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British Journal of Pharmacology Mar 2022The rupture of unstable atherosclerotic plaques is the major cause of cardiovascular mortality and morbidity. Despite significant limitations in our understanding and... (Review)
Review
The rupture of unstable atherosclerotic plaques is the major cause of cardiovascular mortality and morbidity. Despite significant limitations in our understanding and ability to identify unstable plaque pathology and prevent plaque rupture, most atherosclerosis research utilises preclinical animal models exhibiting stable atherosclerosis. Here, we introduce the tandem stenosis (TS) mouse model that reflects plaque instability and rupture, as seen in patients. The TS model involves dual ligation of the right carotid artery, leading to locally predefined unstable atherosclerosis in hypercholesterolaemic mice. It exhibits key characteristics of human unstable plaques, including plaque rupture, luminal thrombosis, intraplaque haemorrhage, large necrotic cores, thin or ruptured fibrous caps and extensive immune cell accumulation. Altogether, the TS model represents an ideal preclinical tool for improving our understanding of human plaque instability and rupture, for the development of imaging technologies to identify unstable plaques, and for the development and testing of plaque-stabilising treatments for the prevention of atherosclerotic plaque rupture. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.
Topics: Animals; Atherosclerosis; Constriction, Pathologic; Disease Models, Animal; Humans; Mice; Plaque, Atherosclerotic
PubMed: 33368184
DOI: 10.1111/bph.15356 -
Inflammation Research : Official... Jan 2024Atherosclerosis, characterized by abnormal arterial lipid deposition, is an age-dependent inflammatory disease and contributes to elevated morbidity and mortality....
BACKGROUND
Atherosclerosis, characterized by abnormal arterial lipid deposition, is an age-dependent inflammatory disease and contributes to elevated morbidity and mortality. Senescent foamy macrophages are considered to be deleterious at all stages of atherosclerosis, while the underlying mechanisms remain largely unknown. In this study, we aimed to explore the senescence-related genes in macrophages diagnosis for atherosclerotic plaque progression.
METHODS
The atherosclerosis-related datasets were retrieved from the Gene Expression Omnibus (GEO) database, and cellular senescence-associated genes were acquired from the CellAge database. R package Limma was used to screen out the differentially expressed senescence-related genes (DE-SRGs), and then three machine learning algorithms were applied to determine the hub DE-SRGs. Next, we established a nomogram model to further confirm the clinical significance of hub DE-SRGs. Finally, we validated the expression of hub SRG ABI3 by Sc-RNA seq analysis and explored the underlying mechanism of ABI3 in THP-1-derived macrophages and mouse atherosclerotic lesions.
RESULTS
A total of 15 DE-SRGs were identified in macrophage-rich plaques, with five hub DE-SRGs (ABI3, CAV1, NINJ1, Nox4 and YAP1) were further screened using three machine learning algorithms. Subsequently, a nomogram predictive model confirmed the high validity of the five hub DE-SRGs for evaluating atherosclerotic plaque progression. Further, the ABI3 expression was upregulated in macrophages of advanced plaques and senescent THP-1-derived macrophages, which was consistent with the bioinformatics analysis. ABI3 knockdown abolished macrophage senescence, and the NF-κB signaling pathway contributed to ABI3-mediated macrophage senescence.
CONCLUSION
We identified five cellular senescence-associated genes for atherogenesis progression and unveiled that ABI3 might promote macrophage senescence via activation of the NF-κB pathway in atherogenesis progression, which proposes new preventive and therapeutic strategies of senolytic agents for atherosclerosis.
Topics: Animals; Mice; Atherosclerosis; Macrophages; NF-kappa B; Plaque, Atherosclerotic; Signal Transduction
PubMed: 38062164
DOI: 10.1007/s00011-023-01817-w -
Biochemical and Biophysical Research... Feb 2019Atherosclerosis and cancer are the leading causes of mortality around the world that share common pathogenic pathways. The aim of this study is the investigation of the...
Atherosclerosis and cancer are the leading causes of mortality around the world that share common pathogenic pathways. The aim of this study is the investigation of the protein profile of atherosclerotic plaque in order to find similar biomarker between cancer and atherosclerosis. The small pieces of human coronary artery containing advanced atherosclerotic plaque is obtained from patients during bypass surgery. Structural characterization of type V plaque, including fibrous connective tissue, necrotic lipid core, cholesterol clefts and calcium deposits are performed using high resolution transmission electron microscopy (HR-TEM). The protein profile of atherosclerosis plaque is also analyzed using 2-dimensional electrophoresis and matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF). TEM analysis shows that vascular smooth muscle cells (VSMCs) exhibit different and uncommon morphologies in atherosclerotic plaque which is correlated to the proliferative state of the cells. The proteomics analysis reveals proteins related to atherosclerosis formation including Mimecan, Ras Suppressor Protein-1 (RSUP-1) and Cathepsin D which identified as biomarker of cancerous tumors. The expression of Mimecan and RSUP-1 is down-regulated in atherosclerotic plaque while the expression of Cathepsin D is up-regulated. These data support that atherosclerotic plaque presents some degree of tumorgenesis with the significant activity of VSMCs as the key player in atherogenesis.
