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Yang XY, Li F, Zhang G, Foster PS, Yang M. The role of macrophages in asthma-related fibrosis and remodelling. Pharmacol Ther 2025; 269:108820. [PMID: 39983844 DOI: 10.1016/j.pharmthera.2025.108820] [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: 09/05/2024] [Revised: 11/06/2024] [Accepted: 02/12/2025] [Indexed: 02/23/2025]
Abstract
Airway remodelling significantly contributes to the progressive loss of lung function and heightened symptom severity in chronic asthma. Additionally, it often persists and demonstrates reduced responsiveness to the mainstay treatments. The excessive deposition of collagen and extracellular matrix proteins leads to subepithelial fibrosis and airway remodelling, resulting in increased stiffness and decreased elasticity in the airway. Studies have emphasized the crucial role of subepithelial fibrosis in the pathogenesis of asthma. Fibrotic processes eventually cause airway narrowing, reduced lung function, and exacerbation of asthma symptoms. Macrophages play a crucial role in this process by producing pro-fibrotic cytokines, growth factors, and enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Additionally, identification of novel genetic markers has provided evidence for a strong genetic component in fibrosis within macrophage regulated fibrosis. Although macrophages contribute to the progression of airway remodelling and subepithelial fibrosis, interventions targeting macrophage-driven fibrotic changes have not yet been developed. This review synthesizes research on the intricate pathways through which macrophages contribute to subepithelial fibrosis in chronic asthma and its' pathological features. Understanding the interplay between macrophages, fibrosis, and asthma pathogenesis is essential for developing effective therapeutic strategies to manage severe asthma and improve patient outcomes.
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Affiliation(s)
- Xin Yuan Yang
- The School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia
| | - Fuguang Li
- Department of Immunology & Microbiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Guojun Zhang
- Department of Respiratory Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Paul S Foster
- Woolcock Institute of Medical Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2113, Australia
| | - Ming Yang
- Department of Immunology & Microbiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China; Department of Respiratory Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, PR China; Deparment of Respiratory Medicine and Intensive Care Unit, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471009, PR China; School of Biomedical Sciences & Pharmacy, Faculty of Health. Medicine and Wellbeing & Hunter Medical Research Institute, University of Newcastle, Lot 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia.
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Miceli G, Basso MG, Pintus C, Pennacchio AR, Cocciola E, Cuffaro M, Profita M, Rizzo G, Tuttolomondo A. Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review. Int J Mol Sci 2024; 25:4351. [PMID: 38673936 PMCID: PMC11050267 DOI: 10.3390/ijms25084351] [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: 02/26/2024] [Revised: 04/05/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
The concept of vulnerable carotid plaques is pivotal in understanding the pathophysiology of ischemic stroke secondary to large-artery atherosclerosis. In macroscopic evaluation, vulnerable plaques are characterized by one or more of the following features: microcalcification; neovascularization; lipid-rich necrotic cores (LRNCs); intraplaque hemorrhage (IPH); thin fibrous caps; plaque surface ulceration; huge dimensions, suggesting stenosis; and plaque rupture. Recognizing these macroscopic characteristics is crucial for estimating the risk of cerebrovascular events, also in the case of non-significant (less than 50%) stenosis. Inflammatory biomarkers, such as cytokines and adhesion molecules, lipid-related markers like oxidized low-density lipoprotein (LDL), and proteolytic enzymes capable of degrading extracellular matrix components are among the key molecules that are scrutinized for their associative roles in plaque instability. Through their quantification and evaluation, these biomarkers reveal intricate molecular cross-talk governing plaque inflammation, rupture potential, and thrombogenicity. The current evidence demonstrates that plaque vulnerability phenotypes are multiple and heterogeneous and are associated with many highly complex molecular pathways that determine the activation of an immune-mediated cascade that culminates in thromboinflammation. This narrative review provides a comprehensive analysis of the current knowledge on molecular biomarkers expressed by symptomatic carotid plaques. It explores the association of these biomarkers with the structural and compositional attributes that characterize vulnerable plaques.
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Affiliation(s)
- Giuseppe Miceli
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Maria Grazia Basso
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Chiara Pintus
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Andrea Roberta Pennacchio
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Elena Cocciola
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Mariagiovanna Cuffaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Martina Profita
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Giuliana Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (G.M.); (M.G.B.); (C.P.); (A.R.P.); (E.C.); (M.C.); (M.P.); (G.R.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
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Jansen I, Cahalane R, Hengst R, Akyildiz A, Farrell E, Gijsen F, Aikawa E, van der Heiden K, Wissing T. The interplay of collagen, macrophages, and microcalcification in atherosclerotic plaque cap rupture mechanics. Basic Res Cardiol 2024; 119:193-213. [PMID: 38329498 PMCID: PMC11008085 DOI: 10.1007/s00395-024-01033-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 01/17/2024] [Accepted: 01/19/2024] [Indexed: 02/09/2024]
Abstract
The rupture of an atherosclerotic plaque cap overlying a lipid pool and/or necrotic core can lead to thrombotic cardiovascular events. In essence, the rupture of the plaque cap is a mechanical event, which occurs when the local stress exceeds the local tissue strength. However, due to inter- and intra-cap heterogeneity, the resulting ultimate cap strength varies, causing proper assessment of the plaque at risk of rupture to be lacking. Important players involved in tissue strength include the load-bearing collagenous matrix, macrophages, as major promoters of extracellular matrix degradation, and microcalcifications, deposits that can exacerbate local stress, increasing tissue propensity for rupture. This review summarizes the role of these components individually in tissue mechanics, along with the interplay between them. We argue that to be able to improve risk assessment, a better understanding of the effect of these individual components, as well as their reciprocal relationships on cap mechanics, is required. Finally, we discuss potential future steps, including a holistic multidisciplinary approach, multifactorial 3D in vitro model systems, and advancements in imaging techniques. The obtained knowledge will ultimately serve as input to help diagnose, prevent, and treat atherosclerotic cap rupture.
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Affiliation(s)
- Imke Jansen
- Department of Biomedical Engineering, Thorax Center Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Rachel Cahalane
- Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, College of Science and Engineering, University of Galway, Galway, Ireland
- Division of Cardiovascular Medicine, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ranmadusha Hengst
- Department of Biomedical Engineering, Thorax Center Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Ali Akyildiz
- Department of Biomedical Engineering, Thorax Center Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Biomechanical Engineering, Technical University Delft, Delft, The Netherlands
| | - Eric Farrell
- Department of Oral and Maxillofacial Surgery, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Frank Gijsen
- Department of Biomedical Engineering, Thorax Center Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Biomechanical Engineering, Technical University Delft, Delft, The Netherlands
| | - Elena Aikawa
- Division of Cardiovascular Medicine, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kim van der Heiden
- Department of Biomedical Engineering, Thorax Center Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Tamar Wissing
- Department of Biomedical Engineering, Thorax Center Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
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Zaripova LN, Midgley A, Christmas SE, Beresford MW, Pain C, Baildam EM, Oldershaw RA. Mesenchymal Stem Cells in the Pathogenesis and Therapy of Autoimmune and Autoinflammatory Diseases. Int J Mol Sci 2023; 24:16040. [PMID: 38003230 PMCID: PMC10671211 DOI: 10.3390/ijms242216040] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/27/2023] [Accepted: 10/31/2023] [Indexed: 11/26/2023] Open
Abstract
Mesenchymal stem cells (MSCs) modulate immune responses and maintain self-tolerance. Their trophic activities and regenerative properties make them potential immunosuppressants for treating autoimmune and autoinflammatory diseases. MSCs are drawn to sites of injury and inflammation where they can both reduce inflammation and contribute to tissue regeneration. An increased understanding of the role of MSCs in the development and progression of autoimmune disorders has revealed that MSCs are passive targets in the inflammatory process, becoming impaired by it and exhibiting loss of immunomodulatory activity. MSCs have been considered as potential novel cell therapies for severe autoimmune and autoinflammatory diseases, which at present have only disease modifying rather than curative treatment options. MSCs are emerging as potential therapies for severe autoimmune and autoinflammatory diseases. Clinical application of MSCs in rare cases of severe disease in which other existing treatment modalities have failed, have demonstrated potential use in treating multiple diseases, including rheumatoid arthritis, systemic lupus erythematosus, myocardial infarction, liver cirrhosis, spinal cord injury, multiple sclerosis, and COVID-19 pneumonia. This review explores the biological mechanisms behind the role of MSCs in autoimmune and autoinflammatory diseases. It also covers their immunomodulatory capabilities, potential therapeutic applications, and the challenges and risks associated with MSC therapy.
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Affiliation(s)
- Lina N. Zaripova
- Institute of Fundamental and Applied Medicine, National Scientific Medical Center, 42 Abylai Khan Avenue, Astana 010000, Kazakhstan;
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
| | - Angela Midgley
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
| | - Stephen E. Christmas
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, Faculty of Health and Life Sciences, University of Liverpool, The Ronald Ross Building, 8 West Derby Street, Liverpool L69 7BE, UK;
| | - Michael W. Beresford
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
- Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, East Prescott Road, Liverpool L14 5AB, UK
| | - Clare Pain
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
- Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, East Prescott Road, Liverpool L14 5AB, UK
| | - Eileen M. Baildam
- Department of Paediatric Rheumatology, The Alexandra Hospital, Mill Lane, Cheadle SK8 2PX, UK;
| | - Rachel A. Oldershaw
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
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Hu Y, Zhao Y, Li P, Lu H, Li H, Ge J. Hypoxia and panvascular diseases: exploring the role of hypoxia-inducible factors in vascular smooth muscle cells under panvascular pathologies. Sci Bull (Beijing) 2023; 68:1954-1974. [PMID: 37541793 DOI: 10.1016/j.scib.2023.07.032] [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: 04/25/2023] [Revised: 06/13/2023] [Accepted: 07/10/2023] [Indexed: 08/06/2023]
Abstract
As an emerging discipline, panvascular diseases are a set of vascular diseases with atherosclerosis as the common pathogenic hallmark, which mostly affect vital organs like the heart, brain, kidney, and limbs. As the major responser to the most common stressor in the vasculature (hypoxia)-hypoxia-inducible factors (HIFs), and the primary regulator of pressure and oxygen delivery in the vasculature-vascular smooth muscle cells (VSMCs), their own multifaceted nature and their interactions with each other are fascinating. Abnormally active VSMCs (e.g., atherosclerosis, pulmonary hypertension) or abnormally dysfunctional VSMCs (e.g., aneurysms, vascular calcification) are associated with HIFs. These widespread systemic diseases also reflect the interdisciplinary nature of panvascular medicine. Moreover, given the comparable proliferative characteristics exhibited by VSMCs and cancer cells, and the delicate equilibrium between angiogenesis and cancer progression, there is a pressing need for more accurate modulation targets or combination approaches to bolster the effectiveness of HIF targeting therapies. Based on the aforementioned content, this review primarily focused on the significance of integrating the overall and local perspectives, as well as temporal and spatial balance, in the context of the HIF signaling pathway in VSMC-related panvascular diseases. Furthermore, the review discussed the implications of HIF-targeting drugs on panvascular disorders, while considering the trade-offs involved.
