutic targets for delaying atherosclerotic lesion progression and treatment based on the experimental results.
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Affiliation(s)
- Yurong Wang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Qiong Wang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Danyan Xu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
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20
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Integrating multiplex immunofluorescent and mass spectrometry imaging to map myeloid heterogeneity in its metabolic and cellular context. Cell Metab 2022; 34:1214-1225.e6. [PMID: 35858629 DOI: 10.1016/j.cmet.2022.06.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 02/28/2022] [Accepted: 06/23/2022] [Indexed: 12/24/2022]
Abstract
Cells often adopt different phenotypes, dictated by tissue-specific or local signals such as cell-cell and cell-matrix contacts or molecular micro-environment. This holds in extremis for macrophages with their high phenotypic plasticity. Their broad range of functions, some even opposing, reflects their heterogeneity, and a multitude of subsets has been described in different tissues and diseases. Such micro-environmental imprint cannot be adequately studied by single-cell applications, as cells are detached from their context, while histology-based assessment lacks the phenotypic depth due to limitations in marker combination. Here, we present a novel, integrative approach in which 15-color multispectral imaging allows comprehensive cell classification based on multi-marker expression patterns, followed by downstream analysis pipelines to link their phenotypes to contextual, micro-environmental cues, such as their cellular ("community") and metabolic ("local lipidome") niches in complex tissue. The power of this approach is illustrated for myeloid subsets and associated lipid signatures in murine atherosclerotic plaque.
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21
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Liu Y, Yu X, Zhang W, Zhang X, Wang M, Ji F. Mechanistic insight into premature atherosclerosis and cardiovascular complications in systemic lupus erythematosus. J Autoimmun 2022; 132:102863. [PMID: 35853760 DOI: 10.1016/j.jaut.2022.102863] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 07/02/2022] [Indexed: 12/12/2022]
Abstract
Systemic lupus erythematosus (SLE) is associated with a significant risk of cardiovascular disease (CVD), which substantially increases disease mortality and morbidity. The overall mechanisms associated with the development of premature atherosclerosis and CVD in SLE remain unclear, but has been considered as a result of an intricate interplay between the profound immune dysregulation and traditional CVD risk factors. Aberrant systemic inflammation in SLE may lead to an abnormal lipid profile and dysfunction, which can further fuel the pro-atherosclerotic environment. The existence of a strong imbalance between endothelial damage and vascular repair/angiogenesis promotes vascular injury, which is the early step in the progression of atherosclerotic CVD. Profound innate and adaptive immune dysregulation, characterized by excessive type I interferon burden, aberrant macrophage, platelet and complements activation, neutrophil dysregulation and neutrophil extracellular traps formation, uncontrolled T cell activation, and excessive autoantibody production and immune complex formation, have been proposed to promote accelerated CVD in SLE. While designing targeted therapies to correct the dysregulated immune activation may be beneficial in the treatment of SLE-related CVD, much additional work is needed to determine how to translate these findings into clinical practice. Additionally, a number of biomarkers display diagnostic potentials in improving CVD risk stratification in SLE, further prospective studies will help understand which biomarker(s) will be the most impactful one(s) in assessing SLE-linked CVD. Continued efforts to identify novel mechanisms and to establish criteria for assessing CVD risk as well as predicting CVD progression are in great need to improve CVD outcomes in SLE.
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Affiliation(s)
- Yudong Liu
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China; The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China
| | - Xue Yu
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China
| | - Wenduo Zhang
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China
| | - Xuan Zhang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China
| | - Min Wang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China
| | - Fusui Ji
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China.
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22
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Cardiovascular Risk Stratification in Diabetic Retinopathy via Atherosclerotic Pathway in COVID-19/non-COVID-19 Frameworks using Artificial Intelligence Paradigm: A Narrative Review. Diagnostics (Basel) 2022; 12:diagnostics12051234. [PMID: 35626389 PMCID: PMC9140106 DOI: 10.3390/diagnostics12051234] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/11/2022] [Accepted: 05/11/2022] [Indexed: 11/18/2022] Open
Abstract
Diabetes is one of the main causes of the rising cases of blindness in adults. This microvascular complication of diabetes is termed diabetic retinopathy (DR) and is associated with an expanding risk of cardiovascular events in diabetes patients. DR, in its various forms, is seen to be a powerful indicator of atherosclerosis. Further, the macrovascular complication of diabetes leads to coronary artery disease (CAD). Thus, the timely identification of cardiovascular disease (CVD) complications in DR patients is of utmost importance. Since CAD risk assessment is expensive for low-income countries, it is important to look for surrogate biomarkers for risk stratification of CVD in DR patients. Due to the common genetic makeup between the coronary and carotid arteries, low-cost, high-resolution imaging such as carotid B-mode ultrasound (US) can be used for arterial tissue characterization and risk stratification in DR patients. The advent of artificial intelligence (AI) techniques has facilitated the handling of large cohorts in a big data framework to identify atherosclerotic plaque features in arterial ultrasound. This enables timely CVD risk assessment and risk stratification of patients with DR. Thus, this review focuses on understanding the pathophysiology of DR, retinal and CAD imaging, the role of surrogate markers for CVD, and finally, the CVD risk stratification of DR patients. The review shows a step-by-step cyclic activity of how diabetes and atherosclerotic disease cause DR, leading to the worsening of CVD. We propose a solution to how AI can help in the identification of CVD risk. Lastly, we analyze the role of DR/CVD in the COVID-19 framework.
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23
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Chowdhury A, Witte S, Aich A. Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology. Front Cell Dev Biol 2022; 10:796066. [PMID: 35223833 PMCID: PMC8873532 DOI: 10.3389/fcell.2022.796066] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 01/14/2022] [Indexed: 12/23/2022] Open
Abstract
Mitochondria, in symbiosis with the host cell, carry out a wide variety of functions from generating energy, regulating the metabolic processes, cell death to inflammation. The most prominent function of mitochondria relies on the oxidative phosphorylation (OXPHOS) system. OXPHOS heavily influences the mitochondrial-nuclear communication through a plethora of interconnected signaling pathways. Additionally, owing to the bacterial ancestry, mitochondria also harbor a large number of Damage Associated Molecular Patterns (DAMPs). These molecules relay the information about the state of the mitochondrial health and dysfunction to the innate immune system. Consequently, depending on the intracellular or extracellular nature of detection, different inflammatory pathways are elicited. One group of DAMPs, the mitochondrial nucleic acids, hijack the antiviral DNA or RNA sensing mechanisms such as the cGAS/STING and RIG-1/MAVS pathways. A pro-inflammatory response is invoked by these signals predominantly through type I interferon (T1-IFN) cytokines. This affects a wide range of organ systems which exhibit clinical presentations of auto-immune disorders. Interestingly, tumor cells too, have devised ingenious ways to use the mitochondrial DNA mediated cGAS-STING-IRF3 response to promote neoplastic transformations and develop tumor micro-environments. Thus, mitochondrial nucleic acid-sensing pathways are fundamental in understanding the source and nature of disease initiation and development. Apart from the pathological interest, recent studies also attempt to delineate the structural considerations for the release of nucleic acids across the mitochondrial membranes. Hence, this review presents a comprehensive overview of the different aspects of mitochondrial nucleic acid-sensing. It attempts to summarize the nature of the molecular patterns involved, their release and recognition in the cytoplasm and signaling. Finally, a major emphasis is given to elaborate the resulting patho-physiologies.
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Affiliation(s)
- Arpita Chowdhury
- Department of Cellular Biochemistry, University Medical Center, Göttingen, Germany
| | - Steffen Witte
- Department of Cellular Biochemistry, University Medical Center, Göttingen, Germany
| | - Abhishek Aich
- Department of Cellular Biochemistry, University Medical Center, Göttingen, Germany
- Cluster of Excellence “Multiscale Bioimaging, from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany
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24
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Willemsen L, Chen HJ, van Roomen CPAA, Griffith GR, Siebeler R, Neele AE, Kroon J, Hoeksema MA, de Winther MPJ. Monocyte and Macrophage Lipid Accumulation Results in Down-Regulated Type-I Interferon Responses. Front Cardiovasc Med 2022; 9:829877. [PMID: 35224060 PMCID: PMC8869252 DOI: 10.3389/fcvm.2022.829877] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/18/2022] [Indexed: 01/27/2023] Open
Abstract
Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The down regulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signaling pathways and suggest that this phenotype is mediated via down regulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.
