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Clinical Reviews in Allergy & Immunology Feb 2024Mast cells (MCs) are commonly recognized for their crucial involvement in the pathogenesis of allergic diseases, but over time, it has come to light that they also play... (Review)
Review
Mast cells (MCs) are commonly recognized for their crucial involvement in the pathogenesis of allergic diseases, but over time, it has come to light that they also play a role in the pathophysiology of non-allergic disorders including atherosclerosis. The involvement of MCs in the pathology of atherosclerosis is supported by their accumulation in atherosclerotic plaques upon their progression and the association of intraplaque MC numbers with acute cardiovascular events. MCs that accumulate within the atherosclerotic plaque release a cocktail of mediators through which they contribute to neovascularization, plaque progression, instability, erosion, rupture, and thrombosis. At a molecular level, MC-released proteases, especially cathepsin G, degrade low-density lipoproteins (LDL) and mediate LDL fusion and binding of LDL to proteoglycans (PGs). Through a complicated network of chemokines including CXCL1, MCs promote the recruitment of among others CXCR2 neutrophils, therefore, aggravating the inflammation of the plaque environment. Additionally, MCs produce extracellular traps which worsen inflammation and contribute to atherothrombosis. Altogether, evidence suggests that MCs actively, via several underlying mechanisms, contribute to atherosclerotic plaque destabilization and acute cardiovascular syndromes, thus, making the study of interventions to modulate MC activation an interesting target for cardiovascular medicine.
Topics: Humans; Plaque, Atherosclerotic; Mast Cells; Atherosclerosis; Thrombosis; Inflammation
PubMed: 38289515
DOI: 10.1007/s12016-024-08981-9 -
Journal of the American College of... Mar 2020
Topics: Humans; Lipids; Plaque, Atherosclerotic; Stents
PubMed: 32216906
DOI: 10.1016/j.jacc.2020.01.043 -
Arquivos Brasileiros de Cardiologia Nov 2023
Topics: Humans; Plaque, Atherosclerotic; Atherosclerosis; Cysteine Endopeptidases
PubMed: 38126488
DOI: 10.36660/abc.20230743 -
European Journal of Pharmacology Dec 2017Macrophages are key players in atherosclerotic lesions, regulating the local inflammatory milieu and plaque stability by the secretion of many inflammatory molecules,... (Review)
Review
Macrophages are key players in atherosclerotic lesions, regulating the local inflammatory milieu and plaque stability by the secretion of many inflammatory molecules, growth factors and cytokines. Monocytes have long been considered to be the main source of plaque macrophages. However, recent findings provide evidence for proliferation of local macrophages or transdifferentiation from other vascular cells as alternative sources. Recent years of research focused on the further identification and characterisation of macrophage phenotypes and functions. In this review we describe the advances in our understanding of monocyte and macrophage heterogeneity and its implications for specific therapeutic interventions, aiming to reduce the ever growing significant risk of cardiovascular events without any detrimental side effects on the patient's immune response.
Topics: Animals; Humans; Macrophages; Molecular Targeted Therapy; Monocytes; Phenotype; Plaque, Atherosclerotic
PubMed: 28989084
DOI: 10.1016/j.ejphar.2017.10.005 -
Current Opinion in Lipidology Oct 2014Atherosclerotic plaque rupture and subsequent acute events, such as myocardial infarction and stroke, contribute to the majority of cardiovascular-related deaths.... (Review)
Review
PURPOSE OF REVIEW
Atherosclerotic plaque rupture and subsequent acute events, such as myocardial infarction and stroke, contribute to the majority of cardiovascular-related deaths. Calcification has emerged as a significant predictor of cardiovascular morbidity and mortality, challenging previously held notions that calcifications stabilize atherosclerotic plaques. In this review, we address this discrepancy through recent findings that not all calcifications are equivalent in determining plaque stability.
RECENT FINDINGS
The risk associated with calcification is inversely associated with calcification density. As opposed to large calcifications that potentially stabilize the plaque, biomechanical modeling indicates that small microcalcifications within the plaque fibrous cap can lead to sufficient stress accumulation to cause plaque rupture. Microcalcifications appear to derive from matrix vesicles enriched in calcium-binding proteins that are released by cells within the plaque. Clinical detection of microcalcifications has been hampered by the lack of imaging resolution required for in-vivo visualization; however, recent studies have demonstrated promising new techniques to predict the presence of microcalcifications.
