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Peluzzo AM, St Paul A, Corbett CB, Kelemen SE, Fossati S, Liu X, Autieri MV. IL-19 Is a Novel Lymphangiocrine Factor Inducing Lymphangiogenesis and Lymphatic Junctional Regulation. Arterioscler Thromb Vasc Biol 2025. [PMID: 40371466 DOI: 10.1161/atvbaha.125.322669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Accepted: 05/01/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND The lymphatic system functions by removing fluid, macromolecules, and immune cells to maintain tissue homeostasis. The structural organization of junctional protein complexes is vital to lymphatic function where initial lymphatics have permeable button junctions and collecting lymphatics have relatively impermeable zipper junctions. During inflammation, this junctional morphology appears to reverse, contributing to overall lymphatic malfunction. Little is known about the effects of immunomodulatory cytokines on lymphatic vessel formation and function during inflammation. The purpose of this study is to test the hypothesis that IL (interleukin)-19 promotes lymphangiogenesis and proper lymphatic function during inflammation. METHODS We used cultured human dermal lymphatic endothelial cells to determine IL-19 expression and its effects on lymphangiogenesis assays. Immunocytochemistry and electric cell-substrate impedance sensing determined effects on junctional morphology as it relates to permeability in vitro. RNA sequencing determined the effects of IL-19 on gene expression. Il19-/-Ldlr-/- double knockout mice were used to determine IL-19 effects on lymphatic function and lymphatic vessel visualization in vivo. RESULTS Endogenous IL-19 expression is induced by exogenous IL-19 and VEGF (vascular endothelial growth factor) C stimulation. IL-19 is lymphangiogenic, increasing human dermal lymphatic endothelial cell migration, network formation, and proliferation. IL-19 induces expression of transcription factors and permeability-associated genes. IL-19 induces rapid VE-cadherin (vascular endothelial cadherin) phosphorylation, increases permeability of human dermal lymphatic endothelial cell monolayers, and mitigates oxidized low-density lipoprotein-associated decrease in human dermal lymphatic endothelial cell permeability. In vivo, Il19-/-Ldlr-/- double knockout mice on a high-fat diet have impaired lymphatic drainage, decreased lymphatic branch points, and increased percentage of zippered junctions compared with control mice. CONCLUSIONS Taken together, these data show that IL-19 has potent effects on lymphatic vessel formation and function in vitro and that IL-19 regulates lymphatic drainage in vivo. IL-19 may represent an immunomodulatory cytokine with therapeutic potential for improving impaired lymphatic function consequent to inflammation.
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Affiliation(s)
- Amanda M Peluzzo
- Lemole Center for Integrated Lymphatics and Vascular Research (A.M.P., A.S.P., C.B.C., S.E.K., X.L., M.V.A.)
| | - Amanda St Paul
- Lemole Center for Integrated Lymphatics and Vascular Research (A.M.P., A.S.P., C.B.C., S.E.K., X.L., M.V.A.)
| | - Cali B Corbett
- Lemole Center for Integrated Lymphatics and Vascular Research (A.M.P., A.S.P., C.B.C., S.E.K., X.L., M.V.A.)
| | - Sheri E Kelemen
- Lemole Center for Integrated Lymphatics and Vascular Research (A.M.P., A.S.P., C.B.C., S.E.K., X.L., M.V.A.)
| | - Silvia Fossati
- Alzheimer's Center at Temple, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (S.F.)
| | - Xiaolei Liu
- Lemole Center for Integrated Lymphatics and Vascular Research (A.M.P., A.S.P., C.B.C., S.E.K., X.L., M.V.A.)
| | - Michael V Autieri
- Lemole Center for Integrated Lymphatics and Vascular Research (A.M.P., A.S.P., C.B.C., S.E.K., X.L., M.V.A.)
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Zhevlakova I, Liu H, Dudiki T, Gao D, Yakubenko V, Tkachenko S, Cherepanova O, Podrez EA, Byzova TV. Mechanisms and consequences of myeloid adhesome dysfunction in atherogenesis. Cardiovasc Res 2025; 121:62-76. [PMID: 39393814 PMCID: PMC11999018 DOI: 10.1093/cvr/cvae223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 07/24/2024] [Accepted: 08/23/2024] [Indexed: 10/13/2024] Open
Abstract
AIMS In the context of atherosclerosis, macrophages exposed to oxidized low-density lipoproteins (oxLDLs) exhibit cellular abnormalities, specifically in adhesome functions, yet the mechanisms and implications of these adhesive dysfunctions remain largely unexplored. METHODS AND RESULTS This study reveals a significant depletion of Kindlin3 (K3) or Fermt3, an essential component of the adhesome regulating integrin functions, in macrophages located within atherosclerotic plaques in vivo and following oxLDL exposure in vitro. To examine the effects of K3 deficiency, the study utilized hyperlipidaemic bone marrow chimeras devoid of myeloid Kindlin3 expression. The absence of myeloid K3 increased atherosclerotic plaque burden in the aortas in vivo and enhanced lipid accumulation and lipoprotein uptake in macrophages from Kindlin3-null chimeric mice in vitro. Importantly, re-expression of K3 in macrophages ameliorated these abnormalities. RNA sequencing of bone marrow-derived macrophages (BMDM) from K3-deficient mice revealed extensive deregulation in adhesion-related pathways, echoing changes observed in wild-type cells treated with oxLDL. Notably, there was an increase in Olr1 expression [encoding the lectin-like oxidized LDL receptor-1 (LOX1)], a gene implicated in atherogenesis. The disrupted K3-integrin axis in macrophages led to a significant elevation in the LOX1 receptor, contributing to increased oxLDL uptake and foam cell formation. Inhibition of LOX1 normalized lipid uptake in Kindlin3-null macrophages. A similar proatherogenic phenotype, marked by increased macrophage LOX1 expression and foam cell formation, was observed in myeloid-specific Itgβ1-deficient mice but not in Itgβ2-deficient mice, underscoring the critical role of K3/Itgβ1 interaction. CONCLUSION This study shows that the loss of Kindlin3 in macrophages upon exposure to oxLDL leads to adhesome dysfunction in atherosclerosis and reveals the pivotal role of Kindlin3 in macrophage function and its contribution to the progression of atherosclerosis, providing valuable insights into the molecular mechanisms that could be targeted for therapeutic interventions.
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Affiliation(s)
- Irina Zhevlakova
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
| | - Huan Liu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
| | - Tejasvi Dudiki
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
| | - Detao Gao
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
| | - Valentin Yakubenko
- Department of Biomedical Sciences, Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37684, USA
| | - Svyatoslav Tkachenko
- Department of Genetics and Genome Sciences, Case Western Reserve University, 2109 Adelbert Rd Building, Cleveland, OH 44106, USA
| | - Olga Cherepanova
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
| | - Eugene A Podrez
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
| | - Tatiana V Byzova
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
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Williams KJ. Inflammation in atherosclerosis: a Big Idea that has underperformed so far. Curr Opin Lipidol 2025; 36:78-87. [PMID: 39846349 PMCID: PMC11888836 DOI: 10.1097/mol.0000000000000973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
PURPOSE OF REVIEW For many years, inflammation has been a major concept in basic research on atherosclerosis and in the development of potential diagnostic tools and treatments. The purpose of this review is to assess the performance of this concept with an emphasis on recent clinical trials. In addition, contemporary literature may help identify new therapeutic targets, particularly in the context of the treatment of early, rather than end-stage, arterial disease. RECENT FINDINGS Newly reported clinical trials cast doubt on the efficacy of colchicine, the sole anti-inflammatory agent currently approved for use in patients with atherosclerotic cardiovascular disease (ASCVD). New analyses also challenge the hypothesis that residual ASCVD event risk after optimal management of lipids, blood pressure, and smoking arises primarily from residual inflammatory risk. Current clinical practice to initiate interventions so late in the course of atherosclerotic arterial disease may be a better explanation. Lipid-lowering therapy in early atherosclerosis, possibly combined with novel add-on agents to specifically accelerate resolution of maladaptive inflammation, may be more fruitful than the conventional approach of testing immunosuppressive strategies in end-stage arterial disease. Also discussed is the ongoing revolution in noninvasive technologies to image the arterial wall. These technologies are changing screening, diagnosis, and treatment of atherosclerosis, including early and possibly reversable disease. SUMMARY The burden of proof that the Big Idea of inflammation in atherosclerosis has clinical value remains the responsibility of its advocates. This responsibility requires convincing trial data but still seems largely unmet. Unfortunately, the focus on inflammation as the source of residual ASCVD event risk has distracted us from the need to screen and treat earlier.
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Affiliation(s)
- Kevin Jon Williams
- Department of Cardiovascular Sciences and Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
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Dousdampanis P, Aggeletopoulou I, Mouzaki A. The role of M1/M2 macrophage polarization in the pathogenesis of obesity-related kidney disease and related pathologies. Front Immunol 2025; 15:1534823. [PMID: 39867890 PMCID: PMC11758166 DOI: 10.3389/fimmu.2024.1534823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 12/19/2024] [Indexed: 01/28/2025] Open
Abstract
Obesity is a rapidly growing health problem worldwide, affecting both adults and children and increasing the risk of chronic diseases such as type 2 diabetes, hypertension and cardiovascular disease (CVD). In addition, obesity is closely linked to chronic kidney disease (CKD) by either exacerbating diabetic complications or directly causing kidney damage. Obesity-related CKD is characterized by proteinuria, lipid accumulation, fibrosis and glomerulosclerosis, which can gradually impair kidney function. Among the immune cells of the innate and adaptive immune response involved in the pathogenesis of obesity-related diseases, macrophages play a crucial role in the inflammation associated with CKD. In obese individuals, macrophages enter a pro-inflammatory state known as M1 polarization, which contributes to chronic inflammation. This polarization promotes tissue damage, inflammation and fibrosis, leading to progressive loss of kidney function. In addition, macrophage-induced oxidative stress is a key feature of CKD as it also promotes cell damage and inflammation. Macrophages also contribute to insulin resistance in type 2 diabetes by releasing inflammatory molecules that impair glucose metabolism, complicating the management of diabetes in obese patients. Hypertension and atherosclerosis, which are often associated with obesity, also contribute to the progression of CKD via immune and inflammatory pathways. Macrophages influence blood pressure regulation and contribute to vascular inflammation, particularly via the renin-angiotensin system. In atherosclerosis, macrophages accumulate in arterial plaques, leading to chronic inflammation and plaque instability, which may increase the risk of CVD in CKD patients. This review focuses on the involvement of macrophages in CKD and highlights their role as a critical link between CKD and other pathologies. Targeting macrophage polarization and the ensuing macrophage-induced inflammation could be an effective therapeutic strategy for CKD and related diseases and improve outcomes for patients with obesity-related kidney disease.
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Affiliation(s)
| | - Ioanna Aggeletopoulou
- Laboratory of Immunohematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Athanasia Mouzaki
- Laboratory of Immunohematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
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Zhang Y, Ren Y, Zhou T, Qian Z, Bao Z. Vav family exchange factors: Potential regulator in atherosclerosis. Biochem Biophys Rep 2024; 40:101878. [PMID: 39649800 PMCID: PMC11625217 DOI: 10.1016/j.bbrep.2024.101878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 10/26/2024] [Accepted: 11/14/2024] [Indexed: 12/11/2024] Open
Abstract
The Vav family of guanosine nucleotide exchange factors (GEFs) regulates the phosphorylation of tyrosinase, influencing various physiological and pathological processes by modulating the binding of Rho GTPases to GDP/GTP. Recent research has highlighted the critical role of Vav family activation in tumorigenesis, neurological disorders, immune-related dysfunctions, and other diseases. This review offers a comprehensive overview of the structure and function of Vav proteins and their significant impact on the pathophysiology of atherosclerosis. In addition, we pay attention to the development of diagnostic and therapeutic targets centered around Vav proteins.