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Affiliation(s)
- Lisa Willemsen
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Hung-Jen Chen
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Cindy P. A. A. van Roomen
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Guillermo R. Griffith
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Ricky Siebeler
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Annette E. Neele
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Jeffrey Kroon
- Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, Netherlands
| | - Marten A. Hoeksema
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Menno P. J. de Winther
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands,*Correspondence: Menno P. J. de Winther
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25
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Razeghian-Jahromi I, Karimi Akhormeh A, Razmkhah M, Zibaeenezhad MJ. Immune system and atherosclerosis: Hostile or friendly relationship. Int J Immunopathol Pharmacol 2022; 36:3946320221092188. [PMID: 35410514 PMCID: PMC9009140 DOI: 10.1177/03946320221092188] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Coronary artery disease has remained a major health challenge despite enormous
progress in prevention, diagnosis, and treatment strategies. Formation of
atherosclerotic plaque is a chronic process that is developmentally influenced
by intrinsic and extrinsic determinants. Inflammation triggers atherosclerosis,
and the fundamental element of inflammation is the immune system. The immune
system involves in the atherosclerosis process by a variety of immune cells and
a cocktail of mediators. It is believed that almost all main components of this
system possess a profound contribution to the atherosclerosis. However, they
play contradictory roles, either protective or progressive, in different stages
of atherosclerosis progression. It is evident that monocytes are the first
immune cells appeared in the atherosclerotic lesion. With the plaque growth,
other types of the immune cells such as mast cells, and T lymphocytes are
gradually involved. Each cell releases several cytokines which cause the
recruitment of other immune cells to the lesion site. This is followed by
affecting the expression of other cytokines as well as altering certain
signaling pathways. All in all, a mix of intertwined interactions determine the
final outcome in terms of mild or severe manifestations, either clinical or
subclinical. Therefore, it is of utmost importance to precisely understand the
kind and degree of contribution which is made by each immune component in order
to stop the growing burden of cardiovascular morbidity and mortality. In this
review, we present a comprehensive appraisal on the role of immune cells in the
atherosclerosis initiation and development.
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Affiliation(s)
- Iman Razeghian-Jahromi
- Cardiovascular Research Center, 571605Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Karimi Akhormeh
- Cardiovascular Research Center, 571605Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research, 48435Shiraz University of Medical Sciences, Shiraz, Iran
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26
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Cobo I, Tanaka T, Glass CK, Yeang C. Clonal hematopoiesis driven by DNMT3A and TET2 mutations: role in monocyte and macrophage biology and atherosclerotic cardiovascular disease. Curr Opin Hematol 2022; 29:1-7. [PMID: 34654019 PMCID: PMC8639635 DOI: 10.1097/moh.0000000000000688] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Clonal hematopoiesis of indeterminate potential (CHIP), defined by the presence of somatic mutations in hematopoietic cells, is associated with advanced age and increased mortality due to cardiovascular disease. Gene mutations in DNMT3A and TET2 are the most frequently identified variants among patients with CHIP and provide selective advantage that spurs clonal expansion and myeloid skewing. Although DNMT3A and TET2 appear to have opposing enzymatic influence on DNA methylation, mounting data has characterized convergent inflammatory pathways, providing insights to how CHIP may mediate atherosclerotic cardiovascular disease (ASCVD). RECENT FINDINGS We review a multitude of studies that characterize aberrant inflammatory signaling as result of DNMT3A and TET2 deficiency in monocytes and macrophages, immune cells with prominent roles in atherosclerosis. Although specific DNA methylation signatures associated with these known epigenetic regulators have been identified, many studies have also characterized diverse modulatory functions of DNTM3A and TET2 that urge cell and context-specific experimental studies to further define how DNMT3A and TET2 may nonenzymatically activate inflammatory pathways with clinically meaningful consequences. SUMMARY CHIP, common in elderly individuals, provides an opportunity understand and potentially modify age-related chronic inflammatory ASCVD risk.
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Affiliation(s)
- Isidoro Cobo
- Department of Cellular and Molecular Medicine, University of California San Diego
| | - Tiffany Tanaka
- University of California San Diego, Moores Cancer Center
| | - Christopher K. Glass
- Department of Cellular and Molecular Medicine, University of California San Diego
| | - Calvin Yeang
- Sulpizio Cardiovascular Center, Division of Cardiology, University of California San Diego, La Jolla, California, USA
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27
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Farahi L, Sinha SK, Lusis AJ. Roles of Macrophages in Atherogenesis. Front Pharmacol 2021; 12:785220. [PMID: 34899348 PMCID: PMC8660976 DOI: 10.3389/fphar.2021.785220] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/04/2021] [Indexed: 12/18/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disease that may ultimately lead to local proteolysis, plaque rupture, and thrombotic vascular disease, resulting in myocardial infarction, stroke, and sudden cardiac death. Circulating monocytes are recruited to the arterial wall in response to inflammatory insults and differentiate into macrophages which make a critical contribution to tissue damage, wound healing, and also regression of atherosclerotic lesions. Within plaques, macrophages take up aggregated lipoproteins which have entered the vessel wall to give rise to cholesterol-engorged foam cells. Also, the macrophage phenotype is influenced by various stimuli which affect their polarization, efferocytosis, proliferation, and apoptosis. The heterogeneity of macrophages in lesions has recently been addressed by single-cell sequencing techniques. This article reviews recent advances regarding the roles of macrophages in different stages of disease pathogenesis from initiation to advanced atherosclerosis. Macrophage-based therapies for atherosclerosis management are also described.
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Affiliation(s)
- Lia Farahi
- Monoclonal Antibody Research Center, Avicenna Research Institute, Tehran, Iran
| | - Satyesh K. Sinha
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Aldons J. Lusis
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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28
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Dendritic Cells and Antiphospholipid Syndrome: An Updated Systematic Review. Life (Basel) 2021; 11:life11080801. [PMID: 34440545 PMCID: PMC8400181 DOI: 10.3390/life11080801] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 12/23/2022] Open
Abstract
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by autoreactive B and T cells against β2-glycoprotein I (B2GPI), with vascular thrombosis or obstetrical complications. Dendritic cells (DCs) are crucial in the generation of autoimmunity. Here, we conducted a comprehensive systematic review on the relationship between DC and APS. We performed a literature search of PubMed as of 26 March 2021. A total of 33 articles were extracted. DCs are pivotal in inducing inflammatory responses and orchestrating adaptive immunity. DCs contribute to the local inflammation regarding vascular thrombosis or obstetrical complications. Both B2GPI and antiphospholipid antibodies (aPL) can promote antigen presentation by DCs and the generation or maintenance of autoimmunity. In addition, plasmacytoid DC activation is enhanced by aPL, thereby augmenting the inflammatory response. In line with these findings, DC modulation appears promising as a future treatment for APS. In conclusion, our review indicated the crucial role of DCs in the pathogenesis of APS. Deeper understanding of the complex relationship would help in developing new treatment strategies.
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29
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Chen L, Shang C, Wang B, Wang G, Jin Z, Yao F, Yue Z, Bai L, Wang R, Zhao S, Liu E, Wang W. HDAC3 inhibitor suppresses endothelial-to-mesenchymal transition via modulating inflammatory response in atherosclerosis. Biochem Pharmacol 2021; 192:114716. [PMID: 34339713 DOI: 10.1016/j.bcp.2021.114716] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/13/2021] [Accepted: 07/28/2021] [Indexed: 12/16/2022]
Abstract
A total number of 18 different isoforms of histone deacetylases (HDACs) which were categorized into 4 classes have been identified in human. HDAC3 is categorized as class I HDACs and is closely related to the occurrence and development of atherosclerosis. Recent evidence has pointed to endothelial-to-mesenchymal transition (EndMT) as a key process in vascular inflammation in atherosclerosis. However, little is known about the effect of HDAC3 on EndMT in atherosclerosis. Therefore, we aimed to investigate the effect of HDAC3 specific inhibitor on EndMT in ApoE-/- mice fed a Western diet and human umbilical vein endothelial cells (HUVECs) induced by inflammatory cytokines. Firstly, we found that HDAC3 expression was up-regulated and EndMT occurred in the aortas of ApoE-/- mice compared with C57BL/6J mice. However, HDAC3 specific inhibitor RGFP966 alleviated atherosclerotic lesions and inhibited EndMT of the atherosclerotic plaque in ApoE-/- mice. Then, in vitro study showed that inflammatory cytokines TNF-α and IL-1β co-treatment increased the expression of HDAC3 and induced EndMT in HUVECs. HDAC3 inhibition by siRNA or specific inhibitor RGFP966 suppressed EndMT in HUVECs stimulated with TNF-α and IL-1β. By contrast, HDAC3 overexpression by adenovirus further promoted EndMT of HUVECs. In addition, we found that HDAC3 also regulated the inflammatory response of HUVECs by modulating the expression of inflammatory cytokines and the number of monocytes attached to HUVECs. These above results suggest that HDAC3 inhibitor suppresses EndMT via modulating inflammatory response in ApoE-/- mice and HUVECs.
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Affiliation(s)
- Lifang Chen
- Department of Medical Laboratory Animal Science, Xi'an Jiaotong University Health Science Center, Xi'an, China; Research Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an, China
| | - Chenxu Shang
- Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Bo Wang
- Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Guan Wang
- Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Zhen Jin
- Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Feng Yao
- Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Zejun Yue
- Department of Medical Laboratory Animal Science, Xi'an Jiaotong University Health Science Center, Xi'an, China; Research Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an, China
| | - Liang Bai
- Department of Medical Laboratory Animal Science, Xi'an Jiaotong University Health Science Center, Xi'an, China; Research Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an, China
| | - Rong Wang
- Department of Medical Laboratory Animal Science, Xi'an Jiaotong University Health Science Center, Xi'an, China; Research Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an, China
| | - Sihai Zhao
- Department of Medical Laboratory Animal Science, Xi'an Jiaotong University Health Science Center, Xi'an, China; Research Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an, China
| | - Enqi Liu
- Department of Medical Laboratory Animal Science, Xi'an Jiaotong University Health Science Center, Xi'an, China; Research Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an, China
| | - Weirong Wang
- Department of Medical Laboratory Animal Science, Xi'an Jiaotong University Health Science Center, Xi'an, China; Research Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an, China.
