scholarly journals [Corrigendum] Decreased cathepsin K levels in human atherosclerotic plaques are associated with plaque instability

2017 ◽  
Author(s):  
Huiying Zhao ◽  
Xiujiao Qin ◽  
Shuai Wang ◽  
Xiwei Sun ◽  
Bin Dong
Keyword(s):  
Cathepsin K ◽  
Atherosclerotic Plaques ◽  
Plaque Instability

scholarly journals Decreased cathepsin K levels in human atherosclerotic plaques are associated with plaque instability

2017 ◽  
Vol 14 (4) ◽  
pp. 3471-3476 ◽  
Author(s):  
Huiying Zhao ◽  
Xiujiao Qin ◽  
Shuai Wang ◽  
Xiwei Sun ◽  
Bin Dong
Keyword(s):  
Cathepsin K ◽  
Atherosclerotic Plaques ◽  
Plaque Instability

Simvastatin Reduces Expression and Activity of Lipoprotein-Associated Phospholipase A2 in the Aorta of Hypercholesterolaemic Atherosclerotic Rabbits

2009 ◽  
Vol 37 (4) ◽  
pp. 1029-1037 ◽  
Author(s):  
Z Qiao ◽  
J Ren ◽  
H Chen
Keyword(s):  
Atherosclerotic Lesion ◽  
Statin Treatment ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Atherosclerotic Plaques ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Local Inflammatory Response ◽  
Plaque Instability ◽  
Significant Difference

Lipoprotein-associated phospholipase A2 (Lp-PLA2) contributes to atherosclerotic plaque instability and subsequent sudden coronary death. Statins are associated with decreased stroke risk and may improve stability of atherosclerotic plaques. The present study investigated the effect of simvastatin on expression of Lp-PLA2 levels in atherosclerotic plaques and on Lp-PLA2 activity in atherosclerotic aortas. Rabbits were a fed chow (control group) or a high-cholesterol diet (atherosclerosis group) for 12 weeks. An additional group on the high-cholesterol diet received simvastatin (5 mg/kg per day) for the last 4 weeks (simvastatin group). Lp-PLA2 activity in plasma and atherosclerotic aortas was significantly higher in the atherosclerosis group than in the control group and, consistent with this, abundant Lp-PLA2 protein was detected in plaques in the atherosclerosis group. Simvastatin significantly reduced Lp-PLA2 activity in plasma and aorta tissue, and reduced Lp-PLA2 protein level in atherosclerotic plaques. Whereas there was no significant difference in total atherosclerotic lesion area between simvastatin and atherosclerosis groups, simvastatin significantly reduced macrophage content, lipid retention and the intima/media ratio but increased the content of smooth muscle cells in atherosclerotic lesions. Thus, statin treatment markedly reduced Lp-PLA2 in both plasma and atherosclerotic plaques. This was associated with attenuation of the local inflammatory response and improved plaque stability.

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.

scholarly journals Cholesterol Acceptors Regulate the Lipidome of Macrophage Foam Cells

2019 ◽  
Vol 20 (15) ◽  
pp. 3784 ◽  
Author(s):  
Antoni Paul ◽  
Todd A. Lydic ◽  
Ryan Hogan ◽  
Young-Hwa Goo
Keyword(s):  
High Density Lipoprotein ◽  
Free Cholesterol ◽  
Foam Cell ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Atherosclerotic Plaques ◽  
Plaque Instability ◽  
Apolipoprotein A ◽  
Lipid Species ◽  
Macrophage Foam Cells

Arterial foam cells are central players of atherogenesis. Cholesterol acceptors, apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL), take up cholesterol and phospholipids effluxed from foam cells into the circulation. Due to the high abundance of cholesterol in foam cells, most previous studies focused on apoA-I/HDL-mediated free cholesterol (FC) transport. However, recent lipidomics of human atherosclerotic plaques also identified that oxidized sterols (oxysterols) and non-sterol lipid species accumulate as atherogenesis progresses. While it is known that these lipids regulate expression of pro-inflammatory genes linked to plaque instability, how cholesterol acceptors impact the foam cell lipidome, particularly oxysterols and non-sterol lipids, remains unexplored. Using lipidomics analyses, we found cholesterol acceptors remodel foam cell lipidomes. Lipid subclass analyses revealed various oxysterols, sphingomyelins, and ceramides, species uniquely enriched in human plaques were significantly reduced by cholesterol acceptors, especially by apoA-I. These results indicate that the function of lipid-poor apoA-I is not limited to the efflux of cholesterol and phospholipids but suggest that apoA-I serves as a major regulator of the foam cell lipidome and might play an important role in reducing multiple lipid species involved in the pathogenesis of atherosclerosis.