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Affiliation(s)
- Yu Zhang
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214002, China
| | - Yongwei Ren
- Research Institute for Reproductive Health and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, 214002, China
| | - Tao Zhou
- Research Institute for Reproductive Health and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, 214002, China
| | - Zhengtao Qian
- Department of Clinical Laboratory, Changshu Medicine Examination Institute, Changshu, 215500, China
| | - Zhengyang Bao
- Department of Internal Medicine, Wuxi Maternity and Child Health Care Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, 214002, China
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Zhou C, Sun T, Zhao J, Xu Y, Dong Z, Lu F, Li B. Lymphatic Vessel-Mediated Attenuation of Persistent Macrophage Infiltration Improves Fat Grafting Outcomes in Mice Models. Aesthet Surg J 2024; 44:NP737-NP748. [PMID: 38870037 DOI: 10.1093/asj/sjae110] [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] [Indexed: 06/15/2024] Open
Abstract
BACKGROUND Persistent macrophage infiltration may lead to adverse consequences, such as calcifications and nodules in fat grafts. Lymphatic vessels, which transport inflammatory cells, are involved in regulating inflammatory responses. Less is known, however, about lymphatic vessels after fat grafting. OBJECTIVES The aim of this study was to explore the regulation of fat graft survival by lymphatic vessels. METHODS A common adipose graft model was constructed to assess the processes responsible for changes in the number of lymphatic vessels in grafts. Adipose tissue samples from C57/BL6 mice and green fluorescent protein-expressing mice were cross-grafted to determine the source of lymphatic vessels. The number of lymphatic vessels in the grafts was increased by treatment with vascular endothelial growth factor C, and the effects of this increase on fat grafting were evaluated. RESULTS The number of lymphatic vessels was greater in postgrafted fat than in inguinal fat before transplantation, with lymphatic vessels in these grafts gradually transitioning from donor to recipient sources. Lymphatic vessels grew more slowly than blood vessels during early stages of grafting; during later stages, however, the number of blood vessels declined markedly, with more lymphatic vessels than blood vessels being observed 60 days after grafting. Vascular endothelial growth factor C treatment increased graft lymphatics and distant volume retention, while reducing fibrosis and oil sacs. Lymphatic vessels acted as drainage channels for macrophages, with the degree of sustained macrophage infiltration decreasing with increases in the number of lymphatic vessels. CONCLUSIONS Increasing the number of lymphatic vessels is beneficial for fat graft survival, which may be related to a reduction in prolonged macrophage infiltration. LEVEL OF EVIDENCE: 4
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Shi H, Song J, Gao L, Shan X, Panicker SR, Yao L, McDaniel M, Zhou M, McGee S, Zhong H, Griffin CT, Xia L, Shao B. Deletion of Talin1 in Myeloid Cells Facilitates Atherosclerosis in Mice. Arterioscler Thromb Vasc Biol 2024; 44:1799-1812. [PMID: 38899470 DOI: 10.1161/atvbaha.123.319677] [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: 06/01/2023] [Accepted: 04/23/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND Integrin-regulated monocyte recruitment and cellular responses of monocyte-derived macrophages are critical for the pathogenesis of atherosclerosis. In the canonical model, talin1 controls ligand binding to integrins, a prerequisite for integrins to mediate leukocyte recruitment and induce immune responses. However, the role of talin1 in the development of atherosclerosis has not been studied. Our study investigated how talin1 in myeloid cells regulates the progression of atherosclerosis. METHODS On an Apoe-/- background, myeloid talin1-deficient mice and the control mice were fed with a high-fat diet for 8 or 12 weeks to induce atherosclerosis. The atherosclerosis development in the aorta and monocyte recruitment into atherosclerotic lesions were analyzed. RESULTS Myeloid talin1 deletion facilitated the formation of atherosclerotic lesions and macrophage deposition in lesions. Talin1 deletion abolished integrin β2-mediated adhesion of monocytes but did not impair integrin α4β1-dependent cell adhesion in a flow adhesion assay. Strikingly, talin1 deletion did not prevent Mn2+- or chemokine-induced activation of integrin α4β1 to the high-affinity state for ligands. In an in vivo competitive homing assay, monocyte infiltration into inflamed tissues was prohibited by antibodies to integrin α4β1 but was not affected by talin1 deletion or antibodies to integrin β2. Furthermore, quantitative polymerase chain reaction and ELISA (enzyme-linked immunosorbent assay) analysis showed that macrophages produced cytokines to promote inflammation and the proliferation of smooth muscle cells. Ligand binding to integrin β3 inhibited cytokine generation in macrophages, although talin1 deletion abolished the negative effects of integrin β3. CONCLUSIONS Integrin α4β1 controls monocyte recruitment during atherosclerosis. Talin1 is dispensable for integrin α4β1 activation to the high-affinity state and integrin α4β1-mediated monocyte recruitment. Yet, talin1 is required for integrin β3 to inhibit the production of inflammatory cytokines in macrophages. Thus, intact monocyte recruitment and elevated inflammatory responses cause enhanced atherosclerosis in talin1-deficient mice. Our study provides novel insights into the roles of myeloid talin1 and integrins in the progression of atherosclerosis.
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Affiliation(s)
- Huiping Shi
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center (H.S., L.X.)
| | - Jianhua Song
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Liang Gao
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Xindi Shan
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Sumith R Panicker
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Longbiao Yao
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Michael McDaniel
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Meixiang Zhou
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Samuel McGee
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Hui Zhong
- Lindsley F. Kimball Research Institute, New York Blood Center (H.Z., B.S.)
| | - Courtney T Griffin
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Lijun Xia
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center (H.S., L.X.)
| | - Bojing Shao
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
- Lindsley F. Kimball Research Institute, New York Blood Center (H.Z., B.S.)
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Chen R, Zhang H, Tang B, Luo Y, Yang Y, Zhong X, Chen S, Xu X, Huang S, Liu C. Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:130. [PMID: 38816371 PMCID: PMC11139930 DOI: 10.1038/s41392-024-01840-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 04/02/2024] [Accepted: 04/21/2024] [Indexed: 06/01/2024] Open
Abstract
The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate immune system, macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and severity of cardiovascular diseases, including coronary heart disease, valvular disease, myocarditis, cardiomyopathy, heart failure, atherosclerosis and aneurysm, which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific diseases. Besides, recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity, cell-cell interactions, and downstream mechanisms of therapeutic targets at a higher resolution, which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular diseases. Remarkably, myocardial fibrosis, a prevalent characteristic in most cardiac diseases, remains a formidable clinical challenge, necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac diseases. In this review, we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by single-cell sequencing technologies, with a focus on different causes and characteristics of diseases, especially the relationship between inflammation and fibrosis in cardiac diseases (myocardial infarction, pressure overload, myocarditis, dilated cardiomyopathy, diabetic cardiomyopathy and cardiac aging) and the relationship between inflammation and vascular injury in vascular diseases (atherosclerosis and aneurysm). Finally, we also highlight the preclinical/clinical macrophage targeting strategies and translational implications.
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Affiliation(s)
- Runkai Chen
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Hongrui Zhang
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Botao Tang
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Yukun Luo
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Yufei Yang
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Xin Zhong
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China
| | - Sifei Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Xinjie Xu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
| | - Shengkang Huang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
| | - Canzhao Liu
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510280, China.
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Verovenko V, Tennstedt S, Kleinecke M, Kessler T, Schunkert H, Erdmann J, Ensminger S, Aherrahrou Z. Identification of a functional missense variant in the matrix metallopeptidase 10 (MMP10) gene in two families with premature myocardial infarction. Sci Rep 2024; 14:12212. [PMID: 38806571 PMCID: PMC11133425 DOI: 10.1038/s41598-024-62878-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 05/22/2024] [Indexed: 05/30/2024] Open
Abstract
A positive family history is a major independent risk factor for atherosclerosis, and genetic variation is an important aspect of cardiovascular disease research. We identified a heterozygous missense variant p.L245P in the MMP10 gene in two families with premature myocardial infarction using whole-exome sequencing. The aim of this study was to investigate the consequences of this variant using in-silico and functional in-vitro assays. Molecular dynamics simulations were used to analyze protein interactions, calculate free binding energy, and measure the volume of the substrate-binding cleft of MMP10-TIMP1 models. The p.L245P variant showed an altered protein surface, different intra- and intermolecular interactions of MMP10-TIMP1, a lower total free binding energy between MMP10-TIMP1, and a volume-minimized substrate-binding cleft of MMP10 compared to the wild-type. For the functional assays, human THP-1 cells were transfected with plasmids containing MMP10 cDNA carrying the p.L245P and wild-type variant and differentiated into macrophages. Macrophage adhesion and migration assays were then conducted, and pro-inflammatory chemokine levels were evaluated. The p.L245P variant led to macrophages that were more adherent, less migratory, and secreted higher levels of the pro-inflammatory chemokines CXCL1 and CXCL8 than wild-type macrophages. Thus, the p.L245P variant in MMP10 may influence the pathogenesis of atherosclerosis in families with premature myocardial infarction by altering protein - protein interactions, macrophage adhesion and migration, and expression of pro-inflammatory chemokines, which may increase plaque rupture. These results could contribute to the development of selective MMP10 inhibitors and reduce the risk of atherosclerosis in families with a history of premature myocardial infarction.
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Affiliation(s)
- Viktor Verovenko
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany
- DZHK (German Research Centre for Cardiovascular Research) Partner Site Hamburg/Luebeck/Kiel, Luebeck, Germany
- University Heart Center, Luebeck, Germany
| | - Stephanie Tennstedt
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany
- DZHK (German Research Centre for Cardiovascular Research) Partner Site Hamburg/Luebeck/Kiel, Luebeck, Germany
- University Heart Center, Luebeck, Germany
| | - Mariana Kleinecke
- Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, 0811, Australia
| | - Thorsten Kessler
- Department of Cardiology, German Heart Centre Munich, Technical University of Munich, Munich, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Heribert Schunkert
- Department of Cardiology, German Heart Centre Munich, Technical University of Munich, Munich, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Jeanette Erdmann
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany
- DZHK (German Research Centre for Cardiovascular Research) Partner Site Hamburg/Luebeck/Kiel, Luebeck, Germany
- University Heart Center, Luebeck, Germany
| | - Stephan Ensminger
- University Heart Center, Luebeck, Germany
- Clinic for Cardiac and Thoracic Vascular Surgery, UKSH (University Hospital Schleswig-Holstein), Luebeck, Germany
| | - Zouhair Aherrahrou
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany.
- DZHK (German Research Centre for Cardiovascular Research) Partner Site Hamburg/Luebeck/Kiel, Luebeck, Germany.
- University Heart Center, Luebeck, Germany.
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10
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He C, Kim HI, Park J, Guo J, Huang W. The role of immune cells in different stages of atherosclerosis. Int J Med Sci 2024; 21:1129-1143. [PMID: 38774746 PMCID: PMC11103388 DOI: 10.7150/ijms.94570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/17/2024] [Indexed: 05/24/2024] Open
Abstract
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of immune cells in the intima of arteries. Experimental and clinical evidence shows that both innate and adaptive immunity orchestrate the progression of atherosclerosis. The heterogeneous nature of immune cells within atherosclerosis lesions is important. Studies utilizing high-dimensional mass spectrometry and single-cell RNA sequencing of leukocytes from atherosclerotic lesions show the diversity and adaptability of these immune cell subtypes. Their migration, compositional changes, phenotypic alterations, and adaptive responses are key features throughout atherosclerosis progression. Understanding how these immune cells and their subtypes affect atherogenesis would help to develop novel therapeutic approaches that control atherosclerosis progression. Precise targeting of specific immune system components involved in atherosclerosis, rather than broad suppression of the immune system with anti-inflammatory agents, can more accurately regulate the progress of atherosclerosis with fewer side effects. In this review, we cover the most recent advances in the field of atherosclerosis to understand the role of various immune cells on its development. We focus on the complex network of immune cells and the interaction between the innate immune system and adaptive immune system.
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Affiliation(s)
- Cong He
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing 163319, PR China
| | - Hyo In Kim
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
| | - Jinbong Park
- Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Junli Guo
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, School of Public Health, Hainan Medical University, Haikou 571199, PR China
| | - Wei Huang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou 571199, PR China
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, School of Public Health, Hainan Medical University, Haikou 571199, PR China
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11
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Gianopoulos I, Daskalopoulou SS. Macrophage profiling in atherosclerosis: understanding the unstable plaque. Basic Res Cardiol 2024; 119:35-56. [PMID: 38244055 DOI: 10.1007/s00395-023-01023-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 11/01/2023] [Accepted: 11/01/2023] [Indexed: 01/22/2024]
Abstract
The development and rupture of atherosclerotic plaques is a major contributor to myocardial infarctions and ischemic strokes. The dynamic evolution of the plaque is largely attributed to monocyte/macrophage functions, which respond to various stimuli in the plaque microenvironment. To this end, macrophages play a central role in atherosclerotic lesions through the uptake of oxidized low-density lipoprotein that gets trapped in the artery wall, and the induction of an inflammatory response that can differentially affect the stability of the plaque in men and women. In this environment, macrophages can polarize towards pro-inflammatory M1 or anti-inflammatory M2 phenotypes, which represent the extremes of the polarization spectrum that include Mhem, M(Hb), Mox, and M4 populations. However, this traditional macrophage model paradigm has been redefined to include numerous immune and nonimmune cell clusters based on in-depth unbiased single-cell approaches. The goal of this review is to highlight (1) the phenotypic and functional properties of monocyte subsets in the circulation, and macrophage populations in atherosclerotic plaques, as well as their contribution towards stable or unstable phenotypes in men and women, and (2) single-cell RNA sequencing studies that have advanced our knowledge of immune, particularly macrophage signatures present in the atherosclerotic niche. We discuss the importance of performing high-dimensional approaches to facilitate the development of novel sex-specific immunotherapies that aim to reduce the risk of cardiovascular events.
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Affiliation(s)
- Ioanna Gianopoulos
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine and Health Sciences, Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada
| | - Stella S Daskalopoulou
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine and Health Sciences, Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada.
- Division of Internal Medicine, Department of Medicine, Faculty of Medicine and Health Sciences, McGill University Health Centre, McGill University, Montreal, Canada.