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30
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Fukuda D, Pham PT, Sata M. Emerging Roles of the Innate Immune System Regulated by DNA Sensors in the Development of Vascular and Metabolic Diseases. J Atheroscler Thromb 2021; 29:297-307. [PMID: 34248111 PMCID: PMC8894111 DOI: 10.5551/jat.rv17059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Sterile chronic inflammation causes cardiometabolic disorders; however, the mechanisms are not fully understood. Previous studies have demonstrated the degradation of cells/tissues in the vasculature and metabolic organs in lifestyle-associated diseases, such as diabetes and hyperlipidemia, suggesting the release and/or accumulation of nucleic acids from damaged cells. DNA is indispensable for life; however, DNA fragments, especially those from pathogens, strongly induce inflammation by the activation of DNA sensors. Growing evidence suggests that DNA-sensing mechanisms, which are normally involved in self-defense against pathogens as the innate immune system, are associated with the progression of inflammatory diseases in response to endogenous DNA fragments. There are several types of DNA sensors in our bodies. Toll-like receptor 9 (TLR9)—one of the most studied DNA sensors—recognizes DNA fragments in endosome. In addition, stimulator of interferon genes (STING), which has recently been extensively investigated, recognizes cyclic GMP-AMP (cGAMP) generated from DNA fragments in the cytosol. Both TLR9 and STING are known to play pivotal roles in host defense as the innate immune system. However, recent studies have indicated that the activation of these DNA sensors in immune cells, such as macrophages, promotes inflammation leading to the development of vascular and metabolic diseases associated with lifestyle. In this review, we discuss recent advances in determining the roles of DNA sensors in these disease contexts. Revealing a novel mechanism of sterile chronic inflammation regulated by DNA sensors might facilitate clinical interventions for these health conditions.
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Affiliation(s)
- Daiju Fukuda
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
| | - Phuong Tran Pham
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
| | - Masataka Sata
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
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31
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Li D, Yang S, Xing Y, Pan L, Zhao R, Zhao Y, Liu L, Wu M. Novel Insights and Current Evidence for Mechanisms of Atherosclerosis: Mitochondrial Dynamics as a Potential Therapeutic Target. Front Cell Dev Biol 2021; 9:673839. [PMID: 34307357 PMCID: PMC8293691 DOI: 10.3389/fcell.2021.673839] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular disease (CVD) is the main cause of death worldwide. Atherosclerosis is the underlying pathological basis of CVD. Mitochondrial homeostasis is maintained through the dynamic processes of fusion and fission. Mitochondria are involved in many cellular processes, such as steroid biosynthesis, calcium homeostasis, immune cell activation, redox signaling, apoptosis, and inflammation, among others. Under stress conditions, mitochondrial dynamics, mitochondrial cristae remodeling, and mitochondrial ROS (mitoROS) production increase, mitochondrial membrane potential (MMP) decreases, calcium homeostasis is imbalanced, and mitochondrial permeability transition pore open (mPTP) and release of mitochondrial DNA (mtDNA) are activated. mtDNA recognized by TLR9 can lead to NF-κB pathway activation and pro-inflammatory factor expression. At the same time, TLR9 can also activate NLRP3 inflammasomes and release interleukin, an event that eventually leads to tissue damage and inflammatory responses. In addition, mitochondrial dysfunction may amplify the activation of NLRP3 through the production of mitochondrial ROS, which together aggravate accumulating mitochondrial damage. In addition, mtDNA defects or gene mutation can lead to mitochondrial oxidative stress. Finally, obesity, diabetes, hypertension and aging are risk factors for the progression of CVD, which are closely related to mitochondrial dynamics. Mitochondrial dynamics may represent a new target in the treatment of atherosclerosis. Antioxidants, mitochondrial inhibitors, and various new therapies to correct mitochondrial dysfunction represent a few directions for future research on therapeutic intervention and amelioration of atherosclerosis.
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Affiliation(s)
- Dan Li
- Guang'an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shengjie Yang
- Guang'an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yanwei Xing
- Guang'an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Limin Pan
- Guang'an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ran Zhao
- Guang'an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yixi Zhao
- Guang'an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Longtao Liu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Min Wu
- Guang'an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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32
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Zhao Y, Zhang J, Zhang W, Xu Y. A myriad of roles of dendritic cells in atherosclerosis. Clin Exp Immunol 2021; 206:12-27. [PMID: 34109619 DOI: 10.1111/cei.13634] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/17/2021] [Accepted: 05/28/2021] [Indexed: 11/29/2022] Open
Abstract
Atherosclerosis is an inflammatory disease with break-down of homeostatic immune regulation of vascular tissues. As a critical initiator of host immunity, dendritic cells (DCs) have also been identified in the aorta of healthy individuals and atherosclerotic patients, whose roles in regulating arterial inflammation aroused great interest. Accumulating evidence has now pointed to the fundamental roles for DCs in every developmental stage of atherosclerosis due to their myriad of functions in immunity and tolerance induction, ranging from lipid uptake, efferocytosis and antigen presentation to pro- and anti-inflammatory cytokine or chemokine secretion. In this study we provide a timely summary of the published works in this field, and comprehensively discuss both the direct and indirect roles of DCs in atherogenesis. Understanding the pathogenic roles of DCs during the development of atherosclerosis in vascular tissues would certainly help to open therapeutic avenue to the treatment of cardiovascular diseases.
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Affiliation(s)
- Yanfang Zhao
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, School of Life Science, Anhui Normal University, Wuhu, China
| | - Jing Zhang
- Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wenjie Zhang
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, School of Life Science, Anhui Normal University, Wuhu, China
| | - Yuekang Xu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, School of Life Science, Anhui Normal University, Wuhu, China
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33
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Jin H, Goossens P, Juhasz P, Eijgelaar W, Manca M, Karel JMH, Smirnov E, Sikkink CJJM, Mees BME, Waring O, van Kuijk K, Fazzi GE, Gijbels MJJ, Kutmon M, Evelo CTA, Hedin U, Daemen MJAP, Sluimer JC, Matic L, Biessen EAL. Integrative multiomics analysis of human atherosclerosis reveals a serum response factor-driven network associated with intraplaque hemorrhage. Clin Transl Med 2021; 11:e458. [PMID: 34185408 PMCID: PMC8236116 DOI: 10.1002/ctm2.458] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/21/2021] [Accepted: 05/25/2021] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND While single-omics analyses on human atherosclerotic plaque have been very useful to map stage- or disease-related differences in expression, they only partly capture the array of changes in this tissue and suffer from scale-intrinsic limitations. In order to better identify processes associated with intraplaque hemorrhage and plaque instability, we therefore combined multiple omics into an integrated model. METHODS In this study, we compared protein and gene makeup of low- versus high-risk atherosclerotic lesion segments from carotid endarterectomy patients, as judged from the absence or presence of intraplaque hemorrhage, respectively. Transcriptomic, proteomic, and peptidomic data of this plaque cohort were aggregated and analyzed by DIABLO, an integrative multivariate classification and feature selection method. RESULTS We identified a protein-gene associated multiomics model able to segregate stable, nonhemorrhaged from vulnerable, hemorrhaged lesions at high predictive performance (AUC >0.95). The dominant component of this model correlated with αSMA- PDGFRα+ fibroblast-like cell content (p = 2.4E-05) and Arg1+ macrophage content (p = 2.2E-04) and was driven by serum response factor (SRF), possibly in a megakaryoblastic leukemia-1/2 (MKL1/2) dependent manner. Gene set overrepresentation analysis on the selected key features of this model pointed to a clear cardiovascular disease signature, with overrepresentation of extracellular matrix synthesis and organization, focal adhesion, and cholesterol metabolism terms, suggestive of the model's relevance for the plaque vulnerability. Finally, we were able to corroborate the predictive power of the selected features in several independent mRNA and proteomic plaque cohorts. CONCLUSIONS In conclusion, our integrative omics study has identified an intraplaque hemorrhage-associated cardiovascular signature that provides excellent stratification of low- from high-risk carotid artery plaques in several independent cohorts. Further study revealed suppression of an SRF-regulated disease network, controlling lesion stability, in vulnerable plaque, which can serve as a scaffold for the design of targeted intervention in plaque destabilization.