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Affiliation(s)
- Yiqing Hu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Yongchao Zhao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Peng Li
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Hao Lu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Shanghai Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
| | - Hua Li
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Shanghai Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai 200032, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China.
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Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling. Nat Commun 2022; 13:5117. [PMID: 36071032 PMCID: PMC9452496 DOI: 10.1038/s41467-022-32658-6] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/10/2022] [Indexed: 01/19/2023] Open
Abstract
Although inflammation plays critical roles in the development of atherosclerosis, its regulatory mechanisms remain incompletely understood. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, we show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulate in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by genetically silencing PRDM16, a key regulator to beiging, exacerbates inflammation and vascular remodeling following injury. Conversely, activation of PVAT beiging attenuates inflammation and pathological vascular remodeling. Single-cell RNA sequencing reveals that beige adipocytes abundantly express neuregulin 4 (Nrg4) which critically regulate alternative macrophage activation. Importantly, significant beiging is observed in the diseased aortic PVAT in patients with acute aortic dissection. Taken together, vascular injury induces the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitates alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrates the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, the authors show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response as a protective mechanism.
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Diverse roles of tumor-stromal PDGFB-to-PDGFRβ signaling in breast cancer growth and metastasis. Adv Cancer Res 2022; 154:93-140. [PMID: 35459473 DOI: 10.1016/bs.acr.2022.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Over the last couple of decades, it has become increasingly apparent that the tumor microenvironment (TME) mediates every step of cancer progression and solid tumors are only able to metastasize with a permissive TME. This intricate interaction of cancer cells with their surrounding TME, or stroma, is becoming more understood with an ever greater knowledge of tumor-stromal signaling pairs such as platelet-derived growth factors (PDGF) and their cognate receptors. We and others have focused our research efforts on understanding how tumor-derived PDGFB activates platelet-derived growth factor receptor beta (PDGFRβ) signaling specifically in the breast cancer TME. In this chapter, we broadly discuss PDGF and PDGFR expression patterns and signaling in normal physiology and breast cancer. We then detail the expansive roles played by the PDGFB-to-PDGFRβ signaling pathway in modulating breast tumor growth and metastasis with a focus on specific cellular populations within the TME, which are responsive to tumor-derived PDGFB. Given the increasingly appreciated importance of PDGFB-to-PDGFRβ signaling in breast cancer progression, specifically in promoting metastasis, we end by discussing how therapeutic targeting of PDGFB-to-PDGFRβ signaling holds great promise for improving current breast cancer treatment strategies.
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Xie X. WELL-POSEDNESS OF A MATHEMATICAL MODEL OF DIABETIC ATHEROSCLEROSIS WITH ADVANCED GLYCATION END-PRODUCTS. APPLICABLE ANALYSIS 2022; 101:3989-4013. [PMID: 36188356 PMCID: PMC9524361 DOI: 10.1080/00036811.2022.2060210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/25/2022] [Indexed: 06/16/2023]
Abstract
Atherosclerosis is a leading cause of death worldwide; it emerges as a result of multiple dynamical cell processes including hemodynamics, endothelial damage, innate immunity and sterol biochemistry. Making matters worse, nearly 463 million people have diabetes, which increases atherosclerosis-related inflammation, diabetic patients are twice as likely to have a heart attack or stroke. The pathophysiology of diabetic vascular disease is generally understood. Dyslipidemia with increased levels of atherogenic LDL, hyperglycemia, oxidative stress and increased inflammation are factors that increase the risk and accelerate development of atherosclerosis. In a recent paper [53], we have developed mathematical model that includes the effect of hyperglycemia and insulin resistance on plaque growth. In this paper, we propose a more comprehensive mathematical model for diabetic atherosclerosis which include more variables; in particular it includes the variable for Advanced Glycation End-Products (AGEs)concentration. Hyperglycemia trigger vascular damage by forming AGEs, which are not easily metabolized and may accelerate the progression of vascular disease in diabetic patients. The model is given by a system of partial differential equations with a free boundary. We also establish local existence and uniqueness of solution to the model. The methodology is to use Hanzawa transformation to reduce the free boundary to a fixed boundary and reduce the system of partial differential equations to an abstract evolution equation in Banach spaces, and apply the theory of analytic semigroup.
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Affiliation(s)
- Xuming Xie
- Department of Mathematics, Morgan State University, Baltimore, MD 21251
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9
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Xie X. WELL-POSEDNESS OF A MATHEMATICAL MODEL OF DIABETIC ATHEROSCLEROSIS. JOURNAL OF MATHEMATICAL ANALYSIS AND APPLICATIONS 2022; 505:125606. [PMID: 34483362 PMCID: PMC8415469 DOI: 10.1016/j.jmaa.2021.125606] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Atherosclerosis is a leading cause of death in the United States and worldwide; it emerges as a result of multiple dynamical cell processes including hemodynamics, endothelial damage, innate immunity and sterol biochemistry. Making matters worse, nearly 21 million Americans have diabetes, a disease where patients' cells cannot efficiently take in dietary sugar, causing it to build up in the blood. In part because diabetes increases atherosclerosis-related inflammation, diabetic patients are twice as likely to have a heart attack or stroke. Past work has shown that hyperglycemia and insulin resistance alter function of multiple cell types, including endothelium, smooth muscle cells and platelets, indicating the extent of vascular disarray in this disease. Although the pathophysiology of diabetic vascular disease is generally understood, there is no mathematical model to date that includes the effect of diabetes on plaque growth. In this paper, we propose a mathematical model for diabetic atherosclerosis; the model is given by a system of partial differential equations with a free boundary. We establish local existence and uniqueness of solution to the model. The methodology is to use Hanzawa transformation to reduce the free boundary to a fixed boundary and reduce the system of partial differential equations to an abstract evolution equation in Banach spaces, and apply the theory of analytic semigroup.
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Affiliation(s)
- Xuming Xie
- Department of Mathematics, Morgan State University, Baltimore, MD 21251
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Mao L, Yin R, Yang L, Zhao D. Role of advanced glycation end products on vascular smooth muscle cells under diabetic atherosclerosis. Front Endocrinol (Lausanne) 2022; 13:983723. [PMID: 36120471 PMCID: PMC9470882 DOI: 10.3389/fendo.2022.983723] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/11/2022] [Indexed: 11/30/2022] Open
Abstract
Atherosclerosis (AS) is a chronic inflammatory disease and leading cause of cardiovascular diseases. The progression of AS is a multi-step process leading to high morbidity and mortality. Hyperglycemia, dyslipidemia, advanced glycation end products (AGEs), inflammation and insulin resistance which strictly involved in diabetes are closely related to the pathogenesis of AS. A growing number of studies have linked AGEs to AS. As one of the risk factors of cardiac metabolic diseases, dysfunction of VSMCs plays an important role in AS pathogenesis. AGEs are increased in diabetes, participate in the occurrence and progression of AS through multiple molecular mechanisms of vascular cell injury. As the main functional cells of vascular, vascular smooth muscle cells (VSMCs) play different roles in each stage of atherosclerotic lesions. The interaction between AGEs and receptor for AGEs (RAGE) accelerates AS by affecting the proliferation and migration of VSMCs. In addition, increasing researches have reported that AGEs promote osteogenic transformation and macrophage-like transformation of VSMCs, and affect the progression of AS through other aspects such as autophagy and cell cycle. In this review, we summarize the effect of AGEs on VSMCs in atherosclerotic plaque development and progression. We also discuss the AGEs that link AS and diabetes mellitus, including oxidative stress, inflammation, RAGE ligands, small noncoding RNAs.
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Affiliation(s)
| | | | | | - Dong Zhao
- *Correspondence: Longyan Yang, ; Dong Zhao,
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Hu Q, Chen Z, Yuan X, Li S, Zhang R, Qin X. Common Polymorphisms in the RGMa Promoter Are Associated With Cerebrovascular Atherosclerosis Burden in Chinese Han Patients With Acute Ischemic Cerebrovascular Accident. Front Cardiovasc Med 2021; 8:743868. [PMID: 34722675 PMCID: PMC8554026 DOI: 10.3389/fcvm.2021.743868] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/27/2021] [Indexed: 12/31/2022] Open
Abstract
Repulsive guidance molecule a (RGMa) plays a vital role in the progression of numerous inflammatory diseases. However, whether it participates in atherosclerosis development is not known. Here, we explored the influence of RGMa in atherogenesis by investigating whether an association exists between functional polymorphisms in the RGMa promoter and cerebrovascular atherosclerosis burden (CAB) in Chinese Han patients diagnosed with acute ischemic cerebrovascular accident. To this end, we conducted a genetic association study on 201 patients with prior diagnoses of acute ischemic stroke or transient ischemic attack recruited from our hospital. After admission, we conducted three targeted single-nucleotide polymorphisms (SNPs) genotyping and evaluated CAB by computed tomography angiography. We used logistic regression modeling to analyze genetic associations. Functional polymorphism analysis indicated an independent association between the rs725458 T allele and increased CAB in patients with acute ischemic cerebrovascular accident [adjusted odds ratio (OR) = 1.66, 95% confidence interval (CI) = 1.01–2.74, P = 0.046]. In contrast, an association between the rs4778099 AA genotype and decreased CAB (adjusted OR = 0.10, 95% CI = 0.01–0.77, P = 0.027) was found. Our Gene Expression Omnibus analysis revealed lower RGMa levels in the atherosclerotic aortas and in the macrophages isolated from plaques than that in the normal aortas and macrophages from normal tissue, respectively. In conclusion, the relationship between RGMa and cerebrovascular atherosclerosis suggests that RGMa has a potential vasoprotective effect. The two identified functional SNPs (rs725458 and rs4778099) we identified in the RGMa promoter are associated with CAB in patients diagnosed with acute ischemic cerebrovascular accident. These findings offer a promising research direction for RGMa-related translational studies on atherosclerosis.
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Affiliation(s)
- Qingzhe Hu
- Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zhenlei Chen
- Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xiaofan Yuan
- Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Shucheng Li
- Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Rongrong Zhang
- Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xinyue Qin
- Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Liang G, Huang X, Hirsch J, Mehmi S, Fonda H, Chan K, Huang NF, Aalami O, Froelicher VF, Lee DP, Myers J, Lee AS, Nguyen PK. Modest Gains After an 8-Week Exercise Program Correlate With Reductions in Non-traditional Markers of Cardiovascular Risk. Front Cardiovasc Med 2021; 8:669110. [PMID: 34222367 PMCID: PMC8245677 DOI: 10.3389/fcvm.2021.669110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/13/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Although engaging in physical exercise has been shown to reduce the incidence of cardiovascular events, the molecular mechanisms by which exercise mediates these benefits remain unclear. Based on epidemiological evidence, reductions in traditional risk factors only accounts for 50% of the protective effects of exercise, leaving the remaining mechanisms unexplained. The objective of this study was to determine whether engaging in a regular exercise program in a real world clinical setting mediates cardiovascular protection via modulation of non-traditional risk factors, such as those involved in coagulation, inflammation and metabolic regulation. Methods and Results: We performed a prospective, cohort study in 52 sedentary patients with cardiovascular disease or cardiovascular risk factors at two tertiary medical centers between January 1, 2016 and December 31, 2019. Prior to and at the completion of an 8-week exercise program, we collected information on traditional cardiovascular risk factors, exercise capacity, and physical activity and performed plasma analysis to measure levels of fibrinolytic, inflammatory and metabolic biomarkers to assess changes in non-traditional cardiovascular risk factors. The median weight change, improvement in physical fitness, and change in physical activity for the entire cohort were: -4.6 pounds (IQR: +2 pounds, -11.8 pounds), 0.37 METs (IQR: -0.076 METs, 1.06 METs), and 252.7 kcals/week (IQR: -119, 921.2 kcals/week). In addition to improvement in blood pressure and cholesterol, patients who lost at least 5 pounds, expended at least 1,000 additional kcals/week, and/or achieved ≥0.5 MET increase in fitness had a significant reduction in plasminogen activator inhibitor-1 [9.07 ng/mL (95% CI: 2.78-15.35 ng/mL); P = 0.026], platelet derived growth factor beta [376.077 pg/mL (95% CI: 44.69-707.46 pg/mL); P = 0.026); and angiopoietin-1 [(1104.11 pg/mL (95% CI: 2.92-2205.30 pg/mL); P = 0.049)]. Conclusion: Modest improvements in physical fitness, physical activity, and/or weight loss through a short-term exercise program was associated with decreased plasma levels of plasminogen activator inhibitor, platelet derived growth factor beta, and angiopoietin, which have been associated with impaired fibrinolysis and inflammation.