SUMMARY
Microcalcifications play a major role in destabilizing atherosclerotic plaques. The identification of critical characteristics that lead to instability along with new imaging modalities to detect their presence in vivo may allow early identification and prevention of acute cardiovascular events.
Topics: Calcinosis; Humans; Myocardial Infarction; Plaque, Atherosclerotic; Stroke
PubMed: 25188916
DOI: 10.1097/MOL.0000000000000105 -
ACS Nano Feb 2020The past several decades have brought significant advances in the application of clinical and preclinical nanoparticulate drugs in the field of cancer, but nanodrug... (Review)
Review
The past several decades have brought significant advances in the application of clinical and preclinical nanoparticulate drugs in the field of cancer, but nanodrug development in cardiovascular disease has lagged in comparison. Improved understanding of the spatiotemporal kinetics of nanoparticle delivery to atherosclerotic plaques is required to optimize preclinical nanodrug delivery and to drive their clinical translation. Mechanistic studies using super-resolution and correlative light microscopy/electron microscopy permit a broad, ultra-high-resolution picture of how endothelial barrier integrity impacts the enhanced permeation and retention (EPR) effect for nanoparticles as a function of both atherosclerosis progression and metabolic therapy. Studies by Beldman in the December issue of suggest atherosclerotic plaque progression supports endothelial junction stabilization, which can reduce nanoparticle entry into plaques, and metabolic therapy may induce similar effects. Herein, we examine the potential for advanced dynamic intravital microscopy-based mechanistic studies of nanoparticle entry into atherosclerotic plaques to shed light on the advantages of free extravasation immune-mediated nanoparticle uptake for effective clinical translation. We further explore the potential combination of metabolic therapy with another emerging cardiovascular disease treatment paradigm-efferocytosis stimulation-to enhance atherosclerotic plaque regression.
Topics: Animals; Drug Delivery Systems; Humans; Nanoparticles; Nanotechnology; Particle Size; Plaque, Atherosclerotic; Surface Properties
PubMed: 31986012
DOI: 10.1021/acsnano.0c00245 -
The Biochemical Journal May 2016The formation of atherosclerotic plaques in the large and medium sized arteries is classically driven by systemic factors, such as elevated cholesterol and blood... (Review)
Review
The formation of atherosclerotic plaques in the large and medium sized arteries is classically driven by systemic factors, such as elevated cholesterol and blood pressure. However, work over the past several decades has established that atherosclerotic plaque development involves a complex coordination of both systemic and local cues that ultimately determine where plaques form and how plaques progress. Although current therapeutics for atherosclerotic cardiovascular disease primarily target the systemic risk factors, a large array of studies suggest that the local microenvironment, including arterial mechanics, matrix remodelling and lipid deposition, plays a vital role in regulating the local susceptibility to plaque development through the regulation of vascular cell function. Additionally, these microenvironmental stimuli are capable of tuning other aspects of the microenvironment through collective adaptation. In this review, we will discuss the components of the arterial microenvironment, how these components cross-talk to shape the local microenvironment, and the effect of microenvironmental stimuli on vascular cell function during atherosclerotic plaque formation.
Topics: Animals; Atherosclerosis; Endothelium, Vascular; Humans; Models, Biological; Plaque, Atherosclerotic; Risk Factors
PubMed: 27208212
DOI: 10.1042/BJ20150844 -
Molecules (Basel, Switzerland) Aug 2019Atherosclerosis is a chronic long-lasting vascular disease leading to myocardial infarction and stroke. Vulnerable atherosclerotic (AS) plaques are responsible for these... (Review)
Review
Atherosclerosis is a chronic long-lasting vascular disease leading to myocardial infarction and stroke. Vulnerable atherosclerotic (AS) plaques are responsible for these life-threatening clinical endpoints. To more successfully work against atherosclerosis, improvements in early diagnosis and treatment of AS plaque lesions are required. Vulnerable AS plaques are frequently undetectable by conventional imaging because they are non-stenotic. Although blood biomarkers like lipids, C-reactive protein, interleukin-6, troponins, and natriuretic peptides are in pathological ranges, these markers are insufficient in detecting the critical perpetuation of AS anteceding endpoints. Thus, chances to treat the patient in a preventive way are wasted. It is now time to solve this dilemma because clear results indicate a benefit of anti-inflammatory therapy per se without modification of blood lipids (CANTOS Trial, NCT01327846). This fact identifies modulation of immune-mediated inflammation as a new promising point of action for the eradication of fatal atherosclerotic endpoints.