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Affiliation(s)
- Han Jin
- Department of PathologySchool for Cardiovascular Diseases (CARIM)Maastricht UMC+MaastrichtThe Netherlands
| | - Pieter Goossens
- Department of PathologySchool for Cardiovascular Diseases (CARIM)Maastricht UMC+MaastrichtThe Netherlands
| | | | - Wouter Eijgelaar
- Department of PathologySchool for Cardiovascular Diseases (CARIM)Maastricht UMC+MaastrichtThe Netherlands
| | - Marco Manca
- Department of PathologySchool for Cardiovascular Diseases (CARIM)Maastricht UMC+MaastrichtThe Netherlands
| | - Joël M. H. Karel
- Department of Data Science and Knowledge EngineeringMaastricht UniversityMaastrichtThe Netherlands
| | - Evgueni Smirnov
- Department of Data Science and Knowledge EngineeringMaastricht UniversityMaastrichtThe Netherlands
| | | | | | - Olivia Waring
- Department of PathologySchool for Cardiovascular Diseases (CARIM)Maastricht UMC+MaastrichtThe Netherlands
| | - Kim van Kuijk
- Department of PathologySchool for Cardiovascular Diseases (CARIM)Maastricht UMC+MaastrichtThe Netherlands
| | - Gregorio E. Fazzi
- Department of PathologySchool for Cardiovascular Diseases (CARIM)Maastricht UMC+MaastrichtThe Netherlands
| | - Marion J. J. Gijbels
- Department of PathologySchool for Cardiovascular Diseases (CARIM)Maastricht UMC+MaastrichtThe Netherlands
- Department of Medical BiochemistryExperimental Vascular BiologyAmsterdam UMCAmsterdamThe Netherlands
- School for Oncology and Developmental Biology (GROW)Maastricht UniversityMaastrichtThe Netherlands
| | - Martina Kutmon
- Department of Bioinformatics (BiGCaT)Maastricht Centre for Systems Biology (MaCSBio)Maastricht UniversityMaastrichtThe Netherlands
| | - Chris T. A. Evelo
- Department of Bioinformatics (BiGCaT)Maastricht Centre for Systems Biology (MaCSBio)Maastricht UniversityMaastrichtThe Netherlands
| | - Ulf Hedin
- Department of Molecular Medicine and SurgeryKarolinska InstituteSolnaSweden
| | - Mat J. A. P. Daemen
- Department of PathologyAmsterdam Cardiovascular SciencesAmsterdam UMCAmsterdamThe Netherlands
| | - Judith C. Sluimer
- Department of PathologySchool for Cardiovascular Diseases (CARIM)Maastricht UMC+MaastrichtThe Netherlands
- BHF Centre for Cardiovascular Science (CVS)University of EdinburghEdinburghScotland
| | - Ljubica Matic
- Department of Molecular Medicine and SurgeryKarolinska InstituteSolnaSweden
| | - Erik A. L. Biessen
- Department of PathologySchool for Cardiovascular Diseases (CARIM)Maastricht UMC+MaastrichtThe Netherlands
- Institute for Molecular Cardiovascular ResearchRWTH Aachen UniversityAachenGermany
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34
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Wirestam L, Saleh M, Svensson C, Compagno M, Zachrisson H, Wetterö J, Sjöwall C. Plasma osteopontin versus intima media thickness of the common carotid arteries in well-characterised patients with systemic lupus erythematosus. Lupus 2021; 30:1244-1253. [PMID: 33957796 PMCID: PMC8209759 DOI: 10.1177/09612033211013898] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Objective The progress of accelerated atherosclerosis in systemic lupus erythematosus (SLE) is incompletely understood. Circulating osteopontin (OPN) is increased in autoimmune conditions, e.g. SLE, and its serum concentration was recently reported to associate with subclinical atherosclerosis in SLE, as measured by carotid intima-media thickness. The aim of this study was to investigate whether OPN may be used as a surrogate biomarker of subclinical atherosclerosis in SLE patients with different disease phenotypes. Methods We recruited 60 well-characterised SLE cases and 60 age- and sex-matched healthy controls. The SLE cases were divided into three different disease phenotypes: SLE with antiphospholipid syndrome (APS), lupus nephritis, and isolated skin and joint involvement. Plasma OPN was detected by ELISA (Quantikine®, R&D Systems). Common carotid arteries intima media thickness was compared between the studied groups in relation to OPN levels and risk factors for vascular changes. Intima media thickness of common carotid arteries was measured by using a sensitive ultrasound technique (LOGIQ™ E9 ultrasound, GE Healthcare). Results OPN levels were significantly higher among the entire SLE group (n = 60) compared to the healthy controls (P = 0.03). SLE cases with concomitant APS (n = 20) showed higher OPN levels than the controls (P = 0.004), whereas none of the other two subgroups differed significantly from the healthy controls. OPN and intima media thickness were correlated to several traditional risk factors of atherosclerosis, as well as to SLE-related factors. Yet, no significant correlation was observed between OPN levels and ultrasound findings of the common carotid arteries. Conclusions In line with previous studies, we observed increased OPN levels among SLE patients as compared to matched controls. However, the OPN concentrations did not correlate with intima media thickness of the common carotid arteries. Based on our findings, the use of OPN as a surrogate biomarker of subclinical atherosclerosis in SLE subjects, regardless of clinical phenotypes, cannot be recommended.
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Affiliation(s)
- Lina Wirestam
- Division of Inflammation and Infection/Rheumatology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Muna Saleh
- Division of Inflammation and Infection/Rheumatology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Christina Svensson
- Department of Clinical Physiology, University Hospital and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Michele Compagno
- Department of Clinical Sciences Lund, Rheumatology, Lund University, Lund, Sweden
| | - Helene Zachrisson
- Department of Clinical Physiology, University Hospital and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Jonas Wetterö
- Division of Inflammation and Infection/Rheumatology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Christopher Sjöwall
- Division of Inflammation and Infection/Rheumatology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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Santinelli L, De Girolamo G, Borrazzo C, Vassalini P, Pinacchio C, Cavallari EN, Statzu M, Frasca F, Scordio M, Bitossi C, Viscido A, Ceccarelli G, Mancone M, Mastroianni CM, Antonelli G, d'Ettorre G, Scagnolari C. Alteration of type I interferon response is associated with subclinical atherosclerosis in virologically suppressed HIV-1-infected male patients. J Med Virol 2021; 93:4930-4938. [PMID: 33913525 PMCID: PMC8360015 DOI: 10.1002/jmv.27028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 04/01/2021] [Accepted: 04/06/2021] [Indexed: 12/12/2022]
Abstract
Given human immunodeficiency virus‐1 (HIV‐1)‐infected patients have alterations in the type I interferon (IFN‐I) pathway and are also at elevated risk of atherosclerosis, we evaluated IFN‐I response and subclinical cardiovascular disease (CVD) association in HIV‐1‐infected patients. Transcript levels of IFN‐α/β and IFN‐stimulated gene 56 (ISG56) were evaluated by RT/real‐time PCR in peripheral blood mononuclear cells collected from asymptomatic HIV‐1‐positive male patients at high risk of developing CVD (n = 34) and healthy subjects (n = 21). Stenosis degree (≥ or <50%), calcium volume score, calcium Agatston score, and myocardial extracellular volume were examined by coronary computerized tomography scan. Carotid intima‐media thickness (cIMT), Framingham risk score, atherosclerotic cardiovascular disease (ASCVD) score, and risk score developed by data collection on adverse effects of anti‐HIV drugs (D:A:D) were also measured. Increased IFN‐α, IFN‐β, and ISG56 levels were observed in all HIV‐1‐infected males compared to healthy controls (p < .001 for all genes analyzed). HIV‐1‐infected patients with a stenosis degree ≥50% showed a higher Framingham risk score (p = .019), which was correlated with IFN‐β and ISG56 levels. HIV‐1‐infected males with enhanced IFN‐I levels and stenosis displayed a higher ASCVD calculated risk (p = .011) and D:A:D score (p = .004). Also, there was a trend toward higher IFN‐α and ISG56 mRNA levels in HIV‐1‐positive patients with an increased cIMT (p > .05). Dysregulation of IFN‐I response might participate in the pathogenesis of HIV‐1‐associated CVD.
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Affiliation(s)
- Letizia Santinelli
- Department of Molecular Medicine, Laboratory of Virology, Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Viale di Porta Tiburtina, Rome, Italy
| | - Gabriella De Girolamo
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Viale del Policlinico, Rome, Italy
| | - Cristian Borrazzo
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Viale del Policlinico, Rome, Italy
| | - Paolo Vassalini
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Viale del Policlinico, Rome, Italy
| | - Claudia Pinacchio
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Viale del Policlinico, Rome, Italy
| | - Eugenio Nelson Cavallari
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Viale del Policlinico, Rome, Italy
| | - Maura Statzu
- Department of Molecular Medicine, Laboratory of Virology, Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Viale di Porta Tiburtina, Rome, Italy
| | - Federica Frasca
- Department of Molecular Medicine, Laboratory of Virology, Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Viale di Porta Tiburtina, Rome, Italy
| | - Mirko Scordio
- Department of Molecular Medicine, Laboratory of Virology, Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Viale di Porta Tiburtina, Rome, Italy
| | - Camilla Bitossi
- Department of Molecular Medicine, Laboratory of Virology, Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Viale di Porta Tiburtina, Rome, Italy
| | - Agnese Viscido
- Department of Molecular Medicine, Laboratory of Virology, Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Viale di Porta Tiburtina, Rome, Italy
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Viale del Policlinico, Rome, Italy
| | - Massimo Mancone
- Department of Cardiovascular, Respiratory, Nephrology, Anaesthesiology and Geriatric Sciences, Sapienza University of Rome, Viale del Policlinico, Rome, Italy
| | - Claudio Maria Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Viale del Policlinico, Rome, Italy
| | - Guido Antonelli
- Department of Molecular Medicine, Laboratory of Virology, Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Viale di Porta Tiburtina, Rome, Italy.,Microbiology and Virology Unit, Sapienza University Hospital "Policlinico Umberto I", Rome, Italy
| | - Gabriella d'Ettorre
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Viale del Policlinico, Rome, Italy
| | - Carolina Scagnolari
- Department of Molecular Medicine, Laboratory of Virology, Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Viale di Porta Tiburtina, Rome, Italy
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Kim M, Huda MN, O'Connor A, Albright J, Durbin-Johnson B, Bennett BJ. Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross. Physiol Genomics 2021; 53:173-192. [PMID: 33818129 PMCID: PMC8424536 DOI: 10.1152/physiolgenomics.00140.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 03/23/2021] [Accepted: 03/26/2021] [Indexed: 12/28/2022] Open
Abstract
Mice have provided critical mechanistic understandings of clinical traits underlying metabolic syndrome (MetSyn) and susceptibility to MetSyn in mice is known to vary among inbred strains. We investigated the diet- and strain-dependent effects on metabolic traits in the eight Collaborative Cross (CC) founder strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Liver transcriptomics analysis showed that both atherogenic diet and host genetics have profound effects on the liver transcriptome, which may be related to differences in metabolic traits observed between strains. We found strain differences in circulating trimethylamine N-oxide (TMAO) concentration and liver triglyceride content, both of which are traits associated with metabolic diseases. Using a network approach, we identified a module of transcripts associated with TMAO and liver triglyceride content, which was enriched in functional pathways. Interrogation of the module related to metabolic traits identified NADPH oxidase 4 (Nox4), a gene for a key enzyme in the production of reactive oxygen species, which showed a strong association with plasma TMAO and liver triglyceride. Interestingly, Nox4 was identified as the highest expressed in the C57BL/6J and NZO/HILtJ strains and the lowest expressed in the CAST/EiJ strain. Based on these results, we suggest that there may be genetic variation in the contribution of Nox4 to the regulation of plasma TMAO and liver triglyceride content. In summary, we show that liver transcriptomic analysis identified diet- or strain-specific pathways for metabolic traits in the Collaborative Cross (CC) founder strains.