- Department of Medicine, Research Institute of the McGill University Health Centre, Glen Site, 1001 Decarie Boulevard, EM1.2210, Montreal, Quebec, H4A 3J1, Canada.
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12
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Eisenbaum N, Meunier N. A stochastic lipid structured model for macrophage dynamics in atherosclerotic plaques. J Math Biol 2024; 88:15. [PMID: 38227025 DOI: 10.1007/s00285-023-02029-w] [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: 09/30/2022] [Revised: 09/27/2023] [Accepted: 11/09/2023] [Indexed: 01/17/2024]
Abstract
We propose to model certain aspects of the dynamics of a macrophage that moves randomly in a one dimensional space in arterial wall tissue and grows by accumulating localized lipid particles, thus reducing its motility. This phenomenon has been observed in the context of atherosclerotic plaque formation. For this purpose, we use a system of stochastic differential equations satisfied by the position and diffusion coefficient of a Brownian particle whose diffusion coefficient is modified at each visit to the origin and with a dumping coefficient. The novelty of the model, with respect to Bénichou et al. (Phys Rev E 85(2):021137, 2012), Meunier et al. (Acta Appl Math 161:107-126, 2019), is to include offloading of lipids through the dumping term. We find explicit necessary and sufficient conditions for macrophage trapping in the locally enriched region.
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Affiliation(s)
| | - Nicolas Meunier
- LaMME, UMR 8071, CNRS, Université Paris-Saclay, Gif-sur-Yvette, France
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13
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Christ A, Maas SL, Jin H, Lu C, Legein B, Wijnands E, Temmerman L, Otten J, Isaacs A, Zenke M, Stoll M, Biessen EAL, van der Vorst EPC. In situ lipid-loading activates peripheral dendritic cell subsets characterized by cellular ROS accumulation but compromises their capacity to prime naïve T cells. Free Radic Biol Med 2024; 210:406-415. [PMID: 38061606 DOI: 10.1016/j.freeradbiomed.2023.11.044] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 11/30/2023] [Indexed: 12/22/2023]
Abstract
BACKGROUND AND AIMS Dendritic cells (DCs), professional antigen-presenting cells, play an important role in pathologies by controlling adaptive immune responses. However, their adaptation to and functionality in hypercholesterolemia, a driving factor in disease onset and progression of atherosclerosis remains to be established. METHODS In this study, we addressed the immediate impact of high fat diet-induced hypercholesterolemia in low-density lipoprotein receptor deficient (Ldlr-/-) mice on separate DC subsets, their compartmentalization and functionality. RESULTS While hypercholesterolemia induced a significant rise in bone marrow myeloid and dendritic cell progenitor (MDP) frequency and proliferation rate after high fat diet feeding, it did not affect DC subset numbers in lymphoid tissue. Hypercholesterolemia led to almost immediate and persistent augmentation in granularity of conventional DCs (cDCs), in particular cDC2, reflecting progressive lipid accumulation by these subsets. Plasmacytoid DCs were only marginally and transiently affected. Lipid loading increased co-stimulatory molecule expression and ROS accumulation by cDC2. Despite this hyperactivation, lipid-laden cDC2 displayed a profoundly reduced capacity to stimulate naïve CD4+ T cells. CONCLUSION Our data provide evidence that in hypercholesterolemic conditions, peripheral cDC2 subsets engulf lipids in situ, leading to a more activated status characterized by cellular ROS accumulation while, paradoxically, compromising their T cell priming ability. These findings will have repercussions not only for lipid driven cardiometabolic disorders like atherosclerosis, but also for adaptive immune responses to pathogens and/or endogenous (neo) antigens under conditions of hyperlipidemia.
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Affiliation(s)
- Anette Christ
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Health Office Frankfurt/Main, Frankfurt/Main, Germany.
| | - Sanne L Maas
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
| | - Han Jin
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Chang Lu
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Bart Legein
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Erwin Wijnands
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Lieve Temmerman
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Jeroen Otten
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Aaron Isaacs
- Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
| | - Martin Zenke
- Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, 52074, Aachen, Germany; Department of Hematology, Oncology and Stem Cell Transplantation, RWTH Aachen University Medical School, 52074, Aachen, Germany
| | - Monika Stoll
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms-University, Münster, Germany
| | - Erik A L Biessen
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
| | - Emiel P C van der Vorst
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany.
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14
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Arief Waskito B, Sargowo D, Kalsum U, Tjokroprawiro A. Anti-atherosclerotic activity of aqueous extract of Ipomoea batatas (L.) leaves in high-fat diet-induced atherosclerosis model rats. J Basic Clin Physiol Pharmacol 2023; 34:725-734. [PMID: 34986543 DOI: 10.1515/jbcpp-2021-0080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 10/15/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Cardiovascular diseases, especially atherosclerosis, are the leading cause of human mortality in Indonesia. Ipomoea batatas (L.) is a food plant used in Indonesian traditional medicine to treat cardiovascular diseases and related conditions. We assessed the anti-atherosclerotic activity of the aqueous extract of I. batatas leaves in a rat model of high-fat diet-induced atherosclerosis and its mechanism. METHODS The presence of amino acid content in the I. batatas L. purple variant was determined by liquid chromatography high-resolution mass spectrometry (LC-HRMS). Thirty male Wistar rats were divided into five groups (n=6/group), i.e., standard diet group (SD), high-fat diet group (HF), and HF plus I. batatas L. extracts orally (625; 1,250; or 2,500 mg/kg) groups. The numbers of macrophages and aortic wall thickness were analyzed histologically. Immunohistochemical analyses were performed to assess foam cells-oxidized low-density lipoprotein (oxLDL), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF) expression in the aorta. RESULTS LC-HRMS analysis showed nine amino acid content were identified from I. batatas L. In vivo study revealed that oral administration of I. batatas L. leaf extract alleviated foam cells-oxLDL formation and aortic wall thickness caused by high-fat diet atherosclerosis rats. Further, I. batatas L. leaf extract promoted the number of macrophages and modulated VEGF and eNOS expression in the aorta. CONCLUSIONS I. batatas L. leaf extract shows a positive anti-atherosclerosis effect. Furthermore, the mechanism may promote the macrophages, eNOS, VEGF expressions, and inhibition of foam cells-oxLDL formation and aortic wall thickness with the best dosage at 2,500 mg/kg. This could represent a novel approach to prevent cardiovascular diseases.
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Affiliation(s)
- Budi Arief Waskito
- Doctoral Program of Medical Science, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, Indonesia
- Department of Internal Medicine, Faculty of Medicine, Wijaya Kusuma University, Surabaya, East Java, Indonesia
| | - Djanggan Sargowo
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Brawijaya, Dr. Saiful Anwar General Hospital, Malang, East Java, Indonesia
| | - Umi Kalsum
- Department of Pharmacology, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, Indonesia
| | - Askandar Tjokroprawiro
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo Hospital, Surabaya, East Java, Indonesia
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15
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Ke J, Li J, Chen J, Lai C, Zheng W, Fu X, Fang X, Guo L, Shi Z. A Non-Linear Role of Hyperlipidemia on Progression of Intracranial Atherosclerotic Plaques and Acute Downstream Ischemic Events. J Atheroscler Thromb 2023; 30:1448-1460. [PMID: 36709996 PMCID: PMC10564665 DOI: 10.5551/jat.63971] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/13/2022] [Indexed: 01/28/2023] Open
Abstract
AIM Intracranial atherosclerotic stenosis (ICAS) is the leading cause of ischemic stroke worldwide. Hyperlipidemia is a major contributor to atherosclerosis. However, the effect of hyperlipidemia on the evolution of intracranial atherosclerotic plaques and downstream ischemic episodes remains unclear. In this study, we aimed to assess the radiological features of ICAS plaques and to explore the relationship between hyperlipidemia and plaque progression. METHODS We included people with ICAS (≥50% stenosis) undergoing high-resolution magnetic resonance imaging. The culprit plaque was defined as the sole, or in case of multiple stenosis, the narrowest plaque on the intracranial artery responsible for acute ischemic stroke. Demographic, clinical data, plaque features on MRI, and lipid parameters were compared between culprit and non-culprit plaques. Plaque enhancement was graded as Grade 0, 1 and 2 by comparing to the adjacent normal vessel wall and pituitary funnel after contrast enhancement on T1-weighted sequences. RESULTS 162 patients were included (mean age 57.7±12.1 years, male 61.6%), 110 of whom were identified as culprit plaque with an ipsilateral acute stroke. High-grade enhancement was the most prominent MRI feature of the culpable plaque (Grade-2: OR 6.539, 95%CI 1.706-23.707, p=0.006). LDL cholesterol was significantly associated with overall acute ischemic stroke caused by culprit plaque. After stratification by enhancement grading LDL was independently associated with ischemic events in Grade-1 enhancement plaques (OR 6.778, 95%CI 2.122-21.649, p=0.001). In patients with Grade-2 enhancement plaques, however, LDL was not associated with ischemic event; in contrast, Neutrophil/Lymphocyte ratio was independently associated with ischemic events caused by Grade-2 enhancement plaques (OR 2.188, 95%CI 1.209-3.961, p=0.010). CONCLUSIONS LDL was related with ischemia events in intermediate stage of intracranial atherosclerotic plaque progression, an excellent period for intensive lipid-lowering treatment. In advanced stage, inflammatory agents maybe the main contributor to ischemic events.
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Affiliation(s)
- Jianxia Ke
- Department of Neurology and Stroke Center, Affiliate Dongguan People’s Hospital, Southern Medical University, Dongguan, China
| | - Jinrui Li
- Department of Neurology and Stroke Center, Affiliate Dongguan People’s Hospital, Southern Medical University, Dongguan, China
| | - Junting Chen
- Department of Neurology and Stroke Center, Affiliate Dongguan People’s Hospital, Southern Medical University, Dongguan, China
| | - Chengze Lai
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, China
| | - Weicheng Zheng
- Department of Neurology and Stroke Center, Affiliate Dongguan People’s Hospital, Southern Medical University, Dongguan, China
| | - Xiaoli Fu
- Department of Neurology and Stroke Center, Affiliate Dongguan People’s Hospital, Southern Medical University, Dongguan, China
| | - Xuewen Fang
- Department of Radiology, Affiliate Dongguan People’s Hospital, Southern Medical University, Dongguan, China
| | - Lianxian Guo
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, China
| | - Zhu Shi
- Department of Neurology and Stroke Center, Affiliate Dongguan People’s Hospital, Southern Medical University, Dongguan, China
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16
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Li Y, Luo X, Hua Z, Xue X, Wang X, Pang M, Wang T, Lyu A, Liu Y. Apolipoproteins as potential communicators play an essential role in the pathogenesis and treatment of early atherosclerosis. Int J Biol Sci 2023; 19:4493-4510. [PMID: 37781031 PMCID: PMC10535700 DOI: 10.7150/ijbs.86475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/15/2023] [Indexed: 10/03/2023] Open
Abstract
Atherosclerosis as the leading cause of the cardiovascular disease is closely related to cholesterol deposition within subendothelial areas of the arteries. Significantly, early atherosclerosis intervention is the critical phase for its reversal. As atherosclerosis progresses, early foam cells formation may evolve into fibrous plaques and atheromatous plaque, ulteriorly rupture of atheromatous plaque increases risks of myocardial infarction and ischemic stroke, resulting in high morbidity and mortality worldwide. Notably, amphiphilic apolipoproteins (Apos) can concomitantly combine with lipids to form soluble lipoproteins that have been demonstrated to associate with atherosclerosis. Apos act as crucial communicators of lipoproteins, which not only can mediate lipids metabolism, but also can involve in pro-atherogenic and anti-atherogenic processes of atherosclerosis via affecting subendothelial retention and aggregation of low-density lipoprotein (LDL), oxidative modification of LDL, foam cells formation and reverse cholesterol transport (RCT) in macrophage cells. Correspondingly, Apos can be used as endogenous and/or exogenous targeting agents to effectively attenuate the development of atherosclerosis. The article reviews the classification, structure, and relationship between Apos and lipids, how Apos serve as communicators of lipoproteins to participate in the pathogenesis progression of early atherosclerosis, as well as how Apos as the meaningful targeting mass is used in early atherosclerosis treatment.
