scholarly journals The Elusive Origin of Atherosclerotic Plaque Calcification

2021 ◽  
Vol 9 ◽  
Author(s):  
Emmanuelle Canet-Soulas ◽  
Laurence Bessueille ◽  
Laura Mechtouff ◽  
David Magne
Keyword(s):  
Calcium Phosphate ◽  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Calcium Score ◽  
Inflammatory Cells ◽  
Atherosclerotic Plaques ◽  
Accumulation Of Lipids ◽  
Cardiovascular Mortality Risk ◽  
Human And Mouse ◽  
Necrotic Debris

It has been known for decades or even centuries that arteries calcify as they age. Vascular calcification probably affects all adults, since virtually all have atherosclerotic plaques: an accumulation of lipids, inflammatory cells, necrotic debris, and calcium phosphate crystals. A high vascular calcium score is associated with a high cardiovascular mortality risk, and relatively recent data suggest that even microcalcifications that form in early plaques may destabilize plaques and trigger a cardiovascular event. If the cellular and molecular mechanisms of plaque calcification have been relatively well characterized in mice, human plaques appear to calcify through different mechanisms that remain obscure. In this context, we will first review articles reporting the location and features of early calcifications in human plaques and then review the articles that explored the mechanisms though which human and mouse plaques calcify.

The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability

2019 ◽  
Vol 25 (29) ◽  
pp. 3098-3111 ◽  
Author(s):  
Luca Liberale ◽  
Giovanni G. Camici
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Plaque Burden ◽  
Vascular Aging ◽  
Age Related ◽  
Plaque Development ◽  
Increased Risk ◽  
The Impact ◽  
Over Time

Background: The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. Objective: The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

scholarly journals Clinical Relevance of Coronary Computed Tomography Angiography Beyond Coronary Artery Stenosis

2021 ◽  
Author(s):  
Mohammed Nooruddin Meah ◽  
Michelle C. Williams
Keyword(s):  
Computed Tomography ◽  
Coronary Artery ◽  
High Risk ◽  
Atherosclerotic Plaque ◽  
Computed Tomography Angiography ◽  
Coronary Computed Tomography Angiography ◽  
Calcium Score ◽  
Coronary Plaque ◽  
Coronary Computed Tomography ◽  
Low Attenuation Plaque

Background The capabilities of coronary computed tomography angiography (CCTA) have advanced significantly in the past decade. Its capacity to detect stenotic coronary arteries safely and consistently has led to a marked decline in invasive diagnostic angiography. However, CCTA can do much more than identify coronary artery stenoses. Method This review discusses applications of CCTA beyond coronary stenosis assessment, focusing in particular on the visual and quantitative analysis of atherosclerotic plaque. Results Established signs of visually assessed high-risk plaque on CT include positive remodeling, low-attenuation plaque, spotty calcification, and the napkin-ring sign, which correlate with the histological thin-cap fibroatheroma. Recently, quantification of plaque subtypes has further improved the assessment of coronary plaque on CT. Quantitatively assessed low-attenuation plaque, which correlates with the necrotic core of the thin-cap fibroatheroma, has demonstrated superiority over stenosis severity and coronary calcium score in predicting subsequent myocardial infarction. Current research aims to use radiomic and machine learning methods to further improve our understanding of high-risk atherosclerotic plaque subtypes identified on CCTA. Conclusion Despite rapid technological advances in the field of coronary computed tomography angiography, there remains a significant lag in routine clinical practice where use is often limited to lumenography. We summarize some of the most promising techniques that significantly improve the diagnostic and prognostic potential of CCTA. Key Points:  Citation Format

scholarly journals Pathophysiology of Atherosclerotic Plaque Development-Contemporary Experience and New Directions in Research

2021 ◽  
Vol 22 (7) ◽  
pp. 3513
Author(s):  
Michal Kowara ◽  
Agnieszka Cudnoch-Jedrzejewska
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Cellular Heterogeneity ◽  
Ldl Oxidation ◽  
Plaque Development ◽  
New Directions ◽  
Life Threatening ◽  
Non Coding Rnas ◽  
Cellular Pathways ◽  
Key Aspects