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Affiliation(s)
- Myungsuk Kim
- Department of Nutrition, University of California, Davis, California
- USDA-ARS-Western Human Nutrition Research Center, Davis, California
| | - M Nazmul Huda
- Department of Nutrition, University of California, Davis, California
- USDA-ARS-Western Human Nutrition Research Center, Davis, California
| | - Annalouise O'Connor
- Nutrition Research Institute, University of North Carolina, Kannapolis, North Carolina
| | - Jody Albright
- Nutrition Research Institute, University of North Carolina, Kannapolis, North Carolina
| | | | - Brian J Bennett
- Department of Nutrition, University of California, Davis, California
- USDA-ARS-Western Human Nutrition Research Center, Davis, California
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Lai JH, Hung LF, Huang CY, Wu DW, Wu CH, Ho LJ. Mitochondrial protein CMPK2 regulates IFN alpha-enhanced foam cell formation, potentially contributing to premature atherosclerosis in SLE. Arthritis Res Ther 2021; 23:120. [PMID: 33874983 PMCID: PMC8054390 DOI: 10.1186/s13075-021-02470-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 03/02/2021] [Indexed: 12/22/2022] Open
Abstract
Background Premature atherosclerosis occurs in patients with SLE; however, the mechanisms remain unclear. Both mitochondrial machinery and proinflammatory cytokine interferon alpha (IFN-α) potentially contribute to atherogenic processes in SLE. Here, we explore the roles of the mitochondrial protein cytidine/uridine monophosphate kinase 2 (CMPK2) in IFN-α-mediated pro-atherogenic events. Methods Foam cell measurements were performed by oil red O staining, Dil-oxLDL uptake and the BODIPY approach. The mRNA and protein levels were measured by qPCR and Western blotting, respectively. Isolation of CD4+ T cells and monocytes was performed with monoclonal antibodies conjugated with microbeads. Manipulation of protein expression was conducted by either small interference RNA (siRNA) knockdown or CRISPR/Cas9 knockout. The expression of mitochondrial reactive oxygen species (mtROS) was determined by flow cytometry and confocal microscopy. Results IFN-α enhanced oxLDL-induced foam cell formation and Dil-oxLDL uptake by macrophages. In addition to IFN-α, several triggers of atherosclerosis, including thrombin and IFN-γ, can induce CMPK2 expression, which was elevated in CD4+ T cells and CD14+ monocytes isolated from SLE patients compared to those isolated from controls. The analysis of cellular subfractions revealed that CMPK2 was present in both mitochondrial and cytosolic fractions. IFN-α-induced CMPK2 expression was inhibited by Janus kinase (JAK)1/2 and tyrosine kinase 2 (Tyk2) inhibitors. Both the knockdown and knockout of CMPK2 attenuated IFN-α-mediated foam cell formation, which involved the reduction of scavenger receptor class A (SR-A) expression. CMPK2 also regulated IFN-α-enhanced mtROS production and inflammasome activation. Conclusions The study suggests that CMPK2 plays contributing roles in the pro-atherogenic effects of IFN-α. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-021-02470-6.
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Affiliation(s)
- Jenn-Haung Lai
- Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Lin-Kou, Tao-Yuan, Taiwan, Republic of China.,Graduate Institute of Clinical Research, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Li-Feng Hung
- Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan, Republic of China
| | - Chuan-Yueh Huang
- Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan, Republic of China
| | - De-Wei Wu
- Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Lin-Kou, Tao-Yuan, Taiwan, Republic of China
| | - Chien-Hsiang Wu
- Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Lin-Kou, Tao-Yuan, Taiwan, Republic of China
| | - Ling-Jun Ho
- Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan, Republic of China.
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Wang L, Gao B, Wu M, Yuan W, Liang P, Huang J. Profiles of Immune Cell Infiltration in Carotid Artery Atherosclerosis Based on Gene Expression Data. Front Immunol 2021; 12:599512. [PMID: 33841393 PMCID: PMC8027089 DOI: 10.3389/fimmu.2021.599512] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/09/2021] [Indexed: 12/24/2022] Open
Abstract
Since immune infiltration is closely associated with the progression and prognosis of atherosclerosis, we aimed to describe the abundance of 24 immune cell types within atherosclerotic tissues. In the current study, we used the Immune Cell Abundance Identifier (ImmuCellAI), a web-based tool, to estimate the abundance of 24 immune cells based on the microarray profiles of atherosclerotic carotid artery samples to analyze the proportions and the dysregulation of immune cell types within carotid atherosclerosis. We found that atherosclerotic immune cells had a diverse landscape dominated by T cells and myeloid cells and that macrophages and dendritic cells (DCs) showed different abundance in normal and atherosclerotic tissues. Moreover, the expression of macrophages was closely related to the level of the expression of DCs and of exhausted T cells, while the expression of T-helper type 1 (Th1) cells was strongly correlated with the expression of T-helper type 2 (Th2) cells and effector memory cells. Our data confirm a distinct profile of atherosclerosis-infiltrating immune cell subpopulations, which may inspire an immunological direction for research on atherosclerosis.
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Affiliation(s)
- Long Wang
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Center for Translational Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Beibei Gao
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mingyue Wu
- Department of Cardiology, Nanjing University Medical School, Nanjing, China
| | - Wei Yuan
- Department of Cardiology, Jiangsu Taizhou People's Hospital, Taizhou, China
| | - Ping Liang
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University, Hangzhou, China
| | - Jinyu Huang
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Type I Interferon as cardiovascular risk factor in systemic and cutaneous lupus erythematosus: A systematic review. Autoimmun Rev 2021; 20:102794. [PMID: 33722754 DOI: 10.1016/j.autrev.2021.102794] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 01/14/2021] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Patients with systemic lupus erythematosus (SLE) have a high burden of cardiovascular disease (CVD) of multifactorial origin. The aim of this systematic review is to analyze the role of the interferon I (IFN-I) signature and fibroblast growth factor-23 (FGF-23) in patients with SLE or cutaneous lupus erythematosus (CLE) herein. MATERIALS AND METHODS We conducted a systematic literature search in PubMed and Scopus using keywords for major adverse cardiovascular events (MACE) and intermediate outcomes (endothelial dysfunction, subclinical atherosclerosis, platelet activation) associated with IFN-I or FGF-23 in patients with SLE and CLE. RESULTS 4745 citations were screened, of which 12 studies were included. IFN-I was associated with MACE in two third of the studies and the association was strongest for cardiac events. An association of IFN-I was found in all studies investigating impaired vascular function, but only in 50% (respectively 40%) of reports examining the relation of IFN-I and platelet activation (respectively subclinical atherosclerosis). Altogether the reports were of variable bias and quality due to high variability of examined IFN-I biomarkers and inconsistent results for different outcome measures. No studies investigating the cardiovascular risk of circulating IFN-I in CLE, nor FGF-23 in SLE or CLE were found. CONCLUSION Clinical studies measuring the association between IFN-I and direct / intermediate measures of CVD are rare and ambiguous in SLE and nonexistent in CLE, hampering a definite conclusion.