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Affiliation(s)
- Grace Liang
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States
| | - Xianxi Huang
- Department of Critical Care Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Stanford Cardiovascular Institute, Stanford, CA, United States
| | - James Hirsch
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Sanjeev Mehmi
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Holly Fonda
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Khin Chan
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Ngan F. Huang
- Department of Cardiovascular Surgery, Stanford University, Stanford, CA, United States
| | - Oliver Aalami
- Vascular Surgery Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Victor F. Froelicher
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - David P. Lee
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States
| | - Jonathan Myers
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States
- Stanford Cardiovascular Institute, Stanford, CA, United States
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Andrew S. Lee
- Stanford Cardiovascular Institute, Stanford, CA, United States
- Department of Pathology, Stanford University, Stanford, CA, United States
| | - Patricia K. Nguyen
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States
- Stanford Cardiovascular Institute, Stanford, CA, United States
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
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13
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Simone S, Chieti A, Pontrelli P, Rascio F, Castellano G, Stallone G, Infante B, Gesualdo L, Grandaliano G, Pertosa G. On-line hemodiafiltration modulates atherosclerosis signaling in peripheral lymphomonocytes of hemodialysis patients. J Nephrol 2021; 34:1989-1997. [PMID: 33761122 PMCID: PMC8610953 DOI: 10.1007/s40620-020-00958-z] [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: 08/04/2020] [Accepted: 12/27/2020] [Indexed: 11/18/2022]
Abstract
Background Hemodialysis patients present a dramatic increase in cardiovascular morbidity/mortality. Circulating immune cells, activated by both uremic milieu and dialysis, play a key role in the pathogenesis of dialysis-related vascular disease. The aim of our study was to identify, through a high-throughput approach, differences in gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of patients treated with on-line hemodiafiltration and bicarbonate hemodialysis. Methods The transcriptomic profile was investigated in PBMCs isolated from eight patients on on-line hemodiafiltration and eight patients on bicarbonate hemodialysis by microarray analysis. The results were evaluated by statistical and functional pathway analysis and validated by real time PCR (qPCR) in an independent cohort of patients (on-line hemodiafiltration N = 20, bicarbonate hemodialysis n = 20). Results Eight hundred and forty-seven genes were differentially expressed in patients treated with on-line hemodiafiltration and bicarbonate hemodialysis. Thirty-seven functional gene networks were identified and atherosclerosis signaling was the top canonical pathway regulated by on-line hemodiafiltration. Among the genes of this pathway, on-line hemodiafiltration was associated with a reduced expression of Platelet-derived growth factor A chain (PDGF A), Clusterin, Monoamine Oxidase A, Interleukin-6 (IL-6) and Vascular Endothelial Growth
Factor C (VEGF-)C and with an increase of Apolipoprotein E. qPCR confirmed the microarray results. Platelet derived growth factor AA (PDGF-AA), IL-6 and VEGF-C serum levels were significantly lower in the on-line hemodiafiltration group. Finally, 10 patients previously on bicarbonate hemodialysis were switched to on-line hemodiafiltration and PBMCs were harvested after 6 months. The qPCR results from this perspective group confirmed the modulation of atherosclerotic genes observed in the cross-sectional analysis. Conclusions Our data suggest that type of dialysis (on-line hemodiafiltration versus bicarbonate hemodialysis) may modulate the expression of several genes involved in the pathogenesis of atherosclerotic disease.
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Affiliation(s)
- Simona Simone
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari "A. Moro", Piazza G. Cesare 11, 70122, Bari, Italy.
| | - Annarita Chieti
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari "A. Moro", Piazza G. Cesare 11, 70122, Bari, Italy
| | - Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari "A. Moro", Piazza G. Cesare 11, 70122, Bari, Italy
| | - Federica Rascio
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari "A. Moro", Piazza G. Cesare 11, 70122, Bari, Italy
| | - Giuseppe Grandaliano
- Nephrology Unit, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.,Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giovanni Pertosa
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari "A. Moro", Piazza G. Cesare 11, 70122, Bari, Italy
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14
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Immunological Aspects of Age-Related Macular Degeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1256:143-189. [PMID: 33848001 DOI: 10.1007/978-3-030-66014-7_6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Increasing evidence over the past two decades points to a pivotal role for immune mechanisms in age-related macular degeneration (AMD) pathobiology. In this chapter, we will explore immunological aspects of AMD, with a specific focus on how immune mechanisms modulate clinical phenotypes of disease and severity and how components of the immune system may serve as triggers for disease progression in both dry and neovascular AMD. We will briefly review the biology of the immune system, defining the role of immune mechanisms in chronic degenerative disease and differentiating from immune responses to acute injury or infection. We will explore current understanding of the roles of innate immunity (especially macrophages), antigen-specific immunity (T cells, B cells, and autoimmunity), immune amplifications systems, especially complement activity and the NLRP3 inflammasome, in the pathogenesis of both dry and neovascular AMD, reviewing data from pathology, experimental animal models, and clinical studies of AMD patients. We will also assess how interactions between the immune system and infectious pathogens could potentially modulate AMD pathobiology via alterations in in immune effector mechanisms. We will conclude by reviewing the paradigm of "response to injury," which provides a means to integrate various immunologic mechanisms along with nonimmune mechanisms of tissue injury and repair as a model to understand the pathobiology of AMD.
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15
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Ye F, Garton HJL, Hua Y, Keep RF, Xi G. The Role of Thrombin in Brain Injury After Hemorrhagic and Ischemic Stroke. Transl Stroke Res 2020; 12:496-511. [PMID: 32989665 DOI: 10.1007/s12975-020-00855-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/22/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023]
Abstract
Thrombin is increased in the brain after hemorrhagic and ischemic stroke primarily due to the prothrombin entry from blood either with a hemorrhage or following blood-brain barrier disruption. Increasing evidence indicates that thrombin and its receptors (protease-activated receptors (PARs)) play a major role in brain pathology following ischemic and hemorrhagic stroke (including intracerebral, intraventricular, and subarachnoid hemorrhage). Thrombin and PARs affect brain injury via multiple mechanisms that can be detrimental or protective. The cleavage of prothrombin into thrombin is the key step of hemostasis and thrombosis which takes place in every stroke and subsequent brain injury. The extravascular effects and direct cellular interactions of thrombin are mediated by PARs (PAR-1, PAR-3, and PAR-4) and their downstream signaling in multiple brain cell types. Such effects include inducing blood-brain-barrier disruption, brain edema, neuroinflammation, and neuronal death, although low thrombin concentrations can promote cell survival. Also, thrombin directly links the coagulation system to the immune system by activating interleukin-1α. Such effects of thrombin can result in both short-term brain injury and long-term functional deficits, making extravascular thrombin an understudied therapeutic target for stroke. This review examines the role of thrombin and PARs in brain injury following hemorrhagic and ischemic stroke and the potential treatment strategies which are complicated by their role in both hemostasis and brain.
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Affiliation(s)
- Fenghui Ye
- Department of Neurosurgery, University of Michigan, R5018 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA
| | - Hugh J L Garton
- Department of Neurosurgery, University of Michigan, R5018 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA
| | - Ya Hua
- Department of Neurosurgery, University of Michigan, R5018 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA
| | - Richard F Keep
- Department of Neurosurgery, University of Michigan, R5018 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA
| | - Guohua Xi
- Department of Neurosurgery, University of Michigan, R5018 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA.
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16
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Takada K, Kashiwagi S, Asano Y, Goto W, Morisaki T, Takahashi K, Fujita H, Takashima T, Tomita S, Hirakawa K, Ohira M. Factors predictive of invasive ductal carcinoma in cases preoperatively diagnosed as ductal carcinoma in situ. BMC Cancer 2020; 20:513. [PMID: 32493410 PMCID: PMC7268513 DOI: 10.1186/s12885-020-07001-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 05/25/2020] [Indexed: 12/24/2022] Open
Abstract
Background Invasion is often found during postoperative pathological examination of cases diagnosed as ductal carcinoma in situ (DCIS) by histological examinations such as core needle biopsy (CNB) or vacuum-assisted biopsy (VAB). A meta-analysis reported that 25.9% of invasive ductal carcinoma (IDC) cases are preoperatively diagnosed by CNB as DCIS. Risk factors for invasion have been studied by postoperative examination, but no factors have been found that could be obtained preoperatively from blood tests. In this study, we investigated factors predictive of invasion based on preoperative blood tests in patients diagnosed with DCIS by preoperative biopsy. Methods In this study, 118 patients who were diagnosed with DCIS by preoperative biopsy were included. Biopsies were performed with 16-gauge CNB or VAB. Peripheral blood was obtained at the time of diagnosis. This study evaluated absolute platelet count, absolute lymphocyte count, lactate dehydrogenase, carcinoembryonic antigen, and cancer antigen 15–3 (CA15–3). The platelet–lymphocyte ratio (PLR) was calculated by dividing the absolute platelet count by the absolute lymphocyte count, and patients were grouped into high PLR (≥160.0) and low PLR (< 160.0) groups. Results Invasion was found more frequently after surgery in pathologically high-grade cases than in pathologically not-high-grade cases (p = 0.015). The median PLR was 138.9 and 48 patients (40.7%) were classified into the high PLR group. The high PLR group was significantly more likely to have invasion detected by the postoperative pathology than the low PLR group (p = 0.018). In multivariate analysis of factors predictive of invasion in postoperative pathology, a high PLR (p = 0.006, odds ratio [OR] = 3.526) and biopsy method (VAB vs. CNB, p = 0.001, OR = 0.201) was an independent risk factor. Conclusions The PLR may be a predictor of invasion in the postoperative pathology for patients diagnosed with DCIS by preoperative biopsy.