Atherosclerotic plaque is the pathophysiological basis of important and life-threatening diseases such as myocardial infarction. Although key aspects of the process of atherosclerotic plaque development and progression such as local inflammation, LDL oxidation, macrophage activation, and necrotic core formation have already been discovered, many molecular mechanisms affecting this process are still to be revealed. This minireview aims to describe the current directions in research on atherogenesis and to summarize selected studies published in recent years—in particular, studies on novel cellular pathways, epigenetic regulations, the influence of hemodynamic parameters, as well as tissue and microorganism (microbiome) influence on atherosclerotic plaque development. Finally, some new and interesting ideas are proposed (immune cellular heterogeneity, non-coding RNAs, and immunometabolism) which will hopefully bring new discoveries in this area of investigation.

scholarly journals Molecular mechanisms of microvascular failure in central nervous system injury—synergistic roles of NKCC1 and SUR1/TRPM4

2010 ◽  
Vol 113 (3) ◽  
pp. 622-629 ◽  
Author(s):  
J. Marc Simard ◽  
Kristopher T. Kahle ◽  
Volodymyr Gerzanich
Keyword(s):  
Endothelial Cells ◽  
Cerebral Edema ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Extracellular Fluid ◽  
Inflammatory Cells ◽  
Atp Depletion ◽  
Energy Status ◽  
Edema Formation ◽  
Trpm4 Channel

Microvascular failure largely underlies the damaging secondary events that accompany traumatic brain injury (TBI). Changes in capillary permeability result in the extravasation of extracellular fluid, inflammatory cells, and blood, thereby producing cerebral edema, inflammation, and progressive secondary hemorrhage (PSH). Recent work in rat models of TBI and stroke have implicated 2 ion transport proteins expressed in brain endothelial cells as critical mediators of edema formation: the constitutively expressed Na+-K+-2Cl– cotransporter, NKCC1, and the trauma/ischemia-induced SUR1-regulated NCCa-ATP (SUR1/TRPM4) channel. Whereas NKCC1 function requires adenosine 5′-triphosphate (ATP), activation of SUR1/TRPM4 occurs only after ATP depletion. This opposite dependence on intracellular ATP levels implies that one or the other mechanism will activate/deactivate as ATP concentrations rise and fall during periods of ischemia/reperfusion, resulting in continuous edema formation regardless of cellular energy status. Moreover, with critical ATP depletion, sustained opening of SUR1/TRPM4 channels results in the oncotic death of endothelial cells, leading to capillary fragmentation and PSH. Bumetanide and glibenclamide are 2 well-characterized, safe, FDA-approved drugs that inhibit NKCC1 and the SUR1/TRPM4 channel, respectively. When used alone, these drugs have provided documented beneficial effects in animal models of TBI- and ischemiaassociated cerebral edema and PSH. Given the mechanistic and temporal differences by which NKCC1 and the SUR1/TRPM4 channel contribute to the pathophysiological mechanisms of these events, combination therapy with bumetanide and glibenclamide may yield critical synergy in preventing injury-associated capillary failure.

scholarly journals Type II transmembrane serine proteases as potential targets for cancer therapy

2016 ◽  
Vol 397 (9) ◽  
pp. 815-826 ◽  
Author(s):  
Andrew S. Murray ◽  
Fausto A. Varela ◽  
Karin List
Keyword(s):  
Cancer Progression ◽  
Serine Proteases ◽  
Molecular Mechanisms ◽  
Inflammatory Cells ◽  
Activity Levels ◽  
Type Ii ◽  
Neoplastic Progression ◽  
Treatment Regimens ◽  
Proinflammatory Mediators ◽  
Transmembrane Serine Protease

Abstract Carcinogenesis is accompanied by increased protein and activity levels of extracellular cell-surface proteases that are capable of modifying the tumor microenvironment by directly cleaving the extracellular matrix, as well as activating growth factors and proinflammatory mediators involved in proliferation and invasion of cancer cells, and recruitment of inflammatory cells. These complex processes ultimately potentiate neoplastic progression leading to local tumor cell invasion, entry into the vasculature, and metastasis to distal sites. Several members of the type II transmembrane serine protease (TTSP) family have been shown to play critical roles in cancer progression. In this review the knowledge collected over the past two decades about the molecular mechanisms underlying the pro-cancerous properties of selected TTSPs will be summarized. Furthermore, we will discuss how these insights may facilitate the translation into clinical settings in the future by specifically targeting TTSPs as part of novel cancer treatment regimens.