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Bi X, Du C, Wang X, Wang X, Han W, Wang Y, Qiao Y, Zhu Y, Ran L, Liu Y, Xiong J, Huang Y, Liu M, Liu C, Zeng C, Wang J, Yang K, Zhao J. Mitochondrial Damage-Induced Innate Immune Activation in Vascular Smooth Muscle Cells Promotes Chronic Kidney Disease-Associated Plaque Vulnerability. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2002738. [PMID: 33717842 PMCID: PMC7927614 DOI: 10.1002/advs.202002738] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 10/06/2020] [Indexed: 05/02/2023]
Abstract
Chronic kidney disease (CKD) is associated with accelerated atherosclerosis progression and high incidence of cardiovascular events, hinting that atherosclerotic plaques in CKD may be vulnerable. However, its cause and mechanism remain obscure. Here, it is shown that apolipoprotein E-deficient (ApoE-/-) mouse with CKD (CKD/ApoE-/- mouse) is a useful model for investigating the pathogenesis of plaque vulnerability, and premature senescence and phenotypic switching of vascular smooth muscle cells (VSMCs) contributes to CKD-associated plaque vulnerability. Subsequently, VSMC phenotypes in patients with CKD and CKD/ApoE-/- mice are comprehensively investigated. Using multi-omics analysis and targeted and VSMC-specific gene knockout mice, VSMCs are identified as both type-I-interferon (IFN-I)-responsive and IFN-I-productive cells. Mechanistically, mitochondrial damage resulting from CKD-induced oxidative stress primes the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to trigger IFN-I response in VSMCs. Enhanced IFN-I response then induces VSMC premature senescence and phenotypic switching in an autocrine/paracrine manner, resulting in the loss of fibrous cap VSMCs and fibrous cap thinning. Conversely, blocking IFN-I response remarkably attenuates CKD-associated plaque vulnerability. These findings reveal that IFN-I response in VSMCs through immune sensing of mitochondrial damage is essential for the pathogenesis of CKD-associated plaque vulnerability. Mitigating IFN-I response may hold promise for the treatment of CKD-associated cardiovascular diseases.
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Affiliation(s)
- Xianjin Bi
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Changhong Du
- State Key Laboratory of TraumaBurns and Combined InjuryInstitute of Combined InjuryChongqing Engineering Research Center for NanomedicineCollege of Preventive MedicineArmy Medical University (Third Military Medical University)Chongqing400038China
| | - Xinmiao Wang
- State Key Laboratory of TraumaBurns and Combined InjuryInstitute of Combined InjuryChongqing Engineering Research Center for NanomedicineCollege of Preventive MedicineArmy Medical University (Third Military Medical University)Chongqing400038China
| | - Xue‐Yue Wang
- Laboratory of Stem Cell & Developmental BiologyDepartment of Histology and EmbryologyCollege of Basic Medical SciencesArmy Medical University (Third Military Medical University)Chongqing400038China
| | - Wenhao Han
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Yue Wang
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Yu Qiao
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Yingguo Zhu
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Li Ran
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Yong Liu
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Jiachuan Xiong
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Yinghui Huang
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Mingying Liu
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Chi Liu
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Chunyu Zeng
- Department of CardiologyDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Junping Wang
- State Key Laboratory of TraumaBurns and Combined InjuryInstitute of Combined InjuryChongqing Engineering Research Center for NanomedicineCollege of Preventive MedicineArmy Medical University (Third Military Medical University)Chongqing400038China
| | - Ke Yang
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Jinghong Zhao
- Department of Nephrologythe Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of ChongqingKidney Center of PLAXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
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Lu GF, Chen SC, Xia YP, Ye ZM, Cao F, Hu B. Synergistic inflammatory signaling by cGAS may be involved in the development of atherosclerosis. Aging (Albany NY) 2021; 13:5650-5673. [PMID: 33589571 PMCID: PMC7950297 DOI: 10.18632/aging.202491] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 10/23/2020] [Indexed: 12/29/2022]
Abstract
Inappropriate activation or overactivation of cyclic GMP-AMP synthase (cGAS) by double-stranded deoxyribonucleic acid (dsDNA) initiates a regulatory signaling cascade triggering a variety of inflammatory responses, which are a great threat to human health. This study focused on identifying the role of cGAS in atherosclerosis and its potential mechanisms. The relationship between cGAS and atherosclerosis was identified in an ApoE -/- mouse model. Meanwhile, RNA sequencing (RNA-seq) analysis of the underlying mechanisms of atherosclerosis in RAW264.7 macrophages treated with cGAS inhibition was conducted. Results showed that cGAS was positively correlated with atherosclerotic plaque area, and was mainly distributed in macrophages. RNA-seq analysis revealed that inflammatory response, immune response and cytokine–cytokine receptor interaction may play important roles in the development of atherosclerosis. Real-time quantitative polymerase chain reaction (RT-qPCR) results showed that the expression of the pro-inflammatory factors, signal transducer and activator of transcription (Stat), interferon regulatory factor (Irf), toll-like receptors (Tlrs), and type I interferons (Ifns) were synergistically reduced when cGAS was inhibited. Furthermore, cGAS inhibition significantly inhibited RAW264.7 macrophage M1 polarization. These results demonstrate that cGAS may contribute to the development of atherosclerosis through synergistic inflammatory signaling of TLRs, STAT/IRF as well as IFNs, leading to macrophage M1 polarization.
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Affiliation(s)
- Guan-Feng Lu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Sheng-Cai Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yuan-Peng Xia
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zi-Ming Ye
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.,Department of Neurology, The First Affiliated Hospital, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Fei Cao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Bo Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Gupta S, Kaplan MJ. Bite of the wolf: innate immune responses propagate autoimmunity in lupus. J Clin Invest 2021; 131:144918. [PMID: 33529160 PMCID: PMC7843222 DOI: 10.1172/jci144918] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The etiopathogenesis of systemic lupus erythematosus (SLE), a clinically heterogeneous multisystemic syndrome that derives its name from the initial characterization of facial lesions that resemble the bite of a wolf, is considered a complex, multifactorial interplay between underlying genetic susceptibility factors and the environment. Prominent pathogenic factors include the induction of aberrant cell death pathways coupled with defective cell death clearance mechanisms that promote excessive externalization of modified cellular and nuclear debris with subsequent loss of tolerance to a wide variety of autoantigens and innate and adaptive immune dysregulation. While abnormalities in adaptive immunity are well recognized and are key to the pathogenesis of SLE, recent findings have emphasized fundamental roles of the innate immune system in the initiation and propagation of autoimmunity and the development of organ damage in this disease. This Review focuses on recent discoveries regarding the role of components of the innate immune system, specifically neutrophils and interferons, in promoting various aspects of lupus pathogenesis, with potential implications for novel therapeutic strategies.
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Mitochondrial DAMPs and altered mitochondrial dynamics in OxLDL burden in atherosclerosis. Mol Cell Biochem 2021; 476:1915-1928. [PMID: 33492610 DOI: 10.1007/s11010-021-04061-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 01/11/2021] [Indexed: 10/22/2022]
Abstract
Atherosclerosis results in life-threatening cardiovascular pathologies, including ischemic heart disease, stroke, myocardial infarction, and peripheral arterial disease. The role of increased serum low-density lipoprotein (LDL) and resultant accumulation of oxidized-LDL (oxLDL) in atheroma formation is well established. Recent findings elucidate the significance of mitochondrial damage-associated molecular patterns (mtDAMPs) in triggering sterile inflammation in concert with oxLDL. The mtDAMPs including mitochondrial DNA (mtDNA), cytochrome C, cardiolipin, heat shock protein 60 (HSP60), mitochondrial transcription factor A (TFAM), and N-formyl peptides, are expected to possess proatherogenic roles. However, limited data are available in the literature. The mtDAMPs initiate sterile inflammation in atherosclerotic lesions via numerous signaling pathways, most of which converge to the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Priming the activation of the NLRP3 inflammasome, mtDAMPs promote secretion of proinflammatory cytokines, including interleukin-1β (IL-1β), implicated in atherosclerotic lesions through vascular smooth muscle and fibroblast proliferation, arterial wall thickening, and plaque formation. In this article we critically reviewed and discussed the central role of the NLRP3 inflammasome in mtDAMP-induced sterile inflammation in atherosclerosis with specific components including caspase-1, pregnane X receptor (PXR), adenosine monophosphate activated protein kinase (AMPK), protein phosphatase 2A (PP2A), thioredoxin-interacting protein (TXNIP), and downstream cytokines including IL-1β and IL-18 as potential mediators of atherosclerosis. Better understanding of the proinflammatory effects of mtDAMPs and its pathological association with oxLDL possess immense translational significance for novel therapeutic intervention.
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The hypoxia-sensor carbonic anhydrase IX affects macrophage metabolism, but is not a suitable biomarker for human cardiovascular disease. Sci Rep 2021; 11:425. [PMID: 33432108 PMCID: PMC7801702 DOI: 10.1038/s41598-020-79978-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 12/11/2020] [Indexed: 01/18/2023] Open
Abstract
Hypoxia is prevalent in atherosclerotic plaques, promoting plaque aggravation and subsequent cardiovascular disease (CVD). Transmembrane protein carbonic anhydrase IX (CAIX) is hypoxia-induced and can be shed into the circulation as soluble CAIX (sCAIX). As plaque macrophages are hypoxic, we hypothesized a role for CAIX in macrophage function, and as biomarker of hypoxic plaque burden and CVD. As tumor patients with probable CVD are treated with CAIX inhibitors, this study will shed light on their safety profile. CAIX co-localized with macrophages (CD68) and hypoxia (pimonidazole), and correlated with lipid core size and pro-inflammatory iNOS+ macrophages in unstable human carotid artery plaques. Although elevated pH and reduced lactate levels in culture medium of CAIX knock-out (CAIXko) macrophages confirmed its role as pH-regulator, only spare respiratory capacity of CAIXko macrophages was reduced. Proliferation, apoptosis, lipid uptake and expression of pro- and anti-inflammatory genes were not altered. Plasma sCAIX levels and plaque-resident CAIX were below the detection threshold in 50 and 90% of asymptomatic and symptomatic cases, respectively, while detectable levels did not associate with primary or secondary events, or intraplaque hemorrhage. Initial findings show that CAIX deficiency interferes with macrophage metabolism. Despite a correlation with inflammatory macrophages, plaque-resident and sCAIX expression levels are too low to serve as biomarkers of future CVD.