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Affiliation(s)
- Yang Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xinyi Luo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zhenglai Hua
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xiaoxia Xue
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xiangpeng Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Mingshi Pang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Tieshan Wang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Aiping Lyu
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong 999077, China
| | - Yuanyan Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
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17
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Watson MG, Chambers KL, Myerscough MR. A Lipid-Structured Model of Atherosclerotic Plaque Macrophages with Lipid-Dependent Kinetics. Bull Math Biol 2023; 85:85. [PMID: 37581687 PMCID: PMC10427559 DOI: 10.1007/s11538-023-01193-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: 12/05/2022] [Accepted: 08/04/2023] [Indexed: 08/16/2023]
Abstract
Atherosclerotic plaques are fatty growths in artery walls that cause heart attacks and strokes. Plaque formation is driven by macrophages that are recruited to the artery wall. These cells consume and remove blood-derived lipids, such as modified low-density lipoprotein. Ineffective lipid removal, due to macrophage death and other factors, leads to the accumulation of lipid-loaded macrophages and formation of a necrotic lipid core. Experimental observations suggest that macrophage functionality varies with the extent of lipid loading. However, little is known about the influence of macrophage lipid loads on plaque fate. Extending work by Ford et al. (J Theor Biol 479:48-63, 2019) and Chambers et al. (A lipid-structured model of atherosclerosis with macrophage proliferation, 2022), we develop a plaque model where macrophages are structured by their ingested lipid load and behave in a lipid-dependent manner. The model considers several macrophage behaviours, including recruitment to and emigration from the artery wall; proliferation and apotosis; ingestion of plaque lipids; and secondary necrosis of apoptotic cells. We consider apoptosis, emigration and proliferation to be lipid-dependent and we model these effects using experimentally informed functions of the internalised lipid load. Our results demonstrate that lipid-dependent macrophage behaviour can substantially alter plaque fate by changing both the total quantity of lipid in the plaque and the distribution of lipid between the live cells, dead cells and necrotic core. The consequences of macrophage lipid-dependence are often unpredictable because lipid-dependent effects introduce subtle, nonlinear interactions between the modelled cell behaviours. These observations highlight the importance of mathematical modelling in unravelling the complexities of macrophage lipid accumulation during atherosclerotic plaque formation.
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Affiliation(s)
- Michael G. Watson
- School of Mathematics and Statistics, University of New South Wales, Kensington, NSW 2052 Australia
| | - Keith L. Chambers
- Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, Oxfordshire OX2 6GG UK
| | - Mary R. Myerscough
- School of Mathematics and Statistics, University of Sydney, Camperdown, NSW 2006 Australia
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18
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Jiang S, Yang H, Li M. Emerging Roles of Lysophosphatidic Acid in Macrophages and Inflammatory Diseases. Int J Mol Sci 2023; 24:12524. [PMID: 37569902 PMCID: PMC10419859 DOI: 10.3390/ijms241512524] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 08/13/2023] Open
Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates physiological and pathological processes in numerous cell biological functions, including cell migration, apoptosis, and proliferation. Macrophages are found in most human tissues and have multiple physiological and pathological functions. There is growing evidence that LPA signaling plays a significant role in the physiological function of macrophages and accelerates the development of diseases caused by macrophage dysfunction and inflammation, such as inflammation-related diseases, cancer, atherosclerosis, and fibrosis. In this review, we summarize the roles of LPA in macrophages, analyze numerous macrophage- and inflammation-associated diseases triggered by LPA, and discuss LPA-targeting therapeutic strategies.
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Affiliation(s)
- Shufan Jiang
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
- Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Huili Yang
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
| | - Mingqing Li
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
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19
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Moreno-Gonzalez MA, Ortega-Rivera OA, Steinmetz NF. Two decades of vaccine development against atherosclerosis. NANO TODAY 2023; 50:101822. [PMID: 37860053 PMCID: PMC10586238 DOI: 10.1016/j.nantod.2023.101822] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2023]
Abstract
Atherosclerosis is an immune-mediated chronic inflammatory disease that leads to the development of fatty plaques in the arterial walls, ultimately increasing the risk of thrombosis, stroke, and myocardial infarction. The immune response in this complex disease is both atheroprotective and pro-atherogenic, involving both innate and adaptive immunity. Current treatments include the adjustment of lifestyle factors, cholesterol-lowering drugs such as statins, and immunotherapy, whereas vaccine development has received comparatively little attention. In this review, we discuss the potential of antigen-specific vaccination as a preventative approach based on more than 20 years of research and innovation. Vaccination targets include proteins that are more abundant in atherosclerotic patients, such as oxidized low-density lipoprotein (LDL), apolipoprotein B-100, proprotein convertase subtilisin/kexin type-9 serine protease (PCSK9), cholesteryl ester transfer protein (CETP), and heat shock proteins HSP60 and HSP65. Immunization with such proteins or their peptide epitopes has been shown to induce T-cell activation, produce antigen-specific antibodies, reduce the size of atherosclerotic lesions, and/or reduce serum cholesterol levels. Vaccination against atherosclerosis therefore offers a new strategy to address the burden on healthcare systems caused by cardiovascular disease, the leading cause of death worldwide.
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Affiliation(s)
- Miguel A. Moreno-Gonzalez
- Department of NanoEngineering, University of California-San Diego, La Jolla, CA 92039, USA
- Center for Nano-ImmunoEngineering, University of California-San Diego, La Jolla, CA 92039, USA
| | - Oscar A. Ortega-Rivera
- Department of NanoEngineering, University of California-San Diego, La Jolla, CA 92039, USA
- Center for Nano-ImmunoEngineering, University of California-San Diego, La Jolla, CA 92039, USA
| | - Nicole F. Steinmetz
- Department of NanoEngineering, University of California-San Diego, La Jolla, CA 92039, USA
- Center for Nano-ImmunoEngineering, University of California-San Diego, La Jolla, CA 92039, USA
- Institute for Materials Discovery and Design, University of California-San Diego, La Jolla, CA 92039, USA
- Department of Bioengineering, University of California-San Diego, La Jolla, CA 92039, USA
- Department of Radiology, University of California-San Diego, La Jolla, CA 92039, USA
- Moores Cancer Center, University of California-San Diego, La Jolla, CA 92039, USA
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20
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He Y, Liu T. Oxidized low-density lipoprotein regulates macrophage polarization in atherosclerosis. Int Immunopharmacol 2023; 120:110338. [PMID: 37210916 DOI: 10.1016/j.intimp.2023.110338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/10/2023] [Accepted: 05/11/2023] [Indexed: 05/23/2023]
Abstract
Atherosclerosis is the pathological basis of acute cardiovascular and cerebrovascular diseases. Oxidized LDL has been recognized as a major atherogenic factor in the vessel wall for decades. A growing body of evidence suggests that oxidized LDL modulates macrophage phenotypes in atherosclerosis. This article reviews the research progress on the regulation of macrophage polarization by oxidized LDL. Mechanistically, oxidized LDL induces macrophage polarization via cell signaling, metabolic reprogramming, epigenetic regulation, and intercellular regulation. This review is expected to provide new targets for the treatment of atherosclerosis.
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Affiliation(s)
- Yonghang He
- The Second Clinical Medical College, Guangdong Medical University, Dongguan, 523808, China
| | - Tingting Liu
- The First Dongguan Affiliated Hospital, Guangdong Medical University, No. 42 Jiaoping Road, Tangxia Town, Dongguan City, Guangdong Province 523710, China; The Second Clinical Medical College, Guangdong Medical University, Dongguan, 523808, China.
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21
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Ahmed IU, Byrne HM, Myerscough MR. Macrophage Anti-inflammatory Behaviour in a Multiphase Model of Atherosclerotic Plaque Development. Bull Math Biol 2023; 85:37. [PMID: 36991234 PMCID: PMC10060284 DOI: 10.1007/s11538-023-01142-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 03/09/2023] [Indexed: 03/31/2023]
Abstract
Atherosclerosis is an inflammatory disease characterised by the formation of plaques, which are deposits of lipids and cholesterol-laden macrophages that form in the artery wall. The inflammation is often non-resolving, due in large part to changes in normal macrophage anti-inflammatory behaviour that are induced by the toxic plaque microenvironment. These changes include higher death rates, defective efferocytic uptake of dead cells, and reduced rates of emigration. We develop a free boundary multiphase model for early atherosclerotic plaques, and we use it to investigate the effects of impaired macrophage anti-inflammatory behaviour on plaque structure and growth. We find that high rates of cell death relative to efferocytic uptake results in a plaque populated mostly by dead cells. We also find that emigration can potentially slow or halt plaque growth by allowing material to exit the plaque, but this is contingent on the availability of live macrophage foam cells in the deep plaque. Finally, we introduce an additional bead species to model macrophage tagging via microspheres, and we use the extended model to explore how high rates of cell death and low rates of efferocytosis and emigration prevent the clearance of macrophages from the plaque.
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Affiliation(s)
- Ishraq U Ahmed
- School of Mathematics and Statistics, University of Sydney, Sydney, Australia.
| | - Helen M Byrne
- Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, UK
| | - Mary R Myerscough
- School of Mathematics and Statistics, University of Sydney, Sydney, Australia
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22
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Razi S, Yaghmoorian Khojini J, Kargarijam F, Panahi S, Tahershamsi Z, Tajbakhsh A, Gheibihayat SM. Macrophage efferocytosis in health and disease. Cell Biochem Funct 2023; 41:152-165. [PMID: 36794573 DOI: 10.1002/cbf.3780] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/31/2023] [Accepted: 02/06/2023] [Indexed: 02/17/2023]
Abstract
Creating cellular homeostasis within a defined tissue typically relates to the processes of apoptosis and efferocytosis. A great example here is cell debris that must be removed to prevent unwanted inflammatory responses and then reduce autoimmunity. In view of that, defective efferocytosis is often assumed to be responsible for the improper clearance of apoptotic cells (ACs). This predicament triggers off inflammation and even results in disease development. Any disruption of phagocytic receptors, molecules as bridging groups, or signaling routes can also inhibit macrophage efferocytosis and lead to the impaired clearance of the apoptotic body. In this line, macrophages as professional phagocytic cells take the lead in the efferocytosis process. As well, insufficiency in macrophage efferocytosis facilitates the spread of a wide variety of diseases, including neurodegenerative diseases, kidney problems, types of cancer, asthma, and the like. Establishing the functions of macrophages in this respect can be thus useful in the treatment of many diseases. Against this background, this review aimed to recapitulate the knowledge about the mechanisms related to macrophage polarization under physiological or pathological conditions, and shed light on its interaction with efferocytosis.
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Affiliation(s)
- Shokufeh Razi
- Department of Genetics, Faculty of Basic Sciences, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Javad Yaghmoorian Khojini
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Kargarijam
- Department of Biotechnology, Faculty of Sciences and Advanced Technology in Biology, University of Science and Culture, Tehran, Iran
| | - Susan Panahi
- Department of Microbiology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Zahra Tahershamsi
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Mohammad Gheibihayat
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Munich, Germany
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23
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Fuller MT, Dadoo O, Xiong T, Chivukula P, MacDonald ME, Lee SK, Austin RC, Igdoura SA, Trigatti BL. Extensive diet-induced atherosclerosis in scavenger receptor class B type 1-deficient mice is associated with substantial leukocytosis and elevated vascular cell adhesion molecule-1 expression in coronary artery endothelium. Front Physiol 2023; 13:1023397. [PMID: 36714321 PMCID: PMC9877335 DOI: 10.3389/fphys.2022.1023397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 12/21/2022] [Indexed: 01/14/2023] Open
Abstract
High levels of low density lipoprotein (LDL) cholesterol and low levels of high density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease. Mice that lack genes involved in the clearance of LDL from the bloodstream, such as the LDL receptor and apolipoprotein E, are widely used models of experimental atherosclerosis. Conversely, mice that lack the HDL receptor, scavenger receptor class B type I, and therefore have disrupted HDL functionality, also develop diet-inducible atherosclerosis but are a seldom-used disease model. In this study, we compared atherosclerosis and associated phenotypes in scavenger receptor class B type I knockout mice with those of wild type, LDL receptor knockout, and apolipoprotein E knockout mice after 20 weeks of being fed an atherogenic diet containing sodium cholate. We found that while scavenger receptor class B type I knockout mice had substantially lower plasma cholesterol than LDL receptor and apolipoprotein E knockout mice, they developed atherosclerotic plaques with similar sizes and compositions in their aortic sinuses, and more extensive atherosclerosis in their descending aortas and coronary arteries. This was associated with elevated tumor necrosis factor alpha levels in scavenger receptor class B type I knockout mice compared to wild type and LDL receptor knockout mice, and lymphocytosis, monocytosis, and elevated vascular cell adhesion molecule expression in coronary artery endothelial cells compared to the other mice examined. We conclude that extensive atherosclerosis in arteries that are not generally susceptible to atherosclerosis in scavenger receptor class B type I knockout mice is driven by factors in addition to hypercholesterolemia, including inflammation, dysregulation of the immune system and increased sensitivity of endothelial cells in arteries that are normally resistant to atherosclerosis. Scavenger receptor class B type I knockout mice fed a cholate containing atherogenic diet may prove to be a useful model to study mechanisms of atherosclerosis and evaluate treatments that rely on intact LDL clearance pathways.