Topics: Biomarkers, Tumor; Cathepsin D; Electrophoresis, Gel, Two-Dimensional; Humans; Intercellular Signaling Peptides and Proteins; Neoplasms; Plaque, Atherosclerotic; Proteome; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Transcription Factors
PubMed: 30616890
DOI: 10.1016/j.bbrc.2018.12.160 -
Biomedicine & Pharmacotherapy =... Jun 2021With the aging population, coronary syndrome is one of the leading causes of mortality. Atherosclerosis is the pathophysiological basis of coronary syndrome, which is...
With the aging population, coronary syndrome is one of the leading causes of mortality. Atherosclerosis is the pathophysiological basis of coronary syndrome, which is caused by plaque rupture and predisposed or aggravated by many perioperative complications. Parecoxib is one of the most widely used nonsteroidal anti-inflammatory perioperative drugs. This study aims to evaluate the potential benefits of parecoxib on atherosclerosis progression. Apolipoprotein E-deficient (Apo E-/-) mice were intraperitoneally injected by parecoxib (par group) or saline (control group) and, meanwhile, were given a western diet for 12 weeks. The aorta and aortic root were examined by oil red O (ORO) staining for atherosclerotic lesions. The expression level of matrix metalloproteinases (MMPs), was investigated using immunofluorescence and western blot. Macrophage inflammation was investigated by Q-PCR. Parecoxib treatment increased the number of vascular smooth muscle cells (VSMC) and amount of collagen, while and decreased the number of macrophages in murine aortic walls. The expression of MMP1, 2, 9, and 13 as well as IL- 1β and IL-6 were also decreased in the par group. However, there was no statistical difference in lipid infiltration between the two groups. Parecoxib could improve plaque stability by suppressing inflammation and inhibiting MMPs production.
Topics: Animals; Cells, Cultured; Cyclooxygenase 2 Inhibitors; Inflammation Mediators; Isoxazoles; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic
PubMed: 33740522
DOI: 10.1016/j.biopha.2021.111423 -
Journal of Atherosclerosis and... Apr 2017Due to the pandemics of obesity and diabetes mellitus, especially in the Western countries, atherosclerotic cardiovascular disease (ASCVD) has become a major health... (Review)
Review
Due to the pandemics of obesity and diabetes mellitus, especially in the Western countries, atherosclerotic cardiovascular disease (ASCVD) has become a major health burden and is expected to increase in the future. Modifying lipid targets, especially low-density lipoprotein cholesterol (LDL-C) level, has become the first-line therapy for primary and secondary prevention of ASCVD. Intravascular imaging modalities have contributed to elucidating clinical efficacy of lipid lowering therapy on atherosclerotic plaques. Optical coherence tomography (OCT) is a high-resolution imaging tool enables visualization of plaque microstructures associated with its instability. This modality has demonstrated favorable changes in plaque microstructures under lowering LDL-C level. In addition, clinical studies using OCT have suggested potential association of other lipid targets, including triglyceride and high-density lipoprotein cholesterol with plaque microstructures. Given continuing cardiovascular risks despite statin therapy, OCT will be an important imaging modality to evaluate novel therapeutic approaches that potentially modulates plaque instability.
Topics: Animals; Cardiovascular Diseases; Humans; Hypolipidemic Agents; Lipids; Plaque, Atherosclerotic
PubMed: 28239070
DOI: 10.5551/jat.RV16009 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Jan 2019In the background of the high incidence and high mortality of cardiovascular diseases,atherosclerosis is the main pathological feature of cardiovascular diseases and the... (Review)
Review
In the background of the high incidence and high mortality of cardiovascular diseases,atherosclerosis is the main pathological feature of cardiovascular diseases and the core pathological basis for disease progression. In the evolution of atherosclerotic plaques,the rupture of unstable plaques,plaque shedding and formation of thrombosis are the most dangerous parts. In this process,the formation of plaque fibrosis is the core mechanism regulating plaque stability. Additionally,fibrosis reflects dynamic changes in the inflammatory processes and pathological changes. In view of the inflammation regulation and fibrosis regulation,this paper clarified the process of atherosclerotic plaque,explained the roles of relevant inflammatory cells and cytokines in plaque stability,and summed up drug researches related with stable plaque in recent years. In the future,improving the fibrosis will be a new idea for stabilizing plaque in atherosclerosis drug development.