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Li J, Huynh L, Cornwell WD, Tang MS, Simborio H, Huang J, Kosmider B, Rogers TJ, Zhao H, Steinberg MB, Thu Thi Le L, Zhang L, Pham K, Liu C, Wang H. Electronic Cigarettes Induce Mitochondrial DNA Damage and Trigger TLR9 (Toll-Like Receptor 9)-Mediated Atherosclerosis. Arterioscler Thromb Vasc Biol 2020; 41:839-853. [PMID: 33380174 DOI: 10.1161/atvbaha.120.315556] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Electronic cigarette (e-cig) use has recently been implicated in promoting atherosclerosis. In this study, we aimed to investigate the mechanism of e-cig exposure accelerated atherosclerotic lesion development. Approach and Results: Eight-week-old ApoE-/- mice fed normal laboratory diet were exposed to e-cig vapor (ECV) for 2 hours/day, 5 days/week for 16 weeks. We found that ECV exposure significantly induced atherosclerotic lesions as examined by Oil Red O staining and greatly upregulated TLR9 (toll-like receptor 9) expression in classical monocytes and in the atherosclerotic plaques, which the latter was corroborated by enhanced TLR9 expression in human femoral artery atherosclerotic plaques from e-cig smokers. Intriguingly, we found a significant increase of oxidative mitochondria DNA lesion in the plasma of ECV-exposed mice. Administration of TLR9 antagonist before ECV exposure not only alleviated atherosclerosis and the upregulation of TLR9 in plaques but also attenuated the increase of plasma levels of inflammatory cytokines, reduced the plaque accumulation of lipid and macrophages, and decreased the frequency of blood CCR2+ (C-C chemokine receptor type 2) classical monocytes. Surprisingly, we found that cytoplasmic mitochondrial DNA isolated from ECV extract-treated macrophages can enhance TLR9 activation in reporter cells and the induction of inflammatory cytokine could be suppressed by TLR9 inhibitor in macrophages. CONCLUSIONS E-cig increases level of damaged mitochondrial DNA in circulating blood and induces the expression of TLR9, which elevate the expression of proinflammatory cytokines in monocyte/macrophage and consequently lead to atherosclerosis. Our results raise the possibility that intervention of TLR9 activation is a potential pharmacological target of ECV-related inflammation and cardiovascular diseases.
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Affiliation(s)
- Jieliang Li
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ (J.L., L.H., J.H., L.T.T.L., H.W.)
| | - Luong Huynh
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ (J.L., L.H., J.H., L.T.T.L., H.W.)
| | - William D Cornwell
- Department of Physiology (W.D.C.), Temple University School of Medicine, Philadelphia, PA
| | - Moon-Shong Tang
- Department of Environment Medicine, New York University School of Medicine, Tuxedo Park (M.-S.T.)
| | - Hannah Simborio
- Center for Inflammation, Translational and Clinical Lung Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (H.S., B.K., T.J.R.)
| | - Jing Huang
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ (J.L., L.H., J.H., L.T.T.L., H.W.)
| | - Beata Kosmider
- Center for Inflammation, Translational and Clinical Lung Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (H.S., B.K., T.J.R.).,Department of Thoracic Medicine and Surgery (B.K.), Temple University School of Medicine, Philadelphia, PA
| | - Thomas J Rogers
- Center for Inflammation, Translational and Clinical Lung Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (H.S., B.K., T.J.R.)
| | - Huaqing Zhao
- Department of Clinical Sciences (H.Z.), Temple University School of Medicine, Philadelphia, PA
| | - Michael B Steinberg
- Division of General Internal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (M.B.S.)
| | - Le Thu Thi Le
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ (J.L., L.H., J.H., L.T.T.L., H.W.)
| | - Lanjing Zhang
- Gastrointestinal and Liver Pathology, Penn Medicine Princeton Medical Center, Plainsboro, New Jersey (L.Z.)
| | - Kien Pham
- Department of Pathology, Yale University School of Medicine, New Haven, CT (K.P., C.L.)
| | - Chen Liu
- Department of Pathology, Yale University School of Medicine, New Haven, CT (K.P., C.L.)
| | - He Wang
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ (J.L., L.H., J.H., L.T.T.L., H.W.)
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Depuydt MA, Prange KH, Slenders L, Örd T, Elbersen D, Boltjes A, de Jager SC, Asselbergs FW, de Borst GJ, Aavik E, Lönnberg T, Lutgens E, Glass CK, den Ruijter HM, Kaikkonen MU, Bot I, Slütter B, van der Laan SW, Yla-Herttuala S, Mokry M, Kuiper J, de Winther MP, Pasterkamp G. Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics. Circ Res 2020; 127:1437-1455. [PMID: 32981416 PMCID: PMC7641189 DOI: 10.1161/circresaha.120.316770] [Citation(s) in RCA: 335] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 09/23/2020] [Accepted: 02/25/2020] [Indexed: 02/01/2023]
Abstract
RATIONALE Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed. OBJECTIVE Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis. METHODS AND RESULTS We performed single-cell RNA and single-cell ATAC sequencing on human carotid atherosclerotic plaques to define the cells at play and determine their transcriptomic and epigenomic characteristics. We identified 14 distinct cell populations including endothelial cells, smooth muscle cells, mast cells, B cells, myeloid cells, and T cells and identified multiple cellular activation states and suggested cellular interconversions. Within the endothelial cell population, we defined subsets with angiogenic capacity plus clear signs of endothelial to mesenchymal transition. CD4+ and CD8+ T cells showed activation-based subclasses, each with a gradual decline from a cytotoxic to a more quiescent phenotype. Myeloid cells included 2 populations of proinflammatory macrophages showing IL (interleukin) 1B or TNF (tumor necrosis factor) expression as well as a foam cell-like population expressing TREM2 (triggering receptor expressed on myeloid cells 2) and displaying a fibrosis-promoting phenotype. ATACseq data identified specific transcription factors associated with the myeloid subpopulation and T cell cytokine profiles underlying mutual activation between both cell types. Finally, cardiovascular disease susceptibility genes identified using public genome-wide association studies data were particularly enriched in lesional macrophages, endothelial, and smooth muscle cells. CONCLUSIONS This study provides a transcriptome-based cellular landscape of human atherosclerotic plaques and highlights cellular plasticity and intercellular communication at the site of disease. This detailed definition of cell communities at play in atherosclerosis will facilitate cell-based mapping of novel interventional targets with direct functional relevance for the treatment of human disease.
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Affiliation(s)
- Marie A.C. Depuydt
- Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Einsteinweg 55, Leiden, the Netherlands (M.A.C.D., I.B., B.S., J.K.)
| | - Koen H.M. Prange
- Amsterdam University Medical Centers–Location AMC, University of Amsterdam, Experimental Vascular Biology, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Meibergdreef 9, the Netherlands (K.H.M.P., M.P.J.d.W.)
| | - Lotte Slenders
- Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands (L.S., A.B., F.W.A., S.W.v.d.L., M.M., G.P.)
| | - Tiit Örd
- A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.O., E.A., M.U.K., S.Y.-H.)
| | - Danny Elbersen
- Laboratory for Experimental Cardiology (D.E., S.C.A.d.J), University Medical Center Utrecht, Heidelberglaan 100, the Netherlands
| | - Arjan Boltjes
- Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands (L.S., A.B., F.W.A., S.W.v.d.L., M.M., G.P.)
| | - Saskia C.A. de Jager
- Laboratory for Experimental Cardiology (D.E., S.C.A.d.J), University Medical Center Utrecht, Heidelberglaan 100, the Netherlands
| | - Folkert W. Asselbergs
- Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands (L.S., A.B., F.W.A., S.W.v.d.L., M.M., G.P.)
| | - Gert J. de Borst
- Vascular Surgery (G.J.d.B.), University Medical Center Utrecht, Heidelberglaan 100, the Netherlands
| | - Einari Aavik
- A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.O., E.A., M.U.K., S.Y.-H.)
| | - Tapio Lönnberg
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Finland (T.L.)
| | - Esther Lutgens
- Institute for Cardiovascular Prevention (IPEK), Munich, Germany (E.L., M.P.J.d.W.)
- German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany (E.L., M.P.J.d.W.)
| | - Christopher K. Glass
- Cell and Molecular Medicine (C.K.G.), University of California San Diego, CA
- School of Medicine (C.K.G.), University of California San Diego, CA
| | - Hester M. den Ruijter
- Cardiology (H.M.d.R., M.M.), University Medical Center Utrecht, Heidelberglaan 100, the Netherlands
| | - Minna U. Kaikkonen
- A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.O., E.A., M.U.K., S.Y.-H.)
| | - Ilze Bot
- Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Einsteinweg 55, Leiden, the Netherlands (M.A.C.D., I.B., B.S., J.K.)
| | - Bram Slütter
- Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Einsteinweg 55, Leiden, the Netherlands (M.A.C.D., I.B., B.S., J.K.)
| | - Sander W. van der Laan
- Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands (L.S., A.B., F.W.A., S.W.v.d.L., M.M., G.P.)
| | - Seppo Yla-Herttuala
- A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.O., E.A., M.U.K., S.Y.-H.)
| | - Michal Mokry
- Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands (L.S., A.B., F.W.A., S.W.v.d.L., M.M., G.P.)