P1942A trait of inflammation pathogenesis in human atherosclerosis: inflammasome driven interleukin-1 signaling in complex atherosclerotic plaques via hyperlipidemia trained innate immunity

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
X Jiang ◽  
F Wang ◽  
J Wang ◽  
A Gistera ◽  
J Roy ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Interleukin 1 ◽  
Atherosclerotic Plaques ◽  
Plaque Instability ◽  
Functional Studies ◽  
Caspase 1 ◽  
Effector Caspase ◽  
Atheromatous Plaques ◽  
Pathways Analysis ◽  
Human Atherosclerosis

Abstract A trait of inflammation pathogenesis in human atherosclerosis: inflammasome driven interleukin-1 signalling in complex atherosclerotic plaques via hyperlipidemia trained innate immunity Objectives We aimed to investigate interleukin (IL)-1 generation and the regulatory role of inflammasome in human advanced atherosclerosis. Background IL-1β is key contributor to the inflammatory process associated with atherosclerosis and its complications. Recent studies suggested that IL-1β blockade reduces the burden of inflammation and recurrence of cardiovascular events. Yet, other cytokines in IL-1 family and the regulation of IL-1 generation in patients with atherosclerosis remains poorly understood. Methods and results A focused transcriptomic analysis in human atherosclerotic specimens discovered that human atherosclerotic plaques host a broad reservoir of inflammasome components, characterised by expression of canonical inflammasome gene NLRP6, NLRP12, NLRC4, NLRP3 and non-canonical inflammasome gene caspase 4 significantly elevated in the symptomatic plaques versus the asymptomatic plaques. Upregulation of NLRP3 inflammasome expression in plaque validated by immunohistochemistry staining suggested it as a distinctive characteristic of plaque vulnerability and complexity. Functional studies on atherosclerotic explants obtained from patients undergoing carotid endarterectomy revealed constitutive generation of IL-1β accompanied by secretion of comparable levels of IL-1α from the majority of the plaques, while IL-18 and IL-33 generation from some of the plaques. Stimulation of the plaques with inflammasome activators showed an inducible generation of both IL-1α and IL-1β, not IL-18 or IL-33, mediated by specific canonical and non-canonical inflammasome pathways. Analysis on the medication records of these patients indicated that plaques from patients with suboptimally controlled hyperlipidemia, imaging signs for plaque instability and inadequate statins therapy possessed higher recruitable production of IL-1β, suggesting the conventional atherogenic factor in regulation of inflammasome immunity and disease activity. Mechanistic studies on tissue and cells isolated from atheromatous plaques demonstrate that generation of mature IL-1β is via a mechanism controlled by NLRP3 and the effector caspase-1. Conclusions The study supports a profound canonical and non-canonical inflammasomes mediated plaque IL-1α/β generation, via a key mechanism by NLRP3 and caspase-1. The results provide biological insights into the clinical merit of high-intensity cholesterol lowering and anti-IL-1 signalling-directed therapies in high-risk patients with atherosclerosis. Acknowledgement/Funding KI-Mayo collaboration project, the Swedish Research Council, the Swedish Heart-Lung Foundation, European Union FP7 projects, the NIH

scholarly journals Matrix Metalloproteinases as Biomarkers of Atherosclerotic Plaque Instability

2020 ◽  
Vol 21 (11) ◽  
pp. 3946 ◽  
Author(s):  
Wioletta Olejarz ◽  
Dominika Łacheta ◽  
Grażyna Kubiak-Tomaszewska
Keyword(s):  
Matrix Metalloproteinases ◽  
Atherosclerotic Plaque ◽  
Atherosclerotic Plaques ◽  
Prognostic Information ◽  
Plaque Instability ◽  
Coronary Syndrome ◽  
Ecm Proteins ◽  
Stable Coronary Heart Disease ◽  
Future Risk ◽  
Traditional Risk Factors