Topics: Atherosclerosis; Cytokines; Fibrosis; Humans; Inflammation; Plaque, Atherosclerotic; Thrombosis
PubMed: 30989939
DOI: 10.19540/j.cnki.cjcmm.20181012.005 -
International Heart Journal 2020
Topics: Humans; Plaque, Atherosclerotic
PubMed: 33250484
DOI: 10.1536/ihj.20-674 -
Clinical Science (London, England :... Aug 2021Atherosclerosis is a systemic inflammation of the arteries characterized by atherosclerotic plaque due to the accumulation of lipids, inflammatory cells, apoptotic... (Review)
Review
Atherosclerosis is a systemic inflammation of the arteries characterized by atherosclerotic plaque due to the accumulation of lipids, inflammatory cells, apoptotic cells, calcium and extracellular matrix (ECM) proteins. Stable plaques present a chronic inflammatory infiltration, whereas vulnerable plaques present an 'active' inflammation involved in the thinning of the fibrous cap that predisposes to plaque rupture. Several complex biological cellular processes lead plaques to evolve from stable to vulnerable predisposing them to rupture and thrombosis. In this review, we analyze some emerging circulating biomarkers related to inflammation, ECM and lipid infiltration, angiogenesis, metalloproteinases and microRNA (miRNA), as possible diagnostic and prognostic indicators of plaque vulnerability.
Topics: Asymptomatic Diseases; Atherosclerosis; Biomarkers; Humans; Phenotype; Plaque, Atherosclerotic; Prognosis; Risk Assessment; Thrombosis
PubMed: 34414413
DOI: 10.1042/CS20210417 -
Trends in Cardiovascular Medicine Feb 2016Coronary atherosclerosis has been considered a chronic disease characterized by ongoing progression in response to systemic risk factors and local pro-atherogenic... (Review)
Review
Coronary atherosclerosis has been considered a chronic disease characterized by ongoing progression in response to systemic risk factors and local pro-atherogenic stimuli. As our understanding of the pathobiological mechanisms implicated in atherogenesis and plaque progression is evolving, effective treatment strategies have been developed that led to substantial reduction of the clinical manifestations and acute complications of coronary atherosclerotic disease. More recently, intracoronary imaging modalities have enabled detailed in vivo quantification and characterization of coronary atherosclerotic plaque, serial evaluation of atherosclerotic changes over time, and assessment of vascular responses to effective anti-atherosclerotic medications. The use of intracoronary imaging modalities has demonstrated that intensive lipid lowering can halt plaque progression and may even result in regression of coronary atheroma when the highest doses of the most potent statins are used. While current evidence indicates the feasibility of atheroma regression and of reversal of presumed high-risk plaque characteristics in response to intensive anti-atherosclerotic therapies, these changes of plaque size and composition are modest and their clinical implications remain largely elusive. Growing interest has focused on achieving more pronounced regression of coronary plaque using novel anti-atherosclerotic medications, and more importantly on elucidating ways toward clinical translation of favorable changes of plaque anatomy into more favorable clinical outcomes for our patients.
Topics: Anticholesteremic Agents; Coronary Artery Disease; Disease Progression; Humans; Patient Outcome Assessment; Plaque, Atherosclerotic
PubMed: 26089122
DOI: 10.1016/j.tcm.2015.05.004 -
Journal of the American College of... Sep 2021The development of optical coherence tomography (OCT) has revolutionized our understanding of coronary artery disease. In vivo OCT research has paralleled with advances... (Review)
Review
The development of optical coherence tomography (OCT) has revolutionized our understanding of coronary artery disease. In vivo OCT research has paralleled with advances in computational fluid dynamics, providing additional insights in the various hemodynamic factors influencing plaque growth and stability. Recent OCT studies introduced a new concept of plaque healing in relation to clinical presentation. In addition to known mechanisms of acute coronary syndromes such as plaque rupture and plaque erosion, a new classification of calcified plaque was recently reported. This review will focus on important new insights that OCT has provided in recent years into coronary plaque development, progression, and destabilization, with a focus on the role of local hemodynamics and endothelial shear stress, the layered plaque (signature of previous subclinical plaque destabilization and healing), and the calcified culprit plaque.
Topics: Acute Coronary Syndrome; Algorithms; Cardiac Imaging Techniques; Coronary Circulation; Disease Progression; Hemodynamics; Humans; Plaque, Atherosclerotic; Tomography, Optical Coherence
PubMed: 34531029
DOI: 10.1016/j.jacc.2021.07.032