- Cardiology (H.M.d.R., M.M.), University Medical Center Utrecht, Heidelberglaan 100, the Netherlands
| | - Johan Kuiper
- Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Einsteinweg 55, Leiden, the Netherlands (M.A.C.D., I.B., B.S., J.K.)
| | - Menno P.J. de Winther
- Amsterdam University Medical Centers–Location AMC, University of Amsterdam, Experimental Vascular Biology, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Meibergdreef 9, the Netherlands (K.H.M.P., M.P.J.d.W.)
- Institute for Cardiovascular Prevention (IPEK), Munich, Germany (E.L., M.P.J.d.W.)
- German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany (E.L., M.P.J.d.W.)
| | - Gerard Pasterkamp
- Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands (L.S., A.B., F.W.A., S.W.v.d.L., M.M., G.P.)
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Gopal R, Marinelli MA, Alcorn JF. Immune Mechanisms in Cardiovascular Diseases Associated With Viral Infection. Front Immunol 2020; 11:570681. [PMID: 33193350 PMCID: PMC7642610 DOI: 10.3389/fimmu.2020.570681] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/28/2020] [Indexed: 12/13/2022] Open
Abstract
Influenza virus infection causes 3-5 million cases of severe illness and 250,000-500,000 deaths worldwide annually. Although pneumonia is the most common complication associated with influenza, there are several reports demonstrating increased risk for cardiovascular diseases. Several clinical case reports, as well as both prospective and retrospective studies, have shown that influenza can trigger cardiovascular events including myocardial infarction (MI), myocarditis, ventricular arrhythmia, and heart failure. A recent study has demonstrated that influenza-infected patients are at highest risk of having MI during the first seven days of diagnosis. Influenza virus infection induces a variety of pro-inflammatory cytokines and chemokines and recruitment of immune cells as part of the host immune response. Understanding the cellular and molecular mechanisms involved in influenza-associated cardiovascular diseases will help to improve treatment plans. This review discusses the direct and indirect effects of influenza virus infection on triggering cardiovascular events. Further, we discussed the similarities and differences in epidemiological and pathogenic mechanisms involved in cardiovascular events associated with coronavirus disease 2019 (COVID-19) compared to influenza infection.
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Affiliation(s)
- Radha Gopal
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States
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Wang F, Liang S, Hu J, Xu Y. Aryl hydrocarbon receptor connects dysregulated immune cells to atherosclerosis. Immunol Lett 2020; 228:55-63. [PMID: 33053378 DOI: 10.1016/j.imlet.2020.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/29/2020] [Accepted: 10/08/2020] [Indexed: 11/20/2022]
Abstract
As a chronic inflammatory disease with autoimmune components, atherosclerosis is the major cause of cardiovascular morbidity and mortality. Recent studies have revealed that the development of atherosclerosis is strongly linked to the functional activities of aryl hydrocarbon receptor (AHR), a chemical sensor that is also important for the development, maintenance, and function of a variety of immune cells. In this review, we focus on the impact of AHR signaling on the different cell types that are closely related to the atherogenesis, including T cells, B cells, dendritic cells, macrophages, foam cells, and hematopoietic stem cells in the arterial walls, and summarize the latest development on the interplay between this environmental sensor and immune cells in the context of atherosclerosis. Hopefully, elucidation of the role of AHR in atherosclerosis will facilitate the understanding of case variation in disease prevalence and may aid in the development of novel therapies.
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Affiliation(s)
- Fengge Wang
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, School of Life Science, Anhui Normal University, Wuhu, 241000, China
| | - Shuangchao Liang
- Department of Vascular Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China
| | - Jiqiong Hu
- Department of Vascular Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China
| | - Yuekang Xu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, School of Life Science, Anhui Normal University, Wuhu, 241000, China.
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Franke K, Pillai SY, Hoogenboezem M, Gijbels MJJ, Matlung HL, Geissler J, Olsman H, Pottgens C, van Gorp PJ, Ozsvar-Kozma M, Saito Y, Matozaki T, Kuijpers TW, Hendriks RW, Kraal G, Binder CJ, de Winther MPJ, van den Berg TK. SIRPα on Mouse B1 Cells Restricts Lymphoid Tissue Migration and Natural Antibody Production. Front Immunol 2020; 11:570963. [PMID: 33162986 PMCID: PMC7581795 DOI: 10.3389/fimmu.2020.570963] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 09/17/2020] [Indexed: 01/19/2023] Open
Abstract
The inhibitory immunoreceptor SIRPα is expressed on myeloid and neuronal cells and interacts with the broadly expressed CD47. CD47-SIRPα interactions form an innate immune checkpoint and its targeting has shown promising results in cancer patients. Here, we report expression of SIRPα on B1 lymphocytes, a subpopulation of murine B cells responsible for the production of natural antibodies. Mice defective in SIRPα signaling (SIRPαΔCYT mice) displayed an enhanced CD11b/CD18 integrin-dependent B1 cell migration from the peritoneal cavity to the spleen, local B1 cell accumulation, and enhanced circulating natural antibody levels, which was further amplified upon immunization with T-independent type 2 antigen. As natural antibodies are atheroprotective, we investigated the involvement of SIRPα signaling in atherosclerosis development. Bone marrow (SIRPαΔCYT>LDLR−/−) chimaeric mice developed reduced atherosclerosis accompanied by increased natural antibody production. Collectively, our data identify SIRPα as a unique B1 cell inhibitory receptor acting to control B1 cell migration, and imply SIRPα as a potential therapeutic target in atherosclerosis.
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Affiliation(s)
- Katka Franke
- Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | | | - Mark Hoogenboezem
- Sanquin Research and Landsteiner Laboratory, Department of Plasma Protein, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Marion J J Gijbels
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Pathology, CARIM, Cardiovascular Research Institute Maastricht, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Hanke L Matlung
- Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Judy Geissler
- Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Hugo Olsman
- Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Chantal Pottgens
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Patrick J van Gorp
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Maria Ozsvar-Kozma
- Department of Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
| | - Yasuyuki Saito
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takashi Matozaki
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Taco W Kuijpers
- Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Pediatric Hematology, Immunology and Infectious Disease, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Rudi W Hendriks
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
| | - Georg Kraal
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands
| | - Christoph J Binder
- Department of Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
| | - Menno P J de Winther
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Institute for Cardiovascular Prevention (IPEK), Munich, Germany
| | - Timo K van den Berg
- Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands
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50
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Kostopoulou M, Nikolopoulos D, Parodis I, Bertsias G. Cardiovascular Disease in Systemic Lupus Erythematosus: Recent Data on Epidemiology, Risk Factors and Prevention. Curr Vasc Pharmacol 2020; 18:549-565. [DOI: 10.2174/1570161118666191227101636] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 11/20/2019] [Accepted: 12/12/2019] [Indexed: 12/22/2022]
Abstract
Systemic Lupus Erythematosus (SLE) is associated with increased risk for accelerated atherosclerosis
and cardiovascular (CV) events including coronary heart disease, cerebrovascular and peripheral
artery disease. CV events occur both early and late during the disease course, with younger
patients being at much higher risk than age-matched counterparts. The risk cannot be fully accounted for
by the increased prevalence of traditional atherosclerotic factors and may be due to pathophysiologic
intermediates such as type I interferons and other inflammatory cytokines, oxidative stress, activated
granulocytes and production of extracellular chromatin traps, antiphospholipid and other autoantibodies
causing dysfunction of lipoproteins, altogether resulting in endothelial injury and pro-atherogenic
dyslipidaemia. These mechanisms may be further aggravated by chronic intake of prednisone (even at
doses <7.5 mg/day), whereas immunomodulatory drugs, especially hydroxychloroquine, may exert antiatherogenic
properties. To date, there is a paucity of randomized studies regarding the effectiveness of
preventative strategies and pharmacological interventions specifically in patients with SLE. Nevertheless,
both the European League Against Rheumatism recommendations and extrapolated evidence from
the general population emphasize that SLE patients should undergo regular monitoring for atherosclerotic
risk factors and calculation of the 10-year CV risk. Risk stratification should include diseaserelated
factors and accordingly, general (lifestyle modifications/smoking cessation, antihypertensive and
statin treatment, low-dose aspirin in selected cases) and SLE-specific (control of disease activity, minimization
of glucocorticoids, use of hydroxychloroquine) preventive measures be applied as appropriate.
Further studies will be required regarding the use of non-invasive tools and biomarkers for CV assessment
and of risk-lowering strategies tailored to SLE.
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Affiliation(s)
- Myrto Kostopoulou
- 4th Department of Internal Medicine, Attikon University Hospital, Joint Rheumatology Program, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Dionysis Nikolopoulos
- 4th Department of Internal Medicine, Attikon University Hospital, Joint Rheumatology Program, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Ioannis Parodis
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - George Bertsias
- Department of Rheumatology, Clinical Rheumatology and Allergy, University of Crete Medical School, Iraklio, Greece
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