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Affiliation(s)
- Mark T. Fuller
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada,Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada
| | - Omid Dadoo
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada,Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada
| | - Ting Xiong
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada,Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada
| | - Pardh Chivukula
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada,Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada
| | - Melissa E. MacDonald
- Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada
| | - Samuel K. Lee
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada,Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada
| | - Richard C. Austin
- Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada,Department of Medicine, Division of Nephrology, The Research Institute of St. Joe’s Hamilton and the Hamilton Center for Kidney Research, McMaster University, Hamilton, ON, Canada
| | - Suleiman A. Igdoura
- Department of Biology and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Bernardo L. Trigatti
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada,Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada,*Correspondence: Bernardo L. Trigatti,
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24
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Yin Z, Zhang J, Xu S, Liu J, Xu Y, Yu J, Zhao M, Pan W, Wang M, Wan J. The role of semaphorins in cardiovascular diseases: Potential therapeutic targets and novel biomarkers. FASEB J 2022; 36:e22509. [PMID: 36063107 DOI: 10.1096/fj.202200844r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/24/2022] [Accepted: 08/09/2022] [Indexed: 12/17/2022]
Abstract
Semaphorins (Semas), which belongs to the axonal guidance molecules, include 8 classes and could affect axon growth in the nervous system. Recently, semaphorins were found to regulate other pathophysiological processes, such as immune response, oncogenesis, tumor angiogenesis, and bone homeostasis, through binding with their plexin and neuropilin receptors. In this review, we summarized the detailed role of semaphorins and their receptors in the pathological progression of various cardiovascular diseases (CVDs), highlighting that semaphorins may be potential therapeutic targets and novel biomarkers for CVDs.
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Affiliation(s)
- Zheng Yin
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jishou Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Shuwan Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jianfang Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Yao Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Junping Yu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Mengmeng Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Wei Pan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Menglong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jun Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
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25
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Palshikar MG, Palli R, Tyrell A, Maggirwar S, Schifitto G, Singh MV, Thakar J. Executable models of immune signaling pathways in HIV-associated atherosclerosis. NPJ Syst Biol Appl 2022; 8:35. [PMID: 36131068 PMCID: PMC9492768 DOI: 10.1038/s41540-022-00246-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 09/01/2022] [Indexed: 11/09/2022] Open
Abstract
Atherosclerosis (AS)-associated cardiovascular disease is an important cause of mortality in an aging population of people living with HIV (PLWH). This elevated risk has been attributed to viral infection, anti-retroviral therapy, chronic inflammation, and lifestyle factors. However, the rates at which PLWH develop AS vary even after controlling for length of infection, treatment duration, and for lifestyle factors. To investigate the molecular signaling underlying this variation, we sequenced 9368 peripheral blood mononuclear cells (PBMCs) from eight PLWH, four of whom have atherosclerosis (AS+). Additionally, a publicly available dataset of PBMCs from persons before and after HIV infection was used to investigate the effect of acute HIV infection. To characterize dysregulation of pathways rather than just measuring enrichment, we developed the single-cell Boolean Omics Network Invariant Time Analysis (scBONITA) algorithm. scBONITA infers executable dynamic pathway models and performs a perturbation analysis to identify high impact genes. These dynamic models are used for pathway analysis and to map sequenced cells to characteristic signaling states (attractor analysis). scBONITA revealed that lipid signaling regulates cell migration into the vascular endothelium in AS+ PLWH. Pathways implicated included AGE-RAGE and PI3K-AKT signaling in CD8+ T cells, and glucagon and cAMP signaling pathways in monocytes. Attractor analysis with scBONITA facilitated the pathway-based characterization of cellular states in CD8+ T cells and monocytes. In this manner, we identify critical cell-type specific molecular mechanisms underlying HIV-associated atherosclerosis using a novel computational method.
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Affiliation(s)
- Mukta G Palshikar
- Biophysics, Structural, and Computational Biology Program, University of Rochester School of Medicine and Dentistry, Rochester, USA
| | - Rohith Palli
- Medical Scientist Training Program, University of Rochester School of Medicine and Dentistry, Rochester, USA
| | - Alicia Tyrell
- University of Rochester Clinical & Translational Science Institute, Rochester, USA
| | - Sanjay Maggirwar
- Department of Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Giovanni Schifitto
- Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, USA
- Department of Imaging Sciences, University of Rochester School of Medicine and Dentistry, Rochester, USA
| | - Meera V Singh
- Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, USA
- Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, USA
| | - Juilee Thakar
- Biophysics, Structural, and Computational Biology Program, University of Rochester School of Medicine and Dentistry, Rochester, USA.
- Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, USA.
- Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, USA.
- Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, USA.
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26
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Rezende L, Couto NFD, Fernandes-Braga W, Epshtein Y, Alvarez-Leite JI, Levitan I, Andrade LDO. OxLDL induces membrane structure rearrangement leading to biomechanics alteration and migration deficiency in macrophage. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2022; 1864:183951. [PMID: 35504320 DOI: 10.1016/j.bbamem.2022.183951] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 04/20/2022] [Accepted: 04/25/2022] [Indexed: 11/30/2022]
Abstract
Cholesterol sequestration from plasma membrane has been shown to induce lipid packing disruption, causing actin cytoskeleton reorganization and polymerization, increasing cell stiffness and inducing lysosomal exocytosis in non-professional phagocytes. Similarly, oxidized form of low-density lipoprotein (oxLDL) has also been shown to disrupt lipid organization and packing in endothelial cells, leading to biomechanics alterations that interfere with membrane injury and repair. For macrophages, much is known about oxLDL effects in cell activation, cytokine production and foam cell formation. However, little is known about its impact in the organization of macrophage membrane structured domains and cellular mechanics, the focus of the present study. Treatment of bone marrow-derived macrophages (BMDM) with oxLDL not only altered membrane structure, and potentially the distribution of raft domains, but also induced actin rearrangement, diffuse integrin distribution and cell shrinkage, similarly to observed upon treatment of these cells with MβCD. Those alterations led to decreased migration efficiency. For both treatments, higher co-localization of actin cytoskeleton and GM1 was observed, indicating a similar mechanism of action involving raft-like domain dynamics. Lastly, like MβCD treatment, oxLDL also induced lysosomal spreading in BMDM. We propose that OxLDL induced re-organization of membrane/cytoskeleton complex in macrophages can be attributed to the insertion of oxysterols into the membrane, which lead to changes in lipid organization and disruption of membrane structure, similar to the effect of cholesterol depletion by MβCD treatment. These results indicate that oxLDL can induce physical alterations in the complex membrane/cytoskeleton of macrophages, leading to significant biomechanical changes that compromise cell behavior.
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Affiliation(s)
- Luisa Rezende
- Department of Morphology/Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Natalia Fernanda Do Couto
- Department of Morphology/Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Department of Medicine, University of Illinois at Chicago, Chicago, USA
| | - Weslley Fernandes-Braga
- Department of Biochemistry and Immunology/Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Yulia Epshtein
- Department of Medicine, University of Illinois at Chicago, Chicago, USA
| | | | - Irena Levitan
- Department of Medicine, University of Illinois at Chicago, Chicago, USA
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27
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Deletion of Macrophage-Specific Glycogen Synthase Kinase (GSK)-3α Promotes Atherosclerotic Regression in Ldlr−/− Mice. Int J Mol Sci 2022; 23:ijms23169293. [PMID: 36012557 PMCID: PMC9409307 DOI: 10.3390/ijms23169293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/12/2022] [Accepted: 08/14/2022] [Indexed: 11/29/2022] Open
Abstract
Recent evidence from our laboratory suggests that impeding ER stress–GSK3α/β signaling attenuates the progression and development of atherosclerosis in mouse model systems. The objective of this study was to determine if the tissue-specific genetic ablation of GSK3α/β could promote the regression of established atherosclerotic plaques. Five-week-old low-density lipoprotein receptor knockout (Ldlr−/−) mice were fed a high-fat diet for 16 weeks to promote atherosclerotic lesion formation. Mice were then injected with tamoxifen to induce macrophage-specific GSK3α/β deletion, and switched to standard diet for 12 weeks. All mice were sacrificed at 33 weeks of age and atherosclerosis was quantified and characterized. Female mice with induced macrophage-specific GSK3α deficiency, but not GSK3β deficiency, had reduced plaque volume (~25%) and necrosis (~40%) in the aortic sinus, compared to baseline mice. Atherosclerosis was also significantly reduced (~60%) in the descending aorta. Macrophage-specific GSK3α-deficient mice showed indications of increased plaque stability and reduced inflammation in plaques, as well as increased CCR7 and ABCA1 expression in lesional macrophages, consistent with regressive plaques. These results suggest that GSK3α ablation promotes atherosclerotic plaque regression and identify GSK3α as a potential target for the development of new therapies to treat existing atherosclerotic lesions in patients with cardiovascular disease.
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28
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Bellini R, Bonacina F, Norata GD. Crosstalk between dendritic cells and T lymphocytes during atherogenesis: Focus on antigen presentation and break of tolerance. Front Cardiovasc Med 2022; 9:934314. [PMID: 35966516 PMCID: PMC9365967 DOI: 10.3389/fcvm.2022.934314] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/05/2022] [Indexed: 12/14/2022] Open
Abstract
Atherosclerosis is a chronic disease resulting from an impaired lipid and immune homeostasis, where the interaction between innate and adaptive immune cells leads to the promotion of atherosclerosis-associated immune-inflammatory response. Emerging evidence has suggested that this response presents similarities to the reactivity of effector immune cells toward self-epitopes, often as a consequence of a break of tolerance. In this context, dendritic cells, a heterogeneous population of antigen presenting cells, play a key role in instructing effector T cells to react against foreign antigens and T regulatory cells to maintain tolerance against self-antigens and/or to patrol for self-reactive effector T cells. Alterations in this delicate balance appears to contribute to atherogenesis. The aim of this review is to discuss different DC subsets, and their role in atherosclerosis as well as in T cell polarization. Moreover, we will discuss how loss of T cell tolerogenic phenotype participates to the immune-inflammatory response associated to atherosclerosis and how a better understanding of these mechanisms might result in designing immunomodulatory therapies targeting DC-T cell crosstalk for the treatment of atherosclerosis-related inflammation.
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Affiliation(s)
- Rossella Bellini
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Fabrizia Bonacina
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
- *Correspondence: Fabrizia Bonacina,
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
- Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy
- Giuseppe Danilo Norata,
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29
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Low Density Lipoprotein Exposure of Plasmacytoid Dendritic Cells Blunts Toll-like Receptor 7/9 Signaling via NUR77. Biomedicines 2022; 10:biomedicines10051152. [PMID: 35625889 PMCID: PMC9139034 DOI: 10.3390/biomedicines10051152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/16/2022] [Accepted: 04/27/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Pathogens or trauma-derived danger signals induced maturation and activation of plasmacytoid dendritic cells (pDCs) is a pivotal step in pDC-dependent host defense. Exposure of pDC to cardiometabolic disease-associated lipids and proteins may well influence critical signaling pathways, thereby compromising immune responses against endogenous, bacterial and viral pathogens. In this study, we have addressed if hyperlipidemia impacts human pDC activation, cytokine response and capacity to prime CD4+ T cells. METHODS AND RESULTS: We show that exposure to pro-atherogenic oxidized low-density lipoproteins (oxLDL) led to pDC lipid accumulation, which in turn ablated a Toll-like receptor (TLR) 7 and 9 dependent up-regulation of pDC maturation markers CD40, CD83, CD86 and HLA-DR. Moreover, oxLDL dampened TLR9 activation induced the production of pro-inflammatory cytokines in a NUR77/IRF7 dependent manner and impaired the capacity of pDCs to prime and polarize CD4+ T helper (Th) cells. CONCLUSION: Our findings reveal profound effects of dyslipidemia on pDC responses to pathogen-derived signals.
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30
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Manubolu VS, Budoff MJ. Achieving coronary plaque regression: a decades-long battle against coronary artery disease. Expert Rev Cardiovasc Ther 2022; 20:291-305. [PMID: 35466832 DOI: 10.1080/14779072.2022.2069559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
INTRODUCTION Traditionally atherosclerosis was thought to be progressive and medical treatment solely focused on delaying the progression of atherosclerosis rather than treating the disease itself. Multiple recent studies, however, have demonstrated a significant decrease in cardiovascular mortality with the use of additional anti-atherosclerotic therapies beyond statins. Consistent with these observations, mechanistic studies indicate that these additional anti-atherosclerotic therapies have a positive effect on both halting and reversing the course of atherosclerosis. AREAS COVERED We examine the progression of atherosclerosis and the efficacy of various anti-atherosclerotic treatment classes in this review utilizing multimodality imaging techniques. Searches were conducted in electronic databases: PubMed and EMBASE for all peer reviewed publications that examined coronary plaque progression, regression and stabilization using different imaging modalities and antiatherosclerosis therapies. The keywords coronary plaque, coronary angiography, IVUS, intravascular OCT, CCTA in conjunction with the various therapies included in this review were searched in different combinations. All relevant published articles on this topic were identified and their reference lists were screened for relevance. EXPERT COMMENTARY Though lipoprotein levels have traditionally been the target for antiatherosclerosis medication, several newer strategies have emerged creating novel targets in the treatment of coronary atherosclerosis. Using a combination of antiatherosclerosis therapies in conjunction with noninvasive imaging modalities like CCTA to directly visualize the plaque, is currently the focus of the future, with the aim of preventing and reversing atherosclerosis.