Abstract 134: Hypoxia in Coronary Plaque Enhance Thrombogenic Potential of Activated Macrophages

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Kazunari Maekawa ◽  
Atsushi Yamashita ◽  
Eriko Nakamura ◽  
Yujiro Asada
Keyword(s):  
Atherosclerotic Plaque ◽  
Lactate Production ◽  
Hypoxic Condition ◽  
Inflammatory Cells ◽  
Coronary Plaque ◽  
Interferon Γ ◽  
Procoagulant Activity ◽  
Metabolic Markers ◽  
Inflammatory Stimuli ◽  
Thrombogenic Potential

Background: Thrombogenic potential on disrupted atherosclerotic plaque is an important factor on the development of atherothrombosis, and inflammatory stimuli up-regulate thrombogenic factors. We have revealed that arterial glucose metabolism and hypoxia reflect the vascular wall thrombogenicity in rabbit. However, role of inflammation and/or hypoxia on the thrombogenicity in atherosclerotic plaque remain unclear. The present study aims to identify expression of hypoxic/metabolic markers and thrombogenic factors in human coronary plaques and also aims to evaluate the effect of of inflammatory and hypoxic stimuli on thrombogenicity in cultured macrophages. Methods: We immunohistochemically investigated numbers of inflammatory cells and microvessels, and expression of hexokinase (HK)-II, monocarboxylate transportor 4 (MCT4) (hypoxic/metabolic markers), and tissue factor (TF) in human vulnerable coronary plaques (n=22) and stable plaques (n=10). TF expression, procoagulant activity, and lactate production were assessed in THP-1 macrophages stimulated by tumor necrosis factor-α (10ng/mL) and interferon-γ (20ng/mL) under normoxic (21%O 2 ) or hypoxic (1%O 2 ) condition. Results: Numbers of macrophages, HK-II-, MCT4-, TF-immunopositive cells in the vulnerable plaques were significantly larger than those in the stable plaques. Many macrophages expressed HK-II, MCT4, and TF in the plaques. TF expression and procoagulant activity in the cultured macrophages were increased by the inflammatory stimuli, and were enhanced by hypoxia. The hypoxic condition also increased HK-II expression and lactate production, but the inflammatory stimuli did not affect them. Conclusion: Hypoxia in coronary plaque may enhance thrombogenic potential of macrophages activated by inflammatory stimuli.

Lipid Lowering Therapy and Stabilization of Atherosclerotic Plaques

1999 ◽  
Vol 82 (S 01) ◽  
pp. 60-61 ◽  
Author(s):  
Dirk Müller-Wieland ◽  
Wilhelm Krone
Keyword(s):  
Thrombus Formation ◽  
Inflammatory Cells ◽  
Cardiovascular Complications ◽  
Lipid Lowering ◽  
Atherosclerotic Plaques ◽  
Lipid Lowering Therapy ◽  
New Paradigm ◽  
Clinical Prognosis ◽  
Fibrous Cap ◽  
Lowering Therapy

SummaryLipid-lowering therapy leads to a great reduction of cardiovascular complications, but has almost no effect on the degree of stenosis of coronary arteries. These and other studies have lead to a new paradigm of coronary artery disease, i. e. clinical prognosis is not only determined by the extent of a single stenosis, but mainly by the number and structure of atherosclerotic plaques. Rupture of an instable or vulnerable plaque, characterized by a large lipid-rich central core, inflammatory cells, and a thin fibrous cap, causes sudden thrombus formation and thereby acute coronary syndromes. There is accumulating evidence that cholesterol lowering can result in plaque stabilization and improvement of endothelial dysfunction.

scholarly journals The RIG-I Signal Pathway Mediated Panax notoginseng Saponin Anti-Inflammatory Effect in Ischemia Stroke