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Affiliation(s)
- Koji Takada
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Shinichiro Kashiwagi
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
| | - Yuka Asano
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Wataru Goto
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Tamami Morisaki
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Katsuyuki Takahashi
- Department of Pharmacology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Hisakazu Fujita
- Department of Scientific and Linguistic Fundamentals of Nursing, Osaka City University Graduate School of Nursing, 1-5-17 Asahi-machi, Abeno-ku, Osaka, 545-0051, Japan
| | - Tsutomu Takashima
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Shuhei Tomita
- Department of Pharmacology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Kosei Hirakawa
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.,Department of Gastrointestinal Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Masaichi Ohira
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.,Department of Gastrointestinal Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
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17
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Ledard N, Liboz A, Blondeau B, Babiak M, Moulin C, Vallin B, Guillas I, Mateo V, Jumeau C, Blirando K, Meilhac O, Limon I, Glorian M. Slug, a Cancer-Related Transcription Factor, is Involved in Vascular Smooth Muscle Cell Transdifferentiation Induced by Platelet-Derived Growth Factor-BB During Atherosclerosis. J Am Heart Assoc 2020; 9:e014276. [PMID: 31959031 PMCID: PMC7033846 DOI: 10.1161/jaha.119.014276] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background Heart attacks and stroke often result from occlusive thrombi following the rupture of vulnerable atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) play a pivotal role in plaque vulnerability because of their switch towards a proinflammatory/macrophage-like phenotype when in the context of atherosclerosis. The prometastatic transcription factor Slug/Snail2 is a critical regulator of cell phenotypic transition. Here, we aimed to investigate the role of Slug in the transdifferentiation process of VSMCs occurring during atherogenesis. Methods and Results In rat and human primary aortic smooth muscle cells, Slug protein expression is strongly and rapidly increased by platelet-derived growth factor-BB (PDGF-BB). PDGF-BB increases Slug protein without affecting mRNA levels indicating that this growth factor stabilizes Slug protein. Immunocytochemistry and subcellular fractionation experiments reveal that PDGF-BB triggers a rapid accumulation of Slug in VSMC nuclei. Using pharmacological tools, we show that the PDGF-BB-dependent mechanism of Slug stabilization in VSMCs involves the extracellular signal-regulated kinase 1/2 pathway. Immunohistochemistry experiments on type V and type VI atherosclerotic lesions of human carotids show smooth muscle-specific myosin heavy chain-/Slug-positive cells surrounding the prothrombotic lipid core. In VSMCs, Slug siRNAs inhibit prostaglandin E2 secretion and prevent the inhibition of cholesterol efflux gene expression mediated by PDGF-BB, known to be involved in plaque vulnerability and/or thrombogenicity. Conclusions Our results highlight, for the first time, a role of Slug in aortic smooth muscle cell transdifferentiation and enable us to consider Slug as an actor playing a role in the atherosclerotic plaque progression towards a life-threatening phenotype. This also argues for common features between acute cardiovascular events and cancer.
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Affiliation(s)
- Nahéma Ledard
- Institut de Biologie Paris-Seine (IBPS) Biological Adaptation and Ageing UMR 8256 Sorbonne Université Paris France
| | - Alexandrine Liboz
- INSERM Saint-Antoine Research Center Sorbonne Université Paris France
| | - Bertrand Blondeau
- INSERM Saint-Antoine Research Center Sorbonne Université Paris France
| | - Mégane Babiak
- Institut de Biologie Paris-Seine (IBPS) Biological Adaptation and Ageing UMR 8256 Sorbonne Université Paris France
| | - Célia Moulin
- Institut de Biologie Paris-Seine (IBPS) Biological Adaptation and Ageing UMR 8256 Sorbonne Université Paris France
| | - Benjamin Vallin
- Institut de Biologie Paris-Seine (IBPS) Biological Adaptation and Ageing UMR 8256 Sorbonne Université Paris France
| | - Isabelle Guillas
- National Institute for Health and Medical Research (INSERM) Faculté de Médecine Pitié Salpétrière UMR-S 1166 ICAN Sorbonne Université Paris France
| | - Véronique Mateo
- CIMI-Paris INSERM U1135 Faculté de Médecine Sorbonne-Université Site Pitié-Salpêtrière Sorbonne Université Paris France
| | | | - Karl Blirando
- Institut de Biologie Paris-Seine (IBPS) Biological Adaptation and Ageing UMR 8256 Sorbonne Université Paris France
| | - Olivier Meilhac
- Université de La Réunion Diabète, Athérothrombose, Thérapies, Réunion, Océan Indien (UMR DéTROI U1188) - -CYROI- Sainte Clotilde La Réunion
| | - Isabelle Limon
- Institut de Biologie Paris-Seine (IBPS) Biological Adaptation and Ageing UMR 8256 Sorbonne Université Paris France
| | - Martine Glorian
- Institut de Biologie Paris-Seine (IBPS) Biological Adaptation and Ageing UMR 8256 Sorbonne Université Paris France
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18
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Basatemur GL, Jørgensen HF, Clarke MCH, Bennett MR, Mallat Z. Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol 2019; 16:727-744. [PMID: 31243391 DOI: 10.1038/s41569-019-0227-9] [Citation(s) in RCA: 688] [Impact Index Per Article: 114.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/23/2019] [Indexed: 02/08/2023]
Abstract
Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages of an atherosclerotic plaque. According to the 'response to injury' and 'vulnerable plaque' hypotheses, contractile VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that generate extracellular matrix to form the fibrous cap and hence stabilize plaques. However, lineage-tracing studies have highlighted flaws in the interpretation of former studies, revealing that these studies had underestimated both the content and functions of VSMCs in plaques and have thus challenged our view on the role of VSMCs in atherosclerosis. VSMCs are more plastic than previously recognized and can adopt alternative phenotypes, including phenotypes resembling foam cells, macrophages, mesenchymal stem cells and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this Review, we present the evidence for VSMC plasticity and summarize the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatiotemporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.
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Affiliation(s)
- Gemma L Basatemur
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Helle F Jørgensen
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Murray C H Clarke
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Martin R Bennett
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Ziad Mallat
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK.
- INSERM U970, Paris Cardiovascular Research Center, Paris, France.
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
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19
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Higashi Y, Gautam S, Delafontaine P, Sukhanov S. IGF-1 and cardiovascular disease. Growth Horm IGF Res 2019; 45:6-16. [PMID: 30735831 PMCID: PMC6504961 DOI: 10.1016/j.ghir.2019.01.002] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 10/17/2018] [Accepted: 01/30/2019] [Indexed: 12/14/2022]
Abstract
Atherosclerosis is an inflammatory arterial pathogenic condition, which leads to ischemic cardiovascular diseases, such as coronary artery disease and myocardial infarction, stroke, and peripheral arterial disease. Atherosclerosis is a multifactorial disorder and its pathophysiology is highly complex. Changes in expression of multiple genes coupled with environmental and lifestyle factors initiate cascades of adverse events involving multiple types of cells (e.g. vascular endothelial cells, smooth muscle cells, and macrophages). IGF-1 is a pleiotropic factor, which is found in the circulation (endocrine IGF-1) and is also produced locally in arteries (endothelial cells and smooth muscle cells). IGF-1 exerts a variety of effects on these cell types in the context of the pathogenesis of atherosclerosis. In fact, there is an increasing body of evidence suggesting that IGF-1 has beneficial effects on the biology of atherosclerosis. This review will discuss recent findings relating to clinical investigations on the relation between IGF-1 and cardiovascular disease and basic research using animal models of atherosclerosis that have elucidated some of the mechanisms underlying atheroprotective effects of IGF-1.
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Affiliation(s)
- Yusuke Higashi
- Department of Medicine, School of Medicine, University of Missouri, Columbia, MO, United States; Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, United States.
| | - Sandeep Gautam
- Department of Medicine, School of Medicine, University of Missouri, Columbia, MO, United States
| | - Patrick Delafontaine
- Department of Medicine, School of Medicine, University of Missouri, Columbia, MO, United States
| | - Sergiy Sukhanov
- Department of Medicine, School of Medicine, University of Missouri, Columbia, MO, United States
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Wang Y, Song X, Li Z, Liu B. Long non-coding RNAs in coronary atherosclerosis. Life Sci 2018; 211:189-197. [PMID: 30195033 DOI: 10.1016/j.lfs.2018.08.072] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/30/2018] [Accepted: 08/31/2018] [Indexed: 12/26/2022]
Abstract
Coronary atherosclerosis (CAS), a leading cause of cardiovascular disease, is a major cause of death worldwide. CAS is a chronic disease in the aorta that can be caused by dyslipidemia, abnormal glucose metabolism, endothelial cell dysfunction, vascular smooth muscle cell (VSMC) or fibrous connective tissue hyperplasia, immune inflammatory reactions, and many other factors. The pathogenesis of CAS is not fully understood, as it is a complex lesion complicated by multiple factors. Damage-response theories have put forward endothelial cell (EC) injury as the initiating factor for CAS; the addition of lipid metabolism disorders may enhance monocyte adhesion, increase the proliferation and migration of fibroblasts and VSMCs, and accelerate the development of CAS. Furthermore, inflammatory and immune responses can create a vicious cycle of endothelial injury, which also plays key roles in the formation of CAS. Therefore, in order to elucidate the mechanisms controlling CAS, it is important to study the etiology of vascular cell dysfunction, abnormal energy and metabolism disorders, and immune and inflammatory reactions. Non-coding RNAs play regulatory roles in the pathogenesis of CAS, especially long non-coding RNAs (lncRNAs); lncRNAs have recently become a major focus for cardiovascular disease mechanisms, as they play numerous roles in the progression of CAS. Therefore, in this review, we discuss the role of lncRNAs in the pathogenesis of coronary CAS, and their role in the prevention and treatment of coronary CAS.
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Affiliation(s)
- Yiran Wang
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Xianjing Song
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Zhibo Li
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Bin Liu
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, Jilin 130021, China.
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21
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Ghali MGZ, Srinivasan VM, Johnson J, Kan P, Britz G. Therapeutically Targeting Platelet-Derived Growth Factor-Mediated Signaling Underlying the Pathogenesis of Subarachnoid Hemorrhage-Related Vasospasm. J Stroke Cerebrovasc Dis 2018; 27:2289-2295. [PMID: 30037648 DOI: 10.1016/j.jstrokecerebrovasdis.2018.02.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 02/10/2018] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Vasospasm accounts for a large fraction of the morbidity and mortality burden in patients sustaining subarachnoid hemorrhage (SAH). Platelet-derived growth factor (PDGF)-β levels rise following SAH and correlate with incidence and severity of vasospasm. METHODS The literature was reviewed for studies investigating the role of PDGF in the pathogenesis of SAH-related vasospasm and efficacy of pharmacological interventions targeting the PDGF pathway in ameliorating the same and improving clinical outcomes. RESULTS Release of blood under high pressure into the subarachnoid space activates the complement cascade, which results in release of PDGF. Abluminal contact of blood with cerebral vessels increases their contractile response to PDGF-β and thrombin, with the latter upregulating PDGF-β receptors and augmenting effects of PDGF-β. PDGF-β figures prominently in the early and late phases of post-SAH vasospasm. PDGF-β binding to the PDGF receptor-β results in receptor tyrosine kinase domain activation and consequent stimulation of intracellular signaling pathways, including p38 mitogen-activated protein kinase, phosphatidylinositol-3-kinase, Rho-associated protein kinase, and extracellular regulated kinase 1 and 2. Consequent increases in intracellular calcium and increased expression of genes mediating cellular growth and proliferation mediate PDGF-induced augmentation of vascular smooth muscle cell contractility, hypertrophy, and proliferation. CONCLUSION Treatments with statins, serine protease inhibitors, and small molecular pathway inhibitors have demonstrated varying degrees of efficacy in prevention of cerebral vasospasm, which is improved with earlier institution.