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Affiliation(s)
| | - Matthew J Budoff
- Department of Cardiology, Lundquist Institute, Torrance, CA, USA
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31
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von Ehr A, Bode C, Hilgendorf I. Macrophages in Atheromatous Plaque Developmental Stages. Front Cardiovasc Med 2022; 9:865367. [PMID: 35548412 PMCID: PMC9081876 DOI: 10.3389/fcvm.2022.865367] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 03/31/2022] [Indexed: 11/28/2022] Open
Abstract
Atherosclerosis is the main pathomechanism leading to cardiovascular diseases such as myocardial infarction or stroke. There is consensus that atherosclerosis is not only a metabolic disorder but rather a chronic inflammatory disease influenced by various immune cells of the innate and adaptive immune system. Macrophages constitute the largest population of inflammatory cells in atherosclerotic lesions. They play a critical role in all stages of atherogenesis. The heterogenous macrophage population can be subdivided on the basis of their origins into resident, yolk sac and fetal liver monocyte-derived macrophages and postnatal monocyte-derived, recruited macrophages. Recent transcriptomic analyses revealed that the major macrophage populations in atherosclerosis include resident, inflammatory and foamy macrophages, representing a more functional classification. The aim of this review is to provide an overview of the trafficking, fate, and functional aspects of the different macrophage populations in the "life cycle" of an atheromatous plaque. Understanding the chronic inflammatory state in atherosclerotic lesions is an important basis for developing new therapeutic approaches to abolish lesion growth and promote plaque regression in addition to general cholesterol lowering.
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Affiliation(s)
- Alexander von Ehr
- Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christoph Bode
- Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Ingo Hilgendorf
- Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Institute of Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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32
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Pig and Mouse Models of Hyperlipidemia and Atherosclerosis. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2419:379-411. [PMID: 35237978 DOI: 10.1007/978-1-0716-1924-7_24] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Atherosclerosis is a chronic inflammatory disorder that is the underlying cause of most cardiovascular disease. Resident cells of the artery wall and cells of the immune system participate in atherogenesis. This process is influenced by plasma lipoproteins, genetics, and the hemodynamics of the blood flow in the artery. A variety of animal models have been used to study the pathophysiology and mechanisms that contribute to atherosclerotic lesion formation. No model is ideal as each has its own advantages and limitations with respect to manipulation of the atherogenic process and modeling human atherosclerosis and lipoprotein profile. In this chapter we will discuss pig and mouse models of experimental atherosclerosis. The similarity of pig lipoprotein metabolism and the pathophysiology of the lesions in these animals with that of humans is a major advantage. While a few genetically engineered pig models have been generated, the ease of genetic manipulation in mice and the relatively short time frame for the development of atherosclerosis has made them the most extensively used model. Newer approaches to induce hypercholesterolemia in mice have been developed that do not require germline modifications. These approaches will facilitate studies on atherogenic mechanisms.
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33
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Xing Y, Sun X, Dou Y, Wang M, Zhao Y, Yang Q, Zhao Y. The Immuno-Modulation Effect of Macrophage-Derived Extracellular Vesicles in Chronic Inflammatory Diseases. Front Immunol 2022; 12:785728. [PMID: 34975877 PMCID: PMC8716390 DOI: 10.3389/fimmu.2021.785728] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
As natural nanocarriers and intercellular messengers, extracellular vesicles (EVs) control communication among cells. Under physiological and pathological conditions, EVs deliver generic information including proteins and nucleic acids to recipient cells and exert regulatory effects. Macrophages help mediate immune responses, and macrophage-derived EVs may play immunomodulatory roles in the progression of chronic inflammatory diseases. Furthermore, EVs derived from various macrophage phenotypes have different biological functions. In this review, we describe the pathophysiological significance of macrophage-derived extracellular vesicles in the development of chronic inflammatory diseases, including diabetes, cancer, cardiovascular disease, pulmonary disease, and gastrointestinal disease, and the potential applications of these EVs.
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Affiliation(s)
- Yi Xing
- Department of Orthodontics, Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Xun Sun
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
| | - Yiming Dou
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
| | - Min Wang
- Department of Orthodontics, Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Yanmei Zhao
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, China
| | - Qiang Yang
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
| | - Yanhong Zhao
- Department of Orthodontics, Hospital of Stomatology, Tianjin Medical University, Tianjin, China
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Kraft JD, Blomgran R, Bergström I, Soták M, Clark M, Rani A, Rajan MR, Dalli J, Nyström S, Quiding‐Järbrink M, Bromberg J, Skoog P, Börgeson E. Lipoxins modulate neutrophil oxidative burst, integrin expression and lymphatic transmigration differentially in human health and atherosclerosis. FASEB J 2022; 36:e22173. [PMID: 35104001 PMCID: PMC9305188 DOI: 10.1096/fj.202101219rr] [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: 07/30/2021] [Revised: 01/04/2022] [Accepted: 01/10/2022] [Indexed: 12/31/2022]
Abstract
Dysregulated chronic inflammation plays a crucial role in the pathophysiology of atherosclerosis and may be a result of impaired resolution. Thus, restoring levels of specialized pro‐resolving mediators (SPMs) to promote the resolution of inflammation has been proposed as a therapeutic strategy for patients with atherosclerosis, in addition to standard clinical care. Herein, we evaluated the effects of the SPM lipids, lipoxin A4 (LXA4) and lipoxin B4 (LXB4), on neutrophils isolated from patients with atherosclerosis compared with healthy controls. Patients displayed altered endogenous SPM production, and we demonstrated that lipoxin treatment in whole blood from atherosclerosis patients attenuates neutrophil oxidative burst, a key contributor to atherosclerotic development. We found the opposite effect in neutrophils from healthy controls, indicating a potential mechanism whereby lipoxins aid the endogenous neutrophil function in health but reduce its excessive activation in disease. We also demonstrated that lipoxins attenuated upregulation of the high‐affinity conformation of the CD11b/CD18 integrin, which plays a central role in clot activation and atherosclerosis. Finally, LXB4 enhanced lymphatic transmigration of human neutrophils isolated from patients with atherosclerosis. This finding is noteworthy, as impaired lymphatic function is now recognized as an important contributor to atherosclerosis. Although both lipoxins modulated neutrophil function, LXB4 displayed more potent effects than LXA4 in humans. This study highlights the therapeutic potential of lipoxins in atherosclerotic disease and demonstrates that the effect of these SPMs may be specifically tailored to the need of the individual.
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Affiliation(s)
- Jamie D. Kraft
- Department of Molecular and Clinical Medicine Wallenberg Laboratory Institute of Medicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden
- Wallenberg Centre for Molecular and Translational Medicine University of Gothenburg Gothenburg Sweden
| | - Robert Blomgran
- Division of Inflammation and Infection Department of Biomedical and Clinical Sciences Faculty of Medicine and Health Sciences Linköping University Linköping Sweden
| | - Ida Bergström
- Department of Clinical Immunology and Transfusion Medicine Linköping University Linköping Sweden
- Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden
| | - Matúš Soták
- Department of Molecular and Clinical Medicine Wallenberg Laboratory Institute of Medicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden
- Wallenberg Centre for Molecular and Translational Medicine University of Gothenburg Gothenburg Sweden
- Department of Clinical Physiology Region Vaestra Goetaland Sahlgrenska University Hospital Gothenburg Sweden
| | - Madison Clark
- Department of Molecular and Clinical Medicine Wallenberg Laboratory Institute of Medicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden
- Wallenberg Centre for Molecular and Translational Medicine University of Gothenburg Gothenburg Sweden
| | - Alankrita Rani
- Department of Molecular and Clinical Medicine Wallenberg Laboratory Institute of Medicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden
- Wallenberg Centre for Molecular and Translational Medicine University of Gothenburg Gothenburg Sweden
- Department of Clinical Physiology Region Vaestra Goetaland Sahlgrenska University Hospital Gothenburg Sweden
| | - Meenu Rohini Rajan
- Department of Molecular and Clinical Medicine Wallenberg Laboratory Institute of Medicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden
- Wallenberg Centre for Molecular and Translational Medicine University of Gothenburg Gothenburg Sweden
- Department of Clinical Physiology Region Vaestra Goetaland Sahlgrenska University Hospital Gothenburg Sweden
| | - Jesmond Dalli
- William Harvey Research Institute Barts & The London School of Medicine & Dentistry Queen Mary University of London London UK
- Centre for Inflammation and Therapeutic Innovation Queen Mary University of London London UK
| | - Sofia Nyström
- Department of Clinical Immunology and Transfusion Medicine Linköping University Linköping Sweden
- Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden
| | - Marianne Quiding‐Järbrink
- Department of Microbiology and Immunology Institute of Biomedicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden
| | - Jonathan Bromberg
- Department of Surgery University of Maryland School of Medicine Baltimore Maryland USA
- Department of Microbiology and Immunology University of Maryland School of Medicine Baltimore Maryland USA
- Center for Vascular and Inflammatory Diseases University of Maryland School of Medicine Baltimore Maryland USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center University of Maryland Baltimore Maryland USA
| | - Per Skoog
- Department of Vascular Surgery and Institute of Medicine Sahlgrenska University Hospital and Academy Gothenburg Sweden
- Department of Molecular and Clinical Medicine Sahlgrenska University Hospital and Academy Gothenburg Sweden
| | - Emma Börgeson
- Department of Molecular and Clinical Medicine Wallenberg Laboratory Institute of Medicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden
- Wallenberg Centre for Molecular and Translational Medicine University of Gothenburg Gothenburg Sweden
- Department of Clinical Physiology Region Vaestra Goetaland Sahlgrenska University Hospital Gothenburg Sweden
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Ziegon L, Schlegel M. Netrin-1: A Modulator of Macrophage Driven Acute and Chronic Inflammation. Int J Mol Sci 2021; 23:275. [PMID: 35008701 PMCID: PMC8745333 DOI: 10.3390/ijms23010275] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 12/11/2022] Open
Abstract
Netrins belong to the family of laminin-like secreted proteins, which guide axonal migration and neuronal growth in the developing central nervous system. Over the last 20 years, it has been established that netrin-1 acts as a chemoattractive or chemorepulsive cue in diverse biological processes far beyond neuronal development. Netrin-1 has been shown to play a central role in cell adhesion, cell migration, proliferation, and cell survival in neuronal and non-neuronal tissue. In this context, netrin-1 was found to orchestrate organogenesis, angiogenesis, tumorigenesis, and inflammation. In inflammation, as in neuronal development, netrin-1 plays a dichotomous role directing the migration of leukocytes, especially monocytes in the inflamed tissue. Monocyte-derived macrophages have long been known for a similar dual role in inflammation. In response to pathogen-induced acute injury, monocytes are rapidly recruited to damaged tissue as the first line of immune defense to phagocyte pathogens, present antigens to initiate the adaptive immune response, and promote wound healing in the resolution phase. On the other hand, dysregulated macrophages with impaired phagocytosis and egress capacity accumulate in chronic inflammation sites and foster the maintenance-and even the progression-of chronic inflammation. In this review article, we will highlight the dichotomous roles of netrin-1 and its impact on acute and chronic inflammation.
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Affiliation(s)
| | - Martin Schlegel
- Department of Anesthesiology and Intensive Care Medicine, Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany;
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Keyes E, Grinnell M, Jacoby D, Vazquez T, Diaz D, Werth VP, Williams KJ. Assessment and management of the heightened risk for atherosclerotic cardiovascular events in patients with lupus erythematosus or dermatomyositis. Int J Womens Dermatol 2021; 7:560-575. [PMID: 35024413 PMCID: PMC8721062 DOI: 10.1016/j.ijwd.2021.08.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 01/05/2023] Open
Abstract
For patients with lupus erythematosus (LE) or dermatomyositis (DM), there is an urgent need to address a heightened risk of clinical events, chiefly heart attacks and strokes, caused by atherosclerotic cardiovascular disease (ASCVD). Patients with LE or DM frequently exhibit high levels of conventional risk factors for ASCVD events, particularly dyslipoproteinemia and hypertension; an amplified burden of atherosclerotic plaques; and increased age- and sex-adjusted rates of ASCVD events compared with the general population. The rate of ASCVD events exceeds what would be expected from conventional risk factors, suggesting that disease-specific autoimmune processes exacerbate specific, known pathogenic steps in atherosclerosis. Importantly, despite their heightened risk, patients with LE or DM are often undertreated for known causative agents and exacerbators of ASCVD. Herein, we propose an approach to assess and manage the heightened risk of ASCVD events in patients with LE or DM. Our approach is modeled in large part on established approaches to patients with diabetes mellitus or stage 3 or 4 chronic kidney disease, which are well-studied conditions that also show heightened risk for ASCVD events and have been explicitly incorporated into standard clinical guidelines for ASCVD. Based on the available evidence, we conclude that patients with LE or DM require earlier and more aggressive screening and management of ASCVD. We suggest that physicians consider implementing multipliers of conventional risk calculators to trigger earlier initiation of lifestyle modifications and medical therapies in primary prevention of ASCVD events, employ vascular imaging to quantify the burden of subclinical plaques, and treat to lower lipid targets using statins and newer therapies, such as PCSK9 inhibitors, that decrease ASCVD events in nonautoimmune cohorts. More clinical vigilance is needed regarding surveillance, prevention, risk modification, and treatment of dyslipidemias, hypertension, and smoking in patients with LE or DM. All of these goals are achievable.
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Affiliation(s)
- Emily Keyes
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania
| | - Madison Grinnell
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania
| | - Douglas Jacoby
- Cardiovascular Division, Department of Medicine, University of Pennsylvania Health System, Philadelphia, Pennsylvania
| | - Thomas Vazquez
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania
| | - DeAnna Diaz
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania
| | - Victoria P. Werth
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania
| | - Kevin Jon Williams
- Department of Cardiovascular Sciences, Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
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Tomas L, Prica F, Schulz C. Trafficking of Mononuclear Phagocytes in Healthy Arteries and Atherosclerosis. Front Immunol 2021; 12:718432. [PMID: 34759917 PMCID: PMC8573388 DOI: 10.3389/fimmu.2021.718432] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/30/2021] [Indexed: 12/15/2022] Open
Abstract
Monocytes and macrophages play essential roles in all stages of atherosclerosis – from early precursor lesions to advanced stages of the disease. Intima-resident macrophages are among the first cells to be confronted with the influx and retention of apolipoprotein B-containing lipoproteins at the onset of hypercholesterolemia and atherosclerosis development. In this review, we outline the trafficking of monocytes and macrophages in and out of the healthy aorta, as well as the adaptation of their migratory behaviour during hypercholesterolemia. Furthermore, we discuss the functional and ontogenetic composition of the aortic pool of mononuclear phagocytes and its link to the atherosclerotic disease process. The development of mouse models of atherosclerosis regression in recent years, has enabled scientists to investigate the behaviour of monocytes and macrophages during the resolution of atherosclerosis. Herein, we describe the dynamics of these mononuclear phagocytes upon cessation of hypercholesterolemia and how they contribute to the restoration of tissue homeostasis. The aim of this review is to provide an insight into the trafficking, fate and disease-relevant dynamics of monocytes and macrophages during atherosclerosis, and to highlight remaining questions. We focus on the results of rodent studies, as analysis of cellular fates requires experimental manipulations that cannot be performed in humans but point out findings that could be replicated in human tissues. Understanding of the biology of macrophages in atherosclerosis provides an important basis for the development of therapeutic strategies to limit lesion formation and promote plaque regression.
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Affiliation(s)
- Lukas Tomas
- Department of Medicine I, University Hospital, Ludwig Maximilian University, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Filip Prica
- Department of Medicine I, University Hospital, Ludwig Maximilian University, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Christian Schulz
- Department of Medicine I, University Hospital, Ludwig Maximilian University, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
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38
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Park SH. Regulation of Macrophage Activation and Differentiation in Atherosclerosis. J Lipid Atheroscler 2021; 10:251-267. [PMID: 34621697 PMCID: PMC8473962 DOI: 10.12997/jla.2021.10.3.251] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/31/2021] [Accepted: 03/31/2021] [Indexed: 12/29/2022] Open
Abstract
Chronic inflammation is a hallmark of atherosclerosis and macrophages play a central role in controlling inflammation at all stages of atherosclerosis. In atherosclerosis, macrophages and monocyte-derived macrophages are continuously exposed to cholesterol, oxidized lipids, cell debris, cytokines, and chemokines. Not only do these stimuli induce a specific macrophage phenotype, but they also interact extensively, leading to macrophage heterogeneity in atherosclerotic plaques. Herein, we review the diverse phenotypes of macrophages, the mechanisms underlying macrophage activation, and the contributions of macrophages to atherosclerosis in this context. We also summarize recent studies on foamy macrophages and monocyte-derived macrophages in plaque during disease progression. We provide a comprehensive overview of transcriptional, epigenetic, and metabolic reprogramming of macrophages and discuss the emerging concepts of targeting cytokines and macrophages to modulate atherosclerosis.
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Affiliation(s)
- Sung Ho Park
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Korea
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39
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Schlegel M, Sharma M, Brown EJ, Newman AAC, Cyr Y, Afonso MS, Corr EM, Koelwyn GJ, van Solingen C, Guzman J, Farhat R, Nikain CA, Shanley LC, Peled D, Schmidt AM, Fisher EA, Moore KJ. Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression. Circ Res 2021; 129:530-546. [PMID: 34289717 PMCID: PMC8529357 DOI: 10.1161/circresaha.121.319313] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Rationale: Therapeutic efforts to decrease atherosclerotic cardiovascular disease risk have focused largely on reducing atherogenic lipoproteins, yet lipid-lowering therapies alone are insufficient to fully regress plaque burden. We postulate that arterial repair requires resolution of a maladaptive immune response and that targeting factors that hinder inflammation resolution will facilitate plaque regression. Objective: The guidance molecule Ntn1 (netrin-1) is secreted by macrophages in atherosclerotic plaques, where it sustains inflammation by enhancing macrophage survival and blocking macrophage emigration. We tested whether silencing Ntn1 in advanced atherosclerosis could resolve arterial inflammation and regress plaques. Methods and Results: To temporally silence Ntn1 in myeloid cells, we generated genetically modified mice in which Ntn1 could be selectively deleted in monocytes and macrophages using a tamoxifen-induced CX3CR1-driven cre recombinase (Ntn1fl/flCx3cr1creERT2+) and littermate control mice (Ntn1fl/flCx3cr1WT). Mice were fed Western diet in the setting of hepatic PCSK9 (proprotein convertase subtilisin/kexin type 9) overexpression to render them atherosclerotic and then treated with tamoxifen to initiate deletion of myeloid Ntn1 (MøΔNtn1) or not in controls (MøWT). Morphometric analyses performed 4 weeks later showed that myeloid Ntn1 silencing reduced plaque burden in the aorta (−50%) and plaque complexity in the aortic root. Monocyte-macrophage tracing experiments revealed lower monocyte recruitment, macrophage retention, and proliferation in MøΔNtn1 compared with MøWT plaques, indicating a restructuring of monocyte-macrophage dynamics in the artery wall upon Ntn1 silencing. Single-cell RNA sequencing of aortic immune cells before and after Ntn1 silencing revealed upregulation of gene pathways involved in macrophage phagocytosis and migration, including the Ccr7 chemokine receptor signaling pathway required for macrophage emigration from plaques and atherosclerosis regression. Additionally, plaques from MøΔNtn1 mice showed hallmarks of inflammation resolution, including higher levels of proresolving macrophages, IL (interleukin)-10, and efferocytosis, as compared to plaques from MøWT mice. Conclusion: Our data show that targeting Ntn1 in advanced atherosclerosis ameliorates atherosclerotic inflammation and promotes plaque regression.
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Affiliation(s)
- Martin Schlegel
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
- Department of Anesthesiology and Intensive Care, Technical University of Munich, School of Medicine, Germany (M. Schlegel)
| | - Monika Sharma
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Emily J Brown
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Alexandra A C Newman
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Yannick Cyr
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Milessa Silva Afonso
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Emma M Corr
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Graeme J Koelwyn
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Coen van Solingen
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Jonathan Guzman
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Rubab Farhat
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Cyrus A Nikain
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Lianne C Shanley
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Daniel Peled
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Ann Marie Schmidt
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, New York University (A.M.S.). K.J. Moore, M. Schlegel, M. Sharma, A.M. Schmidt, and E.A. Fisher designed the study and performed data analysis and interpretation. M. Schlegel, M. Sharma, M.S. Afonso, E.J. Brown, E.M. Corr, C. van Solingen, G.J. Koelwyn, A.A.C. Newman, Y. Cyr, R. Farhat, J. Guzman, L.C. Shanley, and D. Peled conducted experiments, acquired data, and performed analyses. E.J. Brown analyzed the RNA-sequencing data. K.J. Moore and M. Schlegel wrote the article with input from all authors
| | - Edward A Fisher
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
| | - Kathryn J Moore
- NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.)
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Modelling Preferential Phagocytosis in Atherosclerosis: Delineating Timescales in Plaque Development. Bull Math Biol 2021; 83:96. [PMID: 34390421 DOI: 10.1007/s11538-021-00926-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 07/20/2021] [Indexed: 02/06/2023]
Abstract
Atherosclerotic plaques develop over a long time and can cause heart attacks and strokes. There are no simple mathematical models that capture the different timescales of rapid macrophage and lipid dynamics and slow plaque growth. We propose a simple ODE model for lipid dynamics that includes macrophage preference for ingesting apoptotic material and modified low-density lipoproteins (modLDL) over ingesting necrotic material. We use multiple timescale analysis to show that if the necrosis rate is small then the necrotic core in the model plaque may continue to develop slowly even when the lipid levels in plaque macrophages, apoptotic material and modLDL appear to have reached equilibrium. We use the model to explore the effect of macrophage emigration, apoptotic cell necrosis, total rate of macrophage phagocytosis and modLDL influx into the plaque on plaque lipid accumulation.
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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: 34] [Impact Index Per Article: 8.5] [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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42
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Yeo KP, Lim HY, Angeli V. Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis. Cells 2021; 10:cells10061344. [PMID: 34072313 PMCID: PMC8229118 DOI: 10.3390/cells10061344] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/21/2021] [Accepted: 05/26/2021] [Indexed: 02/03/2023] Open
Abstract
In recent years, lymphatic vessels have received increasing attention and our understanding of their development and functional roles in health and diseases has greatly improved. It has become clear that lymphatic vessels are critically involved in acute and chronic inflammation and its resolution by supporting the transport of immune cells, fluid, and macromolecules. As we will discuss in this review, the involvement of lymphatic vessels has been uncovered in atherosclerosis, a chronic inflammatory disease of medium- and large-sized arteries causing deadly cardiovascular complications worldwide. The progression of atherosclerosis is associated with morphological and functional alterations in lymphatic vessels draining the diseased artery. These defects in the lymphatic vasculature impact the inflammatory response in atherosclerosis by affecting immune cell trafficking, lymphoid neogenesis, and clearance of macromolecules in the arterial wall. Based on these new findings, we propose that targeting lymphatic function could be considered in conjunction with existing drugs as a treatment option for atherosclerosis.
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43
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The Role of Angiotensin Antagonism in Coronary Plaque Regression: Insights from the Glagovian Model. Int J Vasc Med 2021; 2021:8887248. [PMID: 33880191 PMCID: PMC8046567 DOI: 10.1155/2021/8887248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 03/21/2021] [Indexed: 11/17/2022] Open
Abstract
The benefit of antagonizing the effect of the renin angiotensin aldosterone system (RAAS), notably by the use of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor blocker (ARB) for coronary artery disease (CAD), has been demonstrated in multiple studies, which may be attributed to their ability to inhibit the deleterious effect of RAAS to the cardiovascular system. It is well known that angiotensin II (Ang II) plays a vital role in atheromatous plaque formation and progression through multiple pathways, including inflammatory and arterial remodeling aspects. Significant coronary atheromatous plaque regression has been previously demonstrated in various studies using statin agents. Similar results have been reported in different studies using angiotensin inhibitor agents, notably ARB agents. Analysis from various trials utilizing ARB showed a significant plaque regression using olmesartan and telmisartan as evaluated by IVUS studies. In contrary, the use of ACEi did not demonstrated significant plaque regression, which may be attributed to the heavy plaque calcification in respective studies. On this review, we aim to present the basic mechanism on the role of RAAS in plaque modulation and its arterial remodeling aspect, which is then integrated with the clinical evidence based on the available intravascular ultrasonography (IVUS) studies on coronary arteries.
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44
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Zang X, Cheng M, Zhang X, Chen X. Targeting macrophages using nanoparticles: a potential therapeutic strategy for atherosclerosis. J Mater Chem B 2021; 9:3284-3294. [PMID: 33881414 DOI: 10.1039/d0tb02956d] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Atherosclerosis is one of the leading causes of vascular diseases, with high morbidity and mortality worldwide. Macrophages play a critical role in the development and local inflammatory responses of atherosclerosis, contributing to plaque rupture and thrombosis. Considering their central roles, macrophages have gained considerable attention as a therapeutic target to attenuate atherosclerotic progression and stabilize existing plaques. Nanoparticle-based delivery systems further provide possibilities to selectively and effectively deliver therapeutic agents into intraplaque macrophages. Although challenges are numerous and clinical application is still distant, the design and development of macrophage-targeting nanoparticles will generate new knowledge and experiences to improve therapeutic outcomes and minimize toxicity. Hence, the review aims to discuss various strategies for macrophage modulation and the development and evaluation of macrophage targeting nanomedicines for anti-atherosclerosis.
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Affiliation(s)
- Xinlong Zang
- School of Basic Medicine, Qingdao University, Ningxia Road 308, Qingdao, P. R. China.