Topics: Adaptive Immunity; Animals; Biomarkers; Disease Susceptibility; Humans; Immune System; Immunity, Innate; Inflammation; Matrix Metalloproteinases; Neovascularization, Pathologic; Plaque, Atherosclerotic
PubMed: 31450823
DOI: 10.3390/molecules24173072 -
Nature Protocols Mar 2022Macrophages in atherosclerotic lesions promote plaque progression and are an attractive therapeutic target in cardiovascular research. Here we present a protocol for... (Review)
Review
Macrophages in atherosclerotic lesions promote plaque progression and are an attractive therapeutic target in cardiovascular research. Here we present a protocol for synthesis of small interfering RNA (siRNA) nanoparticles (NP) that target lesional macrophages as a potential treatment for atherosclerosis. Ca/calmodulin-dependent protein kinase γ (CaMKIIγ) activity in macrophages of advanced human and mouse atherosclerotic plaques drives necrosis by downregulating the expression of the efferocytosis receptor MerTK. Therefore, selective inhibition of CaMKIIγ in lesional macrophages holds great promise for the treatment of advanced atherosclerosis. We recently developed a siRNA NP platform that can selectively silence CaMKIIγ in macrophages, resulting in increased plaque stability. We provide a detailed protocol for the synthesis of NP components, the preparation and characterization (physicochemical and in vitro) of siRNA NPs, and the evaluation of in vivo therapeutic effects of siRNA NPs and their biocompatibility in atherosclerotic mice. Our siRNA-loaded polymer-lipid hybrid NPs are constructed via a robust self-assembly method, exhibiting excellent in vivo features for systemic siRNA delivery. Following this protocol, it takes 3-5 d to prepare the siRNA NPs, 8-10 d to characterize the NPs and 4-5 weeks to evaluate their therapeutic effects in established atherosclerotic mice. By changing the RNA molecules loaded in the NPs, lesional macrophages can be targeted for the exploration and validation of new targets/pathways in atherosclerosis.
Topics: Animals; Atherosclerosis; Macrophages; Mice; Mice, Inbred C57BL; Nanoparticles; Plaque, Atherosclerotic; RNA, Small Interfering
PubMed: 35121853
DOI: 10.1038/s41596-021-00665-4 -
Experimental Biology and Medicine... Dec 2021Cardiovascular and cerebrovascular diseases, such as coronary heart disease and stroke, caused by atherosclerosis have become the "number one killer", seriously... (Review)
Review
Cardiovascular and cerebrovascular diseases, such as coronary heart disease and stroke, caused by atherosclerosis have become the "number one killer", seriously endangering human health in developing and developed countries. Atherosclerosis mainly occurs in large and medium-sized arteries and involves intimal thickening, accumulation of foam cells, and formation of atheromatous plaques. Autophagy is a cellular catabolic process that has evolved to defend cells from the turnover of intracellular molecules. Autophagy is thought to play an important role in the development of plaques. This review focuses on studies on autophagy in cells involved in the formation of atherosclerotic plaques, such as monocytes, macrophages, endothelial cells, dendritic cells, and vascular smooth muscle cells, indicating that autophagy plays an important role in plaque development. We mainly discuss the roles of autophagy in these cells in maintaining the stability of atherosclerotic plaques, providing a reference for the next steps to unravel the mechanisms of atherogenesis.
Topics: Animals; Atherosclerosis; Autophagy; Humans; Plaque, Atherosclerotic
PubMed: 34407677
DOI: 10.1177/15353702211038894