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Affiliation(s)
- Michael George Zaki Ghali
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas; Department of Neurosurgery, Houston Methodist Hospital, Houston, Texas.
| | | | - Jeremiah Johnson
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
| | - Peter Kan
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
| | - Gavin Britz
- Department of Neurosurgery, Houston Methodist Hospital, Houston, Texas
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22
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Lo HM, Ma MC, Shieh JM, Chen HL, Wu WB. Naked physically synthesized gold nanoparticles affect migration, mitochondrial activity, and proliferation of vascular smooth muscle cells. Int J Nanomedicine 2018; 13:3163-3176. [PMID: 29881271 PMCID: PMC5985769 DOI: 10.2147/ijn.s156880] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Introduction Vascular smooth muscle cells (VSMCs) play an important role in the development and progression of atherosclerosis and vascular injuries in terms of proliferation and migration. Therefore, the aim of this study was to investigate the anti-migratory and proliferative effects of naked gold nanoparticles (AuNPs) on VSMCs. Materials and methods One set of physically synthesized AuNPs (pAuNPs) and three sets of chemically synthesized AuNPs (cAuNPs) were tested. Results and discussion Among them, the pAuNPs were found to significantly and markedly inhibit platelet-derived growth factor (PDGF)-induced VSMC migration. Transmission electron microscopy revealed that the pAuNPs were ingested and aggregated in the cytoplasm at an early stage of treatment, while the viability of VSMCs was not affected within 24 hours of treatment. The pAuNP treatment enhanced cellular mitochondrial activity but inhibited basal and PDGF-induced VSMC proliferation, as determined by MTT, WST-1, and BrdU cell proliferation assays. Furthermore, the pAuNPs did not interfere with PDGF signaling or matrix metalloproteinase-2 expression/activity. Unlike the cAuNPs, the pAuNPs could markedly reduce VSMC adhesion to collagen, which was supported by the findings that the pAuNPs could inhibit collagen-induced tyrosine protein and focal adhesion kinase (FAK) phosphorylation and actin cytoskeleton reorganization during cell adhesion. The in vitro effects of the pAuNPs were confirmed in the in vivo rat balloon-injured carotid artery model by diminishing the proliferating VSMCs. Conclusion Taken together, the present study provides the first evidence that naked pAuNPs can reduce VSMC migration and compromise cell adhesion by affecting FAK and tyrosine-protein activation. The pAuNPs also have an inhibitory effect on PDGF-induced VSMC proliferation and can reduce proliferating/migrating VSMC expression in vivo.
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Affiliation(s)
- Huey-Ming Lo
- School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.,Section of Cardiology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Ming-Chieh Ma
- School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Jiunn-Min Shieh
- Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan.,Department of Recreation and Healthcare Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Hui-Ling Chen
- Holistic Education Center, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Wen-Bin Wu
- School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
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23
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Roostalu U, Wong JK. Arterial smooth muscle dynamics in development and repair. Dev Biol 2018; 435:109-121. [PMID: 29397877 DOI: 10.1016/j.ydbio.2018.01.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 01/08/2018] [Accepted: 01/24/2018] [Indexed: 12/11/2022]
Abstract
Arterial vasculature distributes blood from early embryonic development and provides a nutrient highway to maintain tissue viability. Atherosclerosis, peripheral artery diseases, stroke and aortic aneurysm represent the most frequent causes of death and are all directly related to abnormalities in the function of arteries. Vascular intervention techniques have been established for the treatment of all of these pathologies, yet arterial surgery can itself lead to biological changes in which uncontrolled arterial wall cell proliferation leads to restricted blood flow. In this review we describe the intricate cellular composition of arteries, demonstrating how a variety of distinct cell types in the vascular walls regulate the function of arteries. We provide an overview of the developmental origin of arteries and perivascular cells and focus on cellular dynamics in arterial repair. We summarize the current knowledge of the molecular signaling pathways that regulate vascular smooth muscle differentiation in the embryo and in arterial injury response. Our review aims to highlight the similarities as well as differences between cellular and molecular mechanisms that control arterial development and repair.
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Affiliation(s)
- Urmas Roostalu
- Manchester Academic Health Science Centre, Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, UK.
| | - Jason Kf Wong
- Manchester Academic Health Science Centre, Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, UK; Department of Plastic Surgery, Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, UK.
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24
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Stopeck AT, Vahedian M, Williams SK. Transfer and Expression of the Interferon Gamma Gene in Human Endothelial Cells Inhibits Vascular Smooth Muscle Cell Growth in Vitro. Cell Transplant 2017; 6:1-8. [PMID: 9040949 DOI: 10.1177/096368979700600103] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Intimal hyperplasia in blood vessels is primarily caused by the migration and proliferation of vascular smooth muscle cells. Excessive intimal thickening characterizes atherosclerosis as well as bypass graft and angioplasty failures. Endothelial cell-smooth muscle cell interactions and local cytokine production are important regulators of smooth muscle cell growth. Interferon gamma (γ-IFN), a product of T lymphocytes found in atherosclerotic lesions, inhibits smooth muscle cell proliferation in vitro. To determine if local delivery of γ-IFN may be useful in the treatment or prevention of vascular proliferative diseases, we transferred the human γ-IFN gene into endothelial cells isolated from human arteries and microvessels using a retroviral vector. Biologically active γ-IFN was produced and secreted by γ-IFN transduced endothelial cells, but not by control, nontransduced cells, or cells identically transduced with E. coli beta galactosidase (β-gal). To more closely approximate the microenvironment of blood vessels, subconfluent smooth muscle cells were plated in coculture with control, nontransduced endothelial cells, γ-IFN transduced endothelial cells, or β-gal transduced endothelial cells. Smooth muscle cell growth was inhibited 30-70% by coculture with γ-IFN transduced endothelial cells compared to coculture with β-gal transduced or control endothelial cells (p < 0.05). Our results suggest endothelial cells modified to produce γ-IFN may be a useful therapy in proliferative vascular diseases. Copyright © 1997 Elsevier Science Inc.
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Affiliation(s)
- A T Stopeck
- Section of Hematology/Oncology, Arizona Cancer Center, University of Arizona College of Medicine, Tucson 85724, USA
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25
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Ishii Y, Hamashima T, Yamamoto S, Sasahara M. Pathogenetic significance and possibility as a therapeutic target of platelet derived growth factor. Pathol Int 2017; 67:235-246. [DOI: 10.1111/pin.12530] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 03/27/2017] [Indexed: 12/28/2022]
Affiliation(s)
- Yoko Ishii
- Department of Pathology; Graduate School of Medicine and Pharmaceutical Sciences; University of Toyama; Toyama 930-0194 Japan
| | - Takeru Hamashima
- Department of Pathology; Graduate School of Medicine and Pharmaceutical Sciences; University of Toyama; Toyama 930-0194 Japan
| | - Seiji Yamamoto
- Department of Pathology; Graduate School of Medicine and Pharmaceutical Sciences; University of Toyama; Toyama 930-0194 Japan
| | - Masakiyo Sasahara
- Department of Pathology; Graduate School of Medicine and Pharmaceutical Sciences; University of Toyama; Toyama 930-0194 Japan
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26
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Asano Y, Kashiwagi S, Onoda N, Noda S, Kawajiri H, Takashima T, Ohsawa M, Kitagawa S, Hirakawa K. Platelet-Lymphocyte Ratio as a Useful Predictor of the Therapeutic Effect of Neoadjuvant Chemotherapy in Breast Cancer. PLoS One 2016; 11:e0153459. [PMID: 27472762 PMCID: PMC4966926 DOI: 10.1371/journal.pone.0153459] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 03/30/2016] [Indexed: 01/04/2023] Open
Abstract
Background The peripheral blood platelet–lymphocyte ratio (PLR) has been proposed as an indicator for evaluating systemic inflammatory responses in cancer-bearing patients. While some reports suggest a correlation between PLR and prognosis, few studies have examined the relationship between PLR and sensitivity to chemotherapy. We conducted a study on whether PLR could serve as a predictor of the therapeutic effects of neoadjuvant chemotherapy (NAC). Methods PLR was evaluated in 177 breast cancer patients treated with the NAC 5-fluorouracil, epirubicin and cyclophosphamide, followed by weekly paclitaxel and subsequent curative surgery. The correlation between PLR and prognosis, and between PLR and the efficacy of NAC, were evaluated retrospectively. Results The low PLR group had significantly more patients > 56 years old (p = 0.001) and postmenopausal women (p = 0.001) than the high PLR group. The low PLR group also had a higher pathologic complete response (pCR) rate (p = 0.019). On examining the correlation with prognosis, the low-PLR group was found to have significantly longer disease-free survival (p = 0.004) and overall survival (p = 0.032) than the high PLR group. Multivariate analysis also revealed that lymph node metastasis (p = 0.043, hazard ratio = 4.40) and a high PLR (p = 0.005, hazard ratio = 2.84) were independent, unfavorable prognostic factors. Conclusions For patients with breast cancer treated with NAC, a low PLR indicated high chemotherapy sensitivity, suggesting that PLR could serve as a predictive marker of the therapeutic effect of NAC.
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Affiliation(s)
- Yuka Asano
- Department of Surgical Oncology; Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shinichiro Kashiwagi
- Department of Surgical Oncology; Osaka City University Graduate School of Medicine, Osaka, Japan
- * E-mail:
| | - Naoyoshi Onoda
- Department of Surgical Oncology; Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Satoru Noda
- Department of Surgical Oncology; Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hidemi Kawajiri
- Department of Surgical Oncology; Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tsutomu Takashima
- Department of Surgical Oncology; Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masahiko Ohsawa
- Department of Diagnostic Pathology; Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Seiichi Kitagawa
- Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kosei Hirakawa
- Department of Surgical Oncology; Osaka City University Graduate School of Medicine, Osaka, Japan
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Platelet-derived Growth Factor-B Protects Rat Cardiac Allografts From Ischemia-reperfusion Injury. Transplantation 2016; 100:303-13. [PMID: 26371596 DOI: 10.1097/tp.0000000000000909] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Microvascular dysfunction and cardiomyocyte injury are hallmarks of ischemia-reperfusion injury (IRI) after heart transplantation. Platelet-derived growth factors (PDGF) have an ambiguous role in this deleterious cascade. On one hand, PDGF may exert vascular stabilizing and antiapoptotic actions through endothelial-pericyte and endothelial-cardiomyocyte crosstalk in the heart; and on the other hand, PDGF signaling mediates neointimal formation and exacerbates chronic rejection in cardiac allografts. The balance between these potentially harmful and beneficial actions determines the final outcome of cardiac allografts. METHODS AND RESULTS We transplanted cardiac allografts from Dark Agouti rat and Balb mouse donors to fully major histocompatibility complex-mismatched Wistar Furth rat or C57 mouse recipients with a clinically relevant 2-hour cold ischemia and 1-hour warm ischemia. Ex vivo intracoronary delivery of adenovirus-mediated gene transfer of recombinant human PDGF-BB upregulated messenger RNA expression of anti-mesenchymal transition and survival factors BMP-7 and Bcl-2 and preserved capillary density in rat cardiac allografts at day 10. In mouse cardiac allografts PDGF receptor-β, but not -α intragraft messenger RNA levels were reduced and capillary protein localization was lost during IRI. The PDGF receptor tyrosine kinase inhibitor imatinib mesylate and a monoclonal antibody against PDGF receptor-α enhanced myocardial damage evidenced by serum cardiac troponin T release in the rat and mouse cardiac allografts 6 hours after reperfusion, respectively. Moreover, imatinib mesylate enhanced rat cardiac allograft vasculopathy, cardiac fibrosis, and late allograft loss at day 56. CONCLUSIONS Our results suggest that PDGF-B signaling may play a role in endothelial and cardiomyocyte recovery from IRI after heart transplantation.