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45
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Burger F, Miteva K, Baptista D, Roth A, Fraga-Silva RA, Martel C, Stergiopulos N, Mach F, Brandt KJ. Follicular regulatory helper T cells control the response of regulatory B cells to a high-cholesterol diet. Cardiovasc Res 2021; 117:743-755. [PMID: 32219371 PMCID: PMC7898950 DOI: 10.1093/cvr/cvaa069] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 10/14/2019] [Accepted: 03/23/2020] [Indexed: 01/01/2023] Open
Abstract
AIMS B cell functions in the process of atherogenesis have been investigated but several aspects remain to be clarified. METHODS AND RESULTS In this study, we show that follicular regulatory helper T cells (TFR) control regulatory B cell (BREG) populations in Apoe-/- mice models on a high-cholesterol diet (HCD). Feeding mice with HCD resulted in up-regulation of TFR and BREG cell populations, causing the suppression of proatherogenic follicular helper T cell (TFH) response. TFH cell modulation is correlated with the growth of atherosclerotic plaque size in thoracoabdominal aortas and aortic root plaques, suggesting that TFR cells are atheroprotective. During adoptive transfer experiments, TFR cells transferred into HCD mice decreased TFH cell populations, atherosclerotic plaque size, while BREG cell population and lymphangiogenesis are significantly increased. CONCLUSION Our results demonstrate that, through different strategies, both TFR and TFH cells modulate anti- and pro-atherosclerotic immune processes in an Apoe-/- mice model since TFR cells are able to regulate both TFH and BREG cell populations as well as lymphangiogenesis and lipoprotein metabolism.
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MESH Headings
- Adoptive Transfer
- Animals
- Aorta/immunology
- Aorta/metabolism
- Aorta/pathology
- Aortic Diseases/immunology
- Aortic Diseases/metabolism
- Aortic Diseases/pathology
- Atherosclerosis/immunology
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- B-Lymphocytes, Regulatory/immunology
- B-Lymphocytes, Regulatory/metabolism
- B-Lymphocytes, Regulatory/transplantation
- Cell Differentiation
- Cells, Cultured
- Cholesterol, Dietary
- Diet, High-Fat
- Disease Models, Animal
- Lymphangiogenesis
- Mice, Inbred C57BL
- Mice, Knockout, ApoE
- Phenotype
- Plaque, Atherosclerotic
- T Follicular Helper Cells/immunology
- T Follicular Helper Cells/metabolism
- T Follicular Helper Cells/transplantation
- Mice
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Affiliation(s)
- Fabienne Burger
- Division of Cardiology, Foundation for Medical Research, Department of Medicine Specialized Medicine, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, CH-1211 Geneva 4, Switzerland
| | - Kapka Miteva
- Division of Cardiology, Foundation for Medical Research, Department of Medicine Specialized Medicine, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, CH-1211 Geneva 4, Switzerland
| | - Daniela Baptista
- Division of Cardiology, Foundation for Medical Research, Department of Medicine Specialized Medicine, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, CH-1211 Geneva 4, Switzerland
| | - Aline Roth
- Division of Cardiology, Foundation for Medical Research, Department of Medicine Specialized Medicine, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, CH-1211 Geneva 4, Switzerland
| | - Rodrigo A Fraga-Silva
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Catherine Martel
- Department of Medicine, Faculty of Medicine, Montreal Heart Institute Research Center, Université de Montréal, 5000, Belanger St, Room S5100, Montreal, Quebec, Canada
| | - Nikolaos Stergiopulos
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - François Mach
- Division of Cardiology, Foundation for Medical Research, Department of Medicine Specialized Medicine, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, CH-1211 Geneva 4, Switzerland
| | - Karim J Brandt
- Division of Cardiology, Foundation for Medical Research, Department of Medicine Specialized Medicine, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, CH-1211 Geneva 4, Switzerland
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46
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Hu X, Ma R, Cao J, Du X, Cai X, Fan Y. PTPN2 negatively regulates macrophage inflammation in atherosclerosis. Aging (Albany NY) 2020; 13:2768-2779. [PMID: 33411686 PMCID: PMC7880395 DOI: 10.18632/aging.202326] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 10/27/2020] [Indexed: 01/11/2023]
Abstract
Atherosclerosis is the main cause of cardiovascular disease. Systemic inflammation is one important characteristic in atherosclerosis. Pro-inflammatory macrophages can secrete inflammatory factors and promote the inflammation of atherosclerosis. It has a great value for the treatment of atherosclerosis by inhibiting the release of inflammatory factors in macrophages. However, the detailed mechanism of this process is still unclear. In this study, we constructed an APOE-/- mice model of atherosclerosis to research the molecular mechanism of atherosclerosis. Protein tyrosine phosphatase non-receptor type 2 (PTPN2), an anti-inflammatory gene, was dramatically decreased in inflammatory mice. Deletion of PTPN2 could significantly induce monocytes toward M1 phenotype of macrophages, enhance the secretion of IL-12 and IL-1, and promote cell proliferation, invasion and metastasis. Mechanism research showed that PTPN2-mediated p65/p38/STAT3 de-phosphorylation could block the process of macrophage inflammation. In vivo experiments showed that PTPN2 may effectively inhibit the inflammatory response during atherosclerosis. In conclusion, we uncovered the negative role of PTPN2 in the occurrence of atherosclerosis, and this study provides a new potential target for atherosclerosis treatment.
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Affiliation(s)
- Xiaorong Hu
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Ruisong Ma
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, China
| | - Jianlei Cao
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xianjin Du
- Department of Emergency, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xinyong Cai
- Department of Cardiology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, JiangXi, China
| | - Yongzhen Fan
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
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47
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Engelbrecht E, MacRae CA, Hla T. Lysolipids in Vascular Development, Biology, and Disease. Arterioscler Thromb Vasc Biol 2020; 41:564-584. [PMID: 33327749 DOI: 10.1161/atvbaha.120.305565] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Membrane phospholipid metabolism forms lysophospholipids, which possess unique biochemical and biophysical properties that influence membrane structure and dynamics. However, lysophospholipids also function as ligands for G-protein-coupled receptors that influence embryonic development, postnatal physiology, and disease. The 2 most well-studied species-lysophosphatidic acid and S1P (sphingosine 1-phosphate)-are particularly relevant to vascular development, physiology, and cardiovascular diseases. This review summarizes the role of lysophosphatidic acid and S1P in vascular developmental processes, endothelial cell biology, and their roles in cardiovascular disease processes. In addition, we also point out the apparent connections between lysophospholipid biology and the Wnt (int/wingless family) pathway, an evolutionarily conserved fundamental developmental signaling system. The discovery that components of the lysophospholipid signaling system are key genetic determinants of cardiovascular disease has warranted current and future research in this field. As pharmacological approaches to modulate lysophospholipid signaling have entered the clinical sphere, new findings in this field promise to influence novel therapeutic strategies in cardiovascular diseases.
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Affiliation(s)
- Eric Engelbrecht
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery (E.E., T.H.), Harvard Medical School, Boston, MA
| | - Calum A MacRae
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Department of Medicine (C.A.M.), Harvard Medical School, Boston, MA
| | - Timothy Hla
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery (E.E., T.H.), Harvard Medical School, Boston, MA
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48
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Härdtner C, Kornemann J, Krebs K, Ehlert CA, Jander A, Zou J, Starz C, Rauterberg S, Sharipova D, Dufner B, Hoppe N, Dederichs TS, Willecke F, Stachon P, Heidt T, Wolf D, von Zur Mühlen C, Madl J, Kohl P, Kaeser R, Boettler T, Pieterman EJ, Princen HMG, Ho-Tin-Noé B, Swirski FK, Robbins CS, Bode C, Zirlik A, Hilgendorf I. Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering. Basic Res Cardiol 2020; 115:78. [PMID: 33296022 PMCID: PMC7725697 DOI: 10.1007/s00395-020-00838-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 12/01/2020] [Indexed: 02/08/2023]
Abstract
Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.
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Affiliation(s)
- Carmen Härdtner
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Jan Kornemann
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Katja Krebs
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Carolin A Ehlert
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Alina Jander
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Jiadai Zou
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Christopher Starz
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Simon Rauterberg
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Diana Sharipova
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Bianca Dufner
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Natalie Hoppe
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Tsai-Sang Dederichs
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Florian Willecke
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Peter Stachon
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Timo Heidt
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Dennis Wolf
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Constantin von Zur Mühlen
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Josef Madl
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Peter Kohl
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Rafael Kaeser
- Department of Medicine II, Faculty of Medicine, Medical Center-University Freiburg, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, Faculty of Medicine, Medical Center-University Freiburg, University of Freiburg, Freiburg, Germany
| | - Elsbeth J Pieterman
- The Netherlands Organization for Applied Scientific Research (TNO)-Metabolic Health Research, Leiden, Netherlands
| | - Hans M G Princen
- The Netherlands Organization for Applied Scientific Research (TNO)-Metabolic Health Research, Leiden, Netherlands
| | - Benoît Ho-Tin-Noé
- INSERM Unit 1148, University Paris Diderot, and Laboratory for Vascular Translational Science, Sorbonne Paris Cité, Paris, France
| | - Filip K Swirski
- Center of Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Clinton S Robbins
- Peter Munk Cardiac Centre, University Health Network, Toronto, Canada
| | - Christoph Bode
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany
| | - Andreas Zirlik
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany.,Department of Cardiology, University of Graz, Graz, Austria
| | - Ingo Hilgendorf
- Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany.
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DAPT, a potent Notch inhibitor regresses actively growing abdominal aortic aneurysm via divergent pathways. Clin Sci (Lond) 2020; 134:1555-1572. [PMID: 32490531 DOI: 10.1042/cs20200456] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/01/2020] [Accepted: 06/02/2020] [Indexed: 12/20/2022]
Abstract
Abdominal aortic aneurysm (AAA) is a localized pathological dilation of the aorta exceeding the normal diameter (∼20 mm) by more than 50% of its original size (≥30 mm), accounting for approximately 150000-200000 deaths worldwide per year. We previously reported that Notch inhibition does not decrease the size of pre-established AAA at late stage of the disease. Here, we examined whether a potent pharmacologic inhibitor of Notch signaling (DAPT (N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester)), regresses an actively growing AAA. In a mouse model of an aneurysm (Apoe-/- mice; n=44); DAPT (n=17) or vehicle (n=17) was randomly administered at day 14 of angiotensin II (AngII; 1 µg/min/kg), three times a week and mice were killed on day 42. Progressive increase in aortic stiffness and maximal intraluminal diameter (MILD) was observed in the AngII + vehicle group, which was significantly prevented by DAPT (P<0.01). The regression of aneurysm with DAPT was associated with reduced F4/80+Cd68+ (cluster of differentiation 68) inflammatory macrophages. DAPT improved structural integrity of aorta by reducing collagen fibrils abnormality and restoring their diameter. Mechanistically, C-C chemokine receptor type 7 (Ccr7)+F4/80- dendritic cells (DCs), implicated in the regression of aneurysm, were increased in the aorta of DAPT-treated mice. In the macrophages stimulated with AngII or lipopolysaccharide (LPS), DAPT reverted the expression of pro-inflammatory genes Il6 and Il12 back to baseline within 6 h compared with vehicle (P<0.05). DAPT also significantly increased the expression of anti-inflammatory genes, including c-Myc, Egr2, and Arg1 at 12-24 h in the LPS-stimulated macrophages (P<0.05). Overall, these regressive effects of Notch signaling inhibitor emphasize its therapeutic implications to prevent the progression of active AAAs.
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50
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Mitchell BI, Laws EI, Chow DC, Sah Bandar IN, Gangcuangco LMA, Shikuma CM, Ndhlovu LC. Increased Monocyte Inflammatory Responses to Oxidized LDL Are Associated with Insulin Resistance in HIV-Infected Individuals on Suppressive Antiretroviral Therapy. Viruses 2020; 12:v12101129. [PMID: 33028018 PMCID: PMC7601436 DOI: 10.3390/v12101129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/26/2020] [Accepted: 10/02/2020] [Indexed: 11/25/2022] Open
Abstract
Despite long term antiretroviral therapy (ART), insulin resistance (IR) is common among people living with HIV/AIDS (PLWHA) exposing this population to a greater risk of cardiometabolic complications when compared to their uninfected counterparts. We previously identified an expansion in monocyte subpopulations in blood that were linked to the degree of IR in persons with HIV on stable ART. In this study, we directly assessed monocyte inflammatory functional properties from PLWHA on ART (n = 33) and HIV-uninfected controls (n = 14) of similar age, gender, and cardiovascular disease risk and determined the relationship with IR (homeostatic model assessment-insulin resistance (HOMA-IR)), calculated from fasting blood glucose and insulin measurements. Peripheral blood mononuclear cells were stimulated with oxidized low-density lipoproteins (oxLDL) and polyfunctional monocyte cytokine responses (IL-1β, IL-6, IL-8, or TNF-α) were determined by flow cytometry. Higher monocyte IL-1β and IL-8 responses to oxLDL were associated with higher IR in PLWHA but not in the control group. We observed that higher basal monocyte cytokine responses were associated with both duration since HIV diagnosis and ART initiation. In the management of IR in chronic HIV, strategies lowering monocyte IL-1β and IL-8 responses should be considered in addition to ART in order to limit adverse cardio-metabolic outcomes.
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