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Chujun Zhang ◽  
Sai Zhang ◽  
Lanxiang Wang ◽  
Soyeon Kang ◽  
Jiabao Ma ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Molecular Mechanisms ◽  
Chinese Herb ◽  
Inflammatory Cells ◽  
Panax Notoginseng ◽  
Artery Occlusion ◽  
Blue Staining ◽  
Bioactive Constituents ◽  
Anti Inflammatory ◽  
Cerebral Artery Occlusion

Panax notoginseng saponins (PNS), the main bioactive constituents of a traditional Chinese herb Panax notoginseng, were commonly used for ischemic stroke in China. However, the associated cellular and molecular mechanisms of PNS have not been well examined. This study aimed to decipher the underlying molecular target of PNS in the treatment of cerebral ischemia. The oxygen-glucose-deprived (OGD) model of rat brain microvascular endothelial cells (BMECs) was used in this study. The alteration of gene expression in rat BMECs after PNS treatment was measured by microarray and indicated that there were 38 signaling pathways regulated by PNS. Among them, RIG-I receptor and related signaling molecules TNF receptor-associated factor 2 (Traf2) and nuclear factor-kappa B (NF-κB) were significantly suppressed by PNS, which was verified again in OGD-induced BMECs measured by FQ-PCR and western blotting and in middle cerebral artery occlusion (MCAO) rats measured by immunohistochemistry. The levels of TNF-α, IL-8, and the downstream cytokines regulated by RIG-I receptor pathway were also decreased by PNS. Meanwhile, the neurological evaluation, hematoxylin and eosin (HE) staining, and Evans blue staining were conducted to evaluate the effect of PNS in MCAO rats. Results showed PNS significantly improved functional outcome and cerebral vascular leakage. Flow cytometry showed the number of the inflammatory cells infiltrated in brain tissue was decreased in PNS treatment. Our results identified that RIG-I signaling pathway mediated anti-inflammatory properties of PNS in cerebral ischemia, which provided the novel insights of PNS application in clinics.

scholarly journals Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis

2016 ◽  
Vol 2 (7) ◽  
pp. e1600224 ◽  
Author(s):  
Denuja Karunakaran ◽  
Michele Geoffrion ◽  
Lihui Wei ◽  
Wei Gan ◽  
Laura Richards ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Density Lipoprotein ◽  
Necrotic Core ◽  
Atherosclerotic Plaques ◽  
Core Formation ◽  
Macrophage Cell ◽  
Plaque Instability

Atherosclerosis results from maladaptive inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque necrosis, which underlies the instability that promotes plaque rupture and myocardial infarction. Hence, targeting macrophage cell death pathways may offer promise for the stabilization of vulnerable plaques. Necroptosis is a recently discovered pathway of programmed cell necrosis regulated by RIP3 and MLKL kinases that, in contrast to apoptosis, induces a proinflammatory state. We show herein that necroptotic cell death is activated in human advanced atherosclerotic plaques and can be targeted in experimental atherosclerosis for both therapeutic and diagnostic interventions. In humans with unstable carotid atherosclerosis, expression of RIP3 and MLKL is increased, and MLKL phosphorylation, a key step in the commitment to necroptosis, is detected in advanced atheromas. Investigation of the molecular mechanisms underlying necroptosis showed that atherogenic forms of low-density lipoprotein increase RIP3 and MLKL transcription and phosphorylation—two critical steps in the execution of necroptosis. Using a radiotracer developed with the necroptosis inhibitor necrostatin-1 (Nec-1), we show that 123I-Nec-1 localizes specifically to atherosclerotic plaques in Apoe−/− mice, and its uptake is tightly correlated to lesion areas by ex vivo nuclear imaging. Furthermore, treatment of Apoe−/− mice with established atherosclerosis with Nec-1 reduced lesion size and markers of plaque instability, including necrotic core formation. Collectively, our findings offer molecular insight into the mechanisms of macrophage cell death that drive necrotic core formation in atherosclerosis and suggest that this pathway can be used as both a diagnostic and therapeutic tool for the treatment of unstable atherosclerosis.

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