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28
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Morgan A, Mooney K, Wilkinson S, Pickles N, Mc Auley M. Cholesterol metabolism: A review of how ageing disrupts the biological mechanisms responsible for its regulation. Ageing Res Rev 2016; 27:108-124. [PMID: 27045039 DOI: 10.1016/j.arr.2016.03.008] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 03/22/2016] [Accepted: 03/30/2016] [Indexed: 02/06/2023]
Abstract
Cholesterol plays a vital role in the human body as a precursor of steroid hormones and bile acids, in addition to providing structure to cell membranes. Whole body cholesterol metabolism is maintained by a highly coordinated balancing act between cholesterol ingestion, synthesis, absorption, and excretion. The aim of this review is to discuss how ageing interacts with these processes. Firstly, we will present an overview of cholesterol metabolism. Following this, we discuss how the biological mechanisms which underpin cholesterol metabolism are effected by ageing. Included in this discussion are lipoprotein dynamics, cholesterol absorption/synthesis and the enterohepatic circulation/synthesis of bile acids. Moreover, we discuss the role of oxidative stress in the pathological progression of atherosclerosis and also discuss how cholesterol biosynthesis is effected by both the mammalian target of rapamycin and sirtuin pathways. Next, we examine how diet and alterations to the gut microbiome can be used to mitigate the impact ageing has on cholesterol metabolism. We conclude by discussing how mathematical models of cholesterol metabolism can be used to identify therapeutic interventions.
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29
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Ricci C, Ferri N. Naturally occurring PDGF receptor inhibitors with potential anti-atherosclerotic properties. Vascul Pharmacol 2015; 70:1-7. [DOI: 10.1016/j.vph.2015.02.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 02/18/2015] [Accepted: 02/20/2015] [Indexed: 01/03/2023]
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Gutierrez P, O'Brien KD, Ferguson M, Nikkari ST, Alpers CE, Wight TN. Differences in the distribution of versican, decorin, and biglycan in atherosclerotic human coronary arteries. Cardiovasc Pathol 2015; 6:271-8. [PMID: 25989722 DOI: 10.1016/s1054-8807(97)00001-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
The distributions of versican, biglycan, and decorin have been examined in segments of normal and atherosclerotic human coronary arteries using antibodies directed against the core proteins of these macromolecules. Versican immunostaining was prominent throughout the extracellular matrix (ECM) in regions of the vessels that contained abundant smooth-muscle cells, such as in diffuse intimal thickenings, fibrous caps, and in zones of loose, myxoid connective tissue. Versican also was present in smooth-muscle-rich thrombi and at borders of the lipid-rich cores of advanced atherosclerotic lesions. Biglycan immunostaining was observed in diffuse intimal thickenings, fibrous caps, and myxoid areas, but, unlike versican, it was abundant in the lipid-rich core of advanced plaques. However, biglycan immunostaining was absent in smooth-muscle cell-enriched thrombi. Decorin immunostaining paralleled biglycan immunostaining except that it was conspicuously absent in the myxoid areas of the plaque and markedly reduced in diffuse intimal thickenings. Both biglycan and decorin immunostaining were consistently associated with some of the microvessels in the thrombi and in advanced atherosclerotic plaques. Taken together, these results indicate that specific proteoglycans distribute to topographically defined regions of normal and atherosclerotic human coronary arteries and that these different distributions may indicate a diversity of functions in normal and pathologic processes of the arterial wall.
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Affiliation(s)
- P Gutierrez
- Coracao Institute, Hospital das Clinicas, São Paulo, Brazil
| | - K D O'Brien
- Medicine (Cardiology), University of Washington, Seattle, Washington USA
| | - M Ferguson
- Pathology, University of Washington, Seattle, Washington USA
| | - S T Nikkari
- Pathology, University of Washington, Seattle, Washington USA
| | - C E Alpers
- Pathology, University of Washington, Seattle, Washington USA
| | - T N Wight
- Pathology, University of Washington, Seattle, Washington USA
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31
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Phloretin Inhibits Platelet-derived Growth Factor-BB–induced Rat Aortic Smooth Muscle Cell Proliferation, Migration, and Neointimal Formation After Carotid Injury. J Cardiovasc Pharmacol 2015; 65:444-55. [DOI: 10.1097/fjc.0000000000000213] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Schmidt-Bleek K, Kwee BJ, Mooney DJ, Duda GN. Boon and Bane of Inflammation in Bone Tissue Regeneration and Its Link with Angiogenesis. TISSUE ENGINEERING PART B-REVIEWS 2015; 21:354-64. [PMID: 25742724 DOI: 10.1089/ten.teb.2014.0677] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Delayed healing or nonhealing of bone is an important clinical concern. Although bone, one of the two tissues with scar-free healing capacity, heals in most cases, healing is delayed in more than 10% of clinical cases. Treatment of such delayed healing condition is often painful, risky, time consuming, and expensive. Tissue healing is a multistage regenerative process involving complex and well-orchestrated steps, which are initiated in response to injury. At best, these steps lead to scar-free tissue formation. At the onset of healing, during the inflammatory phase, stationary and attracted macrophages and other immune cells at the fracture site release cytokines in response to injury. This initial reaction to injury is followed by the recruitment, proliferation, and differentiation of mesenchymal stromal cells, synthesis of extracellular matrix proteins, angiogenesis, and finally tissue remodeling. Failure to heal is often associated with poor revascularization. Since blood vessels mediate the transport of circulating cells, oxygen, nutrients, and waste products, they appear essential for successful healing. The strategy of endogenous regeneration in a tissue such as bone is interesting to analyze since it may represent a blueprint of successful tissue formation. This review highlights the interdependency of the time cascades of inflammation, angiogenesis, and tissue regeneration. A better understanding of these inter-relations is mandatory to early identify patients at risk as well as to overcome critical clinical conditions that limit healing. Instead of purely tolerating the inflammatory phase, modulations of inflammation (immunomodulation) might represent a valid therapeutic strategy to enhance angiogenesis and foster later phases of tissue regeneration.
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Affiliation(s)
- Katharina Schmidt-Bleek
- 1 Julius Wolff Institut and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin , Berlin, Germany .,2 Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin , Berlin, Germany
| | - Brian J Kwee
- 3 The Mooney Lab: Laboratory for Cell and Tissue Engineering, Harvard-School of Engineering and Applied Sciences , Cambridge, Massachusetts
| | - David J Mooney
- 3 The Mooney Lab: Laboratory for Cell and Tissue Engineering, Harvard-School of Engineering and Applied Sciences , Cambridge, Massachusetts
| | - Georg N Duda
- 1 Julius Wolff Institut and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin , Berlin, Germany .,2 Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin , Berlin, Germany
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Tazzyman S, Murdoch C, Yeomans J, Harrison J, Muthana M. Macrophage-mediated response to hypoxia in disease. HYPOXIA 2014; 2:185-196. [PMID: 27774476 PMCID: PMC5045066 DOI: 10.2147/hp.s49717] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Hypoxia plays a critical role in the pathobiology of various inflamed, diseased tissues, including malignant tumors, atherosclerotic plaques, myocardial infarcts, the synovia of rheumatoid arthritic joints, healing wounds, and sites of bacterial infection. These areas of hypoxia form when the blood supply is occluded and/or the oxygen supply is unable to keep pace with cell growth and/or infiltration of inflammatory cells. Macrophages are ubiquitous in all tissues of the body and exhibit great plasticity, allowing them to perform divergent functions, including, among others, patrolling tissue, combating invading pathogens and tumor cells, orchestrating wound healing, and restoring homeostasis after an inflammatory response. The number of tissue macrophages increases markedly with the onset and progression of many pathological states, with many macrophages accumulating in avascular and necrotic areas, where they are exposed to hypoxia. Recent studies show that these highly versatile cells then respond rapidly to the hypoxia present by altering their expression of a wide array of genes. Here we review the evidence for hypoxia-driven macrophage inflammatory responses in various disease states, and how this influences disease progression and treatment.
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Affiliation(s)
| | | | | | | | - Munitta Muthana
- Department of Infection and Immunity, University of Sheffield, Sheffield, UK
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34
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A Mathematical Model of Atherosclerosis with Reverse Cholesterol Transport and Associated Risk Factors. Bull Math Biol 2014; 77:758-81. [DOI: 10.1007/s11538-014-0010-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Accepted: 08/13/2014] [Indexed: 01/19/2023]
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Hao W, Friedman A. The LDL-HDL profile determines the risk of atherosclerosis: a mathematical model. PLoS One 2014; 9:e90497. [PMID: 24621857 PMCID: PMC3951264 DOI: 10.1371/journal.pone.0090497] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 02/03/2014] [Indexed: 12/23/2022] Open
Abstract
Atherosclerosis, the leading death in the United State, is a disease in which a plaque builds up inside the arteries. As the plaque continues to grow, the shear force of the blood flow through the decreasing cross section of the lumen increases. This force may eventually cause rupture of the plaque, resulting in the formation of thrombus, and possibly heart attack. It has long been recognized that the formation of a plaque relates to the cholesterol concentration in the blood. For example, individuals with LDL above 190 mg/dL and HDL below 40 mg/dL are at high risk, while individuals with LDL below 100 mg/dL and HDL above 50 mg/dL are at no risk. In this paper, we developed a mathematical model of the formation of a plaque, which includes the following key variables: LDL and HDL, free radicals and oxidized LDL, MMP and TIMP, cytockines: MCP-1, IFN-γ, IL-12 and PDGF, and cells: macrophages, foam cells, T cells and smooth muscle cells. The model is given by a system of partial differential equations with in evolving plaque. Simulations of the model show how the combination of the concentrations of LDL and HDL in the blood determine whether a plaque will grow or disappear. More precisely, we create a map, showing the risk of plaque development for any pair of values (LDL,HDL).