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases responsible for tissue remodeling and degradation of extracellular matrix (ECM) proteins. MMPs may modulate various cellular and signaling pathways in atherosclerosis responsible for progression and rupture of atherosclerotic plaques. The effect of MMPs polymorphisms and the expression of MMPs in both the atherosclerotic plaque and plasma was shown. They are independent predictors of atherosclerotic plaque instability in stable coronary heart disease (CHD) patients. Increased levels of MMPs in patients with advanced cardiovascular disease (CAD) and acute coronary syndrome (ACS) was associated with future risk of cardiovascular events. These data confirm that MMPs may be biomarkers in plaque instability as they target in potential drug therapies for atherosclerosis. They provide important prognostic information, independent of traditional risk factors, and may turn out to be useful in improving risk stratification.

scholarly journals P977 CT phenotype of high-risk atherosclerotic plaques causing an acute coronary syndrome compared to silent vulnerable plaques

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
R I Hodas ◽  
D Opincariu ◽  
N Rat ◽  
I Rodean ◽  
M Chitu ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
High Risk ◽  
Morphological Characteristics ◽  
Plaque Morphology ◽  
Atherosclerotic Plaques ◽  
Plaque Instability ◽  
Coronary Syndrome ◽  
Atheromatous Plaques ◽  
Group 2 ◽  
Group 1

Abstract Funding Acknowledgements PlaqueImage.- research grant no. 103544/2016, contract number 26/01.09.2016 - Background Previous studies demonstrated that plaque morphology has a crucial role in the development of an acute coronary syndrome (ACS). However, not all vulnerable coronary plaques produce an ACS and the prediction power of various vulnerability features to predict an acute coronary event in a close future, has not been elucidated so far. Objective We aimed to use multi-slice computed tomography angiography (CTA) for assessment of morphological characteristics of culprit lesions producing an ACS in the next several months after CT assessment, in comparison with morphological characteristics of unstable coronary atherosclerotic plaques which did not trigger an ACS. Material and methods We analyzed 40 patients in whom CTA revealed presence of unstable coronary lesions, exhibiting at least one marker of vulnerability: napkin ring sign (NRS), spotty calcium (SC), positive remodeling (PR) or presence of low attenuation plaque (LAP), divided in 2 groups: group 1 - 20 patients who developed an ACS in the next 6 months following CTA examination, and group 2 – 20 patients matched for age, gender and risk factors, who did not present any cardiovascular event 6 month after CTA assessment. Post-processing of multi-slice CTA images was performed in order to assess morphological characteristics and CT-derived markers of atherosclerotic plaque instability. Results Similar mean values of plaque length (17.1 +/- 5.9 mm vs 16.9 +/- 3.4 mm; p = 0.6) and total atheroma volume (188.1 +/- 104.7 mm3vs 186.4 +/- 90.7 mm3; p = 0.8) were obtained for both groups. The mean number of vulnerability markers was 1.6 in group 1 vs 1.2 in group 2 (p = 0.07). However, atherosclerotic lesions in patients from group 1 presented significantly higher values of lipid-rich atheroma (9.8 +/- 10.8 mm3vs 2.6 +/- 1.0 mm3; p = 0.01) and remodeling index (1.14 +/- 0.3 in group 1 vs 0.89 +/- 0.19 in group 2, p = 0.04). At the same time, atheromatous plaques in patients who developed an ACS during the 6-months follow-up showed in a significantly higher proportion LAP (45% in group vs 10% in group 2, p = 0.03) and PR (15%in group 1 versus 5% in group 2, p = 0.04), but not NRS (30% vs 25%, p = ns) or SC (65% vs 40%, p = 0.2). Conclusions Atherosclerotic plaques producing an ACS exhibit a different phenotype than unstable plaques that remain silent. The CTA profile of atheromatous plaques producing an ACS includes the presence of low attenuation, positive remodeling, higher RI and lipid-rich atheroma. Presence of these features in high-risk coronary plaques identifies very high risk patients, who can benefit from adapted therapeutic strategy in order to prevent the development of an ACS.

scholarly journals Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