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Affiliation(s)
- Wenrui Hao
- Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, United States of America
| | - Avner Friedman
- Mathematical Biosciences Institute & Department of Mathematics, The Ohio State University, Columbus, Ohio, United States of America
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Wang D, Gao F. Quinazoline derivatives: synthesis and bioactivities. Chem Cent J 2013; 7:95. [PMID: 23731671 PMCID: PMC3679743 DOI: 10.1186/1752-153x-7-95] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Accepted: 04/26/2013] [Indexed: 11/10/2022] Open
Abstract
Owing to the significant biological activities, quinazoline derivatives have drawn more and more attention in the synthesis and bioactivities research. This review summarizes the recent advances in the synthesis and biological activities investigations of quinazoline derivatives. According to the main method the authors adopted in their research design, those synthetic methods were divided into five main classifications, including Aza-reaction, Microwave-assisted reaction, Metal-mediated reaction, Ultrasound-promoted reaction and Phase-transfer catalysis reaction. The biological activities of the synthesized quinazoline derivatives also are discussed.
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Affiliation(s)
- Dan Wang
- Department of Chinese Traditional Herbal, Agronomy College, Sichuan Agricultural University, No, 211, Huiming Road, Wenjiang Region, Chengdu, 611130, P, R, China.
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Huynh J, Bordeleau F, Kraning-Rush CM, Reinhart-King CA. Substrate Stiffness Regulates PDGF-Induced Circular Dorsal Ruffle Formation Through MLCK. Cell Mol Bioeng 2013; 6. [PMID: 24348877 DOI: 10.1007/s12195-013-0278-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
As atherosclerosis progresses, vascular smooth muscle cells (VSMCs) invade from the medial layer into the intimal layer and proliferate, contributing to atherosclerotic plaque formation. This migration is stimulated in part by platelet-derived growth factor (PDGF), which is released by endothelial cells and inflammatory cells, and vessel stiffening, which occurs with age and atherosclerosis progression. PDGF induces the formation of circular dorsal ruffles (CDRs), actin-based structures associated with increased cell motility. Here we show that mechanical changes in matrix stiffness enhance the formation of CDRs in VSMCs in response to PDGF stimulation. Our data indicate that matrix stiffness increases cellular contractility, and that intracellular pre-stress is necessary for robust CDR formation. When treated with agonists that promote contractility, cells increase CDR formation, whereas agonists that inhibit contractility lead to decreased CDR formation. Substrate stiffness promotes CDR formation in response to PDGF by upregulating Src activity through myosin light chain kinase. Together, these data indicate that vessel stiffening accompanying atherogenesis may exacerbate VSMC response to PDGF leading to CDR formation.
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Affiliation(s)
- John Huynh
- Department of Biomedical Engineering, Cornell University, 302 Weill Hall, 526 Campus Road, Ithaca, NY 14853, USA
| | - Francois Bordeleau
- Department of Biomedical Engineering, Cornell University, 302 Weill Hall, 526 Campus Road, Ithaca, NY 14853, USA
| | - Casey M Kraning-Rush
- Department of Biomedical Engineering, Cornell University, 302 Weill Hall, 526 Campus Road, Ithaca, NY 14853, USA
| | - Cynthia A Reinhart-King
- Department of Biomedical Engineering, Cornell University, 302 Weill Hall, 526 Campus Road, Ithaca, NY 14853, USA
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Yanamoto H, Kataoka H, Nakajo Y, Iihara K. The Role of the Host Defense System in the Development of Cerebral Vasospasm: Analogies between Atherosclerosis and Subarachnoid Hemorrhage. Eur Neurol 2012; 68:329-43. [DOI: 10.1159/000341336] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 06/24/2012] [Indexed: 01/13/2023]
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Chen J, Xu L, Chen S, Yang J, Jiang H. Transcriptional regulation of platelet-derived growth factor-B chain by thrombin in endothelial cells: involvement of Egr-1 and CREB-binding protein. Mol Cell Biochem 2012; 366:81-87. [PMID: 22488213 DOI: 10.1007/s11010-012-1285-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Accepted: 03/02/2012] [Indexed: 10/28/2022]
Abstract
Thrombin and platelet-derived growth factor-B chain (PDGF-B) are key factors in the stimulation of atherosclerosis. The effect of thrombin on PDGF-B production has been characterized. However, the underlying mechanism is still far clear. Here, we investigate the transcription factors and regulators that are involved in PDGF-B production caused by thrombin in endothelial cells (ECs). Levels of PDGF were analyzed by real-time RT-PCR and ELISA, while levels of early growth response-1 (Egr-1) were analyzed by real-time RT-PCR and western blot. To evaluate the function of CBP and Egr-1 involved in regulation of PDGF-B, small interfering RNA (siRNA) were used to down-regulate their expression in mRNA and protein level. Interaction of Egr-1 and CBP was measured with immunoprecipitation and western blot. Thrombin induced an early and transient up-regulation of transcription factor early Egr-1, which was followed by a delayed increase of PDGF-B. siRNA against Egr-1-inhibited thrombin-induced PDGF-B production. Furthermore, thrombin could enhance the interaction of Egr-1 with its co-activator CREB-binding protein (CBP). CBP knockdown attenuated this interaction, and led to a reduction of PDGF-B expression induced by thrombin. Our results suggest that CBP might be one of the main interaction targets for Egr-1, and the transient activation of Egr-1 and recruitment of CBP are required for thrombin-induced PDGF-B in ECs.
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Affiliation(s)
- Jing Chen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
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Alexander MR, Murgai M, Moehle CW, Owens GK. Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms. Physiol Genomics 2012; 44:417-29. [PMID: 22318995 PMCID: PMC3339851 DOI: 10.1152/physiolgenomics.00160.2011] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Accepted: 01/17/2012] [Indexed: 12/14/2022] Open
Abstract
Smooth muscle cell (SMC) phenotypic modulation in atherosclerosis and in response to PDGF in vitro involves repression of differentiation marker genes and increases in SMC proliferation, migration, and matrix synthesis. However, SMCs within atherosclerotic plaques can also express a number of proinflammatory genes, and in cultured SMCs the inflammatory cytokine IL-1β represses SMC marker gene expression and induces inflammatory gene expression. Studies herein tested the hypothesis that IL-1β modulates SMC phenotype to a distinct inflammatory state relative to PDGF-DD. Genome-wide gene expression analysis of IL-1β- or PDGF-DD-treated SMCs revealed that although both stimuli repressed SMC differentiation marker gene expression, IL-1β distinctly induced expression of proinflammatory genes, while PDGF-DD primarily induced genes involved in cell proliferation. Promoters of inflammatory genes distinctly induced by IL-1β exhibited over-representation of NF-κB binding sites, and NF-κB inhibition in SMCs reduced IL-1β-induced upregulation of proinflammatory genes as well as repression of SMC differentiation marker genes. Interestingly, PDGF-DD-induced SMC marker gene repression was not NF-κB dependent. Finally, immunofluorescent staining of mouse atherosclerotic lesions revealed the presence of cells positive for the marker of an IL-1β-stimulated inflammatory SMC, chemokine (C-C motif) ligand 20 (CCL20), but not the PDGF-DD-induced gene, regulator of G protein signaling 17 (RGS17). Results demonstrate that IL-1β- but not PDGF-DD-induced phenotypic modulation of SMC is characterized by NF-κB-dependent activation of proinflammatory genes, suggesting the existence of a distinct inflammatory SMC phenotype. In addition, studies provide evidence for the possible utility of CCL20 and RGS17 as markers of inflammatory and proliferative state SMCs within atherosclerotic plaques in vivo.
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Affiliation(s)
- Matthew R Alexander
- Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA
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Abstract
This review emphasizes the effects of resveratrol on factors involved in the mechanism of atherosclerosis and risk factors for atherosclerosis. The effects of wine and resveratrol on atherosclerosis are also discussed. Resveratrol is a potent antioxidant and an anti-inflammatory agent. It reduces the expression of cell adhesion molecules, monocyte colony stimulating factors, matrix metalloproteinases, and growth factors; and inhibits platelet aggregation and vascular smooth muscle cell proliferation. It reduces the serum levels of total cholesterol, triglycerides (TG), and raises high-density lipoprotein cholesterol, inhibits expression of C-reactive protein and lowers the levels of advanced glycation end products and its receptor in the vascular tissue. It lowers the risk factors for plaque rupture. Epidemiological data show that moderate consumption of alcohol has an inverse association with carotid atherosclerosis while high consumption has a positive association with carotid atherosclerosis. Wine reduces the extent of atherosclerosis in animal model. The antiatherosclerotic effect of wine is mainly due to it resveratrol content. Resveratrol reduces the extent of atherosclerosis in animal model of atherosclerosis (apolipoprotein [Apo] E-deficient and Apo E(-/-)/low-density lipoprotein receptor-deficient mice and macrophage). In rabbit model of atherosclerosis, both reduction and acceleration of atherosclerosis have been reported with resveratrol. There are no data for regression and slowing of progression of atherosclerosis. Robust clinical trials for suppression of atherosclerosis are lacking. In conclusion, resveratrol has potential but experimental studies in depth and robust clinical trials are lacking for this agent to be of any value in the primary and secondary prevention of coronary and peripheral artery disease.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Toma I, McCaffrey TA. Transforming growth factor-β and atherosclerosis: interwoven atherogenic and atheroprotective aspects. Cell Tissue Res 2012; 347:155-75. [PMID: 21626289 PMCID: PMC4915479 DOI: 10.1007/s00441-011-1189-3] [Citation(s) in RCA: 134] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Accepted: 05/06/2011] [Indexed: 12/15/2022]
Abstract
Age-related progression of cardiovascular disease is by far the largest health problem in the US and involves vascular damage, progressive vascular fibrosis and the accumulation of lipid-rich atherosclerotic lesions. Advanced lesions can restrict flow to key organs and can trigger occlusive thrombosis resulting in a stroke or myocardial infarction. Transforming growth factor-beta (TGF-β) is a major orchestrator of the fibroproliferative response to tissue damage. In the early stages of repair, TGF-β is released from platelets and activated from matrix reservoirs; it then stimulates the chemotaxis of repair cells, modulates immunity and inflammation and induces matrix production. At later stages, it negatively regulates fibrosis through its strong antiproliferative and apoptotic effects on fibrotic cells. In advanced lesions, TGF-β might be important in arterial calcification, commonly referred to as "hardening of the arteries". Because TGF-β can signal through multiple pathways, namely the SMADs, a MAPK pathway and the Rho/ROCK pathways, selective defects in TGF-β signaling can disrupt otherwise coordinated pathways of tissue regeneration. TGF-β is known to control cell proliferation, cell migration, matrix synthesis, wound contraction, calcification and the immune response, all being major components of the atherosclerotic process. However, many of the effects of TGF-β are essential to normal tissue repair and thus, TGF-β is often thought to be "atheroprotective". The present review attempts to parse systematically the known effects of TGF-β on both the major risk factors for atherosclerosis and to isolate the role of TGF-β in the many component pathways involved in atherogenesis.
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Affiliation(s)
- Ian Toma
- Department of Medicine, Division of Genomic Medicine, The George Washington University Medical Center, 2300 I Street NW. Ross Hall 443, Washington DC 20037, USA
| | - Timothy A. McCaffrey
- Department of Medicine, Division of Genomic Medicine, The George Washington University Medical Center, 2300 I Street NW. Ross Hall 443, Washington DC 20037, USA
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Nishino M, Yoshimura T, Nakamura D, Lee Y, Taniike M, Makino N, Kato H, Egami Y, Shutta R, Tanouchi J, Yamada Y. Comparison of angioscopic findings and three-year cardiac events between sirolimus-eluting stent and bare-metal stent in acute myocardial infarction. Am J Cardiol 2011; 108:1238-43. [PMID: 21840490 DOI: 10.1016/j.amjcard.2011.06.038] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Revised: 06/15/2011] [Accepted: 06/15/2011] [Indexed: 11/19/2022]
Abstract
The safety of sirolimus-eluting stents (SESs) in acute myocardial infarction (AMI) remains controversial. We compared long-term neointimal coverage after stent implantation for AMI evaluated by coronary angioscopy and 3-year clinical events between SESs and bare-metal stents (BMSs). Eighty-seven consecutive patients who received SESs or BMSs for AMI were enrolled. At 8 months after AMI coronary angiography with angioscopy was performed. Using angioscopy we evaluated maximum and minimum grades of neointimal coverage using an angioscopic score (0 to 3). We calculated the heterogeneity score as the maximum grade minus the minimum grade. We compared angioscopic parameters including minimum grade and heterogeneity score of neointimal coverage, thrombi and plaque color, serum parameters, and major adverse cardiac events for 3 years between the 2 groups. The restenosis rate of the SES group (n = 56) was significantly lower than that of the BMS group (n = 31, 9% vs 31%, p = 0.015). The SES group had a lower minimum grade of neointimal coverage and higher heterogeneity score and prevalence of thrombi than the BMS group, but from 8 months to 3 years after stent implantation there were no significant differences in major adverse cardiac events between the 2 groups. In conclusion, a lower minimum grade and greater heterogeneity of neointimal coverage and thrombi were shown for SESs compared to BMSs at 8 months after AMI. However, these findings did not correlate with cardiac events over a period of 3 years in our patients.
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Affiliation(s)
- Masami Nishino
- Division of Cardiology, Osaka Rosai Hospital, Osaka, Japan.
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Zhang Y, Yang M, Yang Y, Zheng SL, Cai Y, Xia P, Chen WW, Chen BC, Yang YR. Thalidomide attenuates graft arteriosclerosis of aortic transplant in a rat model. Transplant Proc 2011; 43:2022-6. [PMID: 21693319 DOI: 10.1016/j.transproceed.2011.03.086] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Accepted: 03/29/2011] [Indexed: 11/24/2022]
Abstract
OBJECTIVE The purpose of the current study was to evaluate the effects of thalidomide on graft arteriosclerosis. MATERIALS AND METHODS Male Lewis rats received abdominal aorta grafts from male Brown-Norway rats. The animals were divided into 4 groups: no treatment controls, a low-dose group that received thalidomide (50 mg/kg per day), a middle dose group that received thalidomide (100 mg/kg per day), and a high-dose group that received thalidomide (200 mg/kg per day) by daily intragastric administration. Rats were humanely killed at 60 days after surgery. The grafted aortas were analyzed by histology, immunohistochemistry, and Western blot analysis. The serum was analyzed by an enzyme-linked immunosorbent assay (ELISA). RESULTS The neointimal thickness of the thalidomide treated aortas was significantly thinner compared with that of no treatment aortas (P < .05). Vascular endothelial growth factor (VEGF), platelet-derived growth factor, and intracellular adhesian molecule (ICAM-1) protein expression in the treatment group were significantly lower than those in the control group (P < .05). Moreover, thalidomide significantly inhibited the production of VEGF and ICAM-1 in serum (P < .05). CONCLUSION Our data suggested that thalidomide can attenuate graft arteriosclerosis so as to protect aortic grafts.
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Affiliation(s)
- Y Zhang
- Transplantation Center, The First Affiliate Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, China
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Larsen K, Cheng C, Duckers HJ. Regulation of vulnerable plaque development by the heme oxygenase/carbon monoxide system. Trends Cardiovasc Med 2011; 20:58-65. [PMID: 20656217 DOI: 10.1016/j.tcm.2010.04.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Plaque rupture and luminal thrombosis is the most common cause of coronary occlusion that leads to acute coronary syndromes. High-risk plaques, or vulnerable plaques, are defined as lesions that are prone to rupture, also known as thin cap fibroatheroma (TCFA), or lesions prone to erosion or with calcified cores. This review will focus mainly on the vulnerable plaque, which is thought to be the precursor of the thrombogenic or ruptured plaque. Heme oxygenase 1 (HO-1) protein expression is specifically increased in lesions with a vulnerable plaque phenotype resembling TCFAs and correlates with a rise in expression levels of intimal proinflammatory markers. Data from several human and animal studies imply an important function for HO-1 in the genetic regulation of early, as well as late atherogenesis, and plaque destabilization toward a vulnerable phenotype. Although a direct association between HO-1, vulnerable plaque development, and clinical outcome is for now missing, the correlations that have been reported for HO-1 and coronary artery disease point to a possible link.
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Affiliation(s)
- Katarína Larsen
- Molecular Cardiology Laboratory, Experimental Cardiology, Thoraxcenter, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands
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Hashizume S, Akaike M, Azuma H, Ishikawa K, Yoshida S, Sumitomo-Ueda Y, Yagi S, Ikeda Y, Iwase T, Aihara KI, Abe M, Sata M, Matsumoto T. Activation of peroxisome proliferator-activated receptor α in megakaryocytes reduces platelet-derived growth factor-BB in platelets. J Atheroscler Thromb 2010; 18:138-47. [PMID: 21060209 DOI: 10.5551/jat.5868] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
AIM Platelet-derived growth factor (PDGF)-BB plays a crucial role in atherosclerosis and vascular remodeling by promoting the migration and proliferation of vascular smooth muscle cells. The objective of this study was to clarify the pleiotropic effect of peroxisome proliferator-activated receptor α (PPARα) activators on PDGF-BB expression in megakaryocytes and platelets. METHODS AND RESULTS The expression of PPARα in a human erythroleukemia (HEL) cells was clearly detected by reverse transcriptase-PCR and immunofluorescence microscopy. The expression level of PPARα in HEL cells was unchanged regardless of differentiation into megakaryocytic cells by treatment with phorbol 12-myristate 13 acetate (TPA). The TPA-induced expression of PDGF-B mRNA and PDGF-BB protein levels in culture media was significantly decreased by treatment with PPARα activators, Wy14643 and fenofibric acid, in a dose-dependent manner. PDGF-BB expression induced by inflammatory cytokines, including interleukin-1β or interleukin-6, was also significantly suppressed by treatment with PPARα activators. Immunohistochemistry of human bone marrow showed the expression of PPARα in both the nucleus and cytoplasm of megakaryocytes. In addition, PDGF-BB levels in platelets were significantly decreased from 1,800±870 to 1,470±840 pg/10(5) platelets (mean±SD, p<0.05) by treatment with 300 mg fenofibrate once daily for 4 weeks in 13 patients with dyslipidemia. CONCLUSIONS Activation of PPARα in megakaryocytes reduces PDGF-BB expression in platelets. PPARα activators may exert vasculo-protective action through suppression of PDGF-BB production in a megakaryocyte/platelet pathway.
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Affiliation(s)
- Shunji Hashizume
- Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan
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Wu LE, Hocking SL, James DE. Macrophage infiltration and cytokine release in adipose tissue: angiogenesis or inflammation? Diabetol Int 2010. [DOI: 10.1007/s13340-010-0003-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Magnesium deficiency promotes a pro-atherogenic phenotype in cultured human endothelial cells via activation of NFkB. Biochim Biophys Acta Mol Basis Dis 2010; 1802:952-8. [DOI: 10.1016/j.bbadis.2010.06.016] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2010] [Revised: 06/11/2010] [Accepted: 06/23/2010] [Indexed: 11/19/2022]
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Yildirim O, Bicer A, Ozkan A, Kurtkaya O, Cirakoglu B, Kilic T. Expression of platelet-derived growth factor ligand and receptor in cerebral arteriovenous and cavernous malformations. J Clin Neurosci 2010; 17:1557-62. [PMID: 20822908 DOI: 10.1016/j.jocn.2010.04.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2010] [Revised: 04/07/2010] [Accepted: 04/08/2010] [Indexed: 11/15/2022]
Abstract
The aim of this study was to investigate the expression of platelet-derived growth factor (PDGF) ligands A and B and receptors α and β in cerebral arteriovenous and cavernous malformations. Fifteen arteriovenous malformation (AVM) and 15 cerebral cavernous malformation (CCM) tissue samples were immunostained for PDGF ligands A and B, PDGF receptors (PDGFR) α and β, and vascular endothelial growth factor. Tissues were compared in terms of expression levels within various vascular layers, and the results were confirmed using western blotting. AVM had higher levels of PDGF-A expression than CCM (p = 0.004, 0.009, 0.001, and 0.027, for endothelium, media, adventitia, and perilesional tissue, respectively) and western blotting showed that there was higher expression of PDGFR-α in AVM tissues. In contrast, CCM endothelium, media, and adventitia had higher PDGF-B expression compared with AVM (p = 0.007, 0.001, and 0.039, respectively). PDGFR-β expression was also significantly higher in the endothelium of CCM tissue (p = 0.007). Overexpression of PDGF ligands and receptors in AVM and CCM may mean that therapeutic strategies targeting the PDGF pathway could be useful in the treatment of these two malformations.
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Affiliation(s)
- Ozlem Yildirim
- Neurosurgical Research Center, Institute of Neurological Sciences, Marmara University, Istanbul, Turkey
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Nishino M, Hoshida S, Taniike M, Kato H, Egami Y, Shutta R, Yamaguchi H, Tanaka K, Tanouchi J, Yamada Y. Vulnerable disease may induce neointimal coverage after sirolimus-eluting stent implantation. Am Heart J 2010; 160:564-9. [PMID: 20826267 DOI: 10.1016/j.ahj.2010.06.043] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2010] [Accepted: 06/25/2010] [Indexed: 01/08/2023]
Abstract
BACKGROUND Neointimal formation can protect against thrombosis after sirolimus-eluting stent (SES) implantation; however, promoters of neointimal formation are unknown. METHODS Six-month follow-up angioscopy was performed in 141 consecutive patients with SES implantation. All patients received aspirin (100 mg) and ticlopidine (200 mg) daily until angioscopy. We defined 2 grades of neointimal coverage as follows: insufficient coverage including no or partial neointimal coverage of stent struts, and sufficient coverage. The possible promoters of neointimal formation that were evaluated in this study were the condition of coronary artery disease (stable angina or acute coronary syndrome); angioscopic markers, including visible thrombus and plaque color (white or yellow); serum markers, including low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fasting blood glucose, hemoglobin A(1c), high-sensitive C-reactive protein, and fibrinogen; blood pressure and smoking; intervention markers, including stent size and length and intravascular ultrasound measurements; and medication, including statins, anticoagulants, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, calcium antagonists, and β-blockers. RESULTS Univariate analysis revealed that high-sensitive C-reactive protein, plaque color, and the condition of coronary artery disease were significantly correlated with the grade of neointimal coverage. Multivariate analysis using these 3 parameters revealed that only acute coronary syndrome (vulnerable disease) significantly promoted neointimal coverage. CONCLUSION Vulnerable disease may promote neointimal coverage after SES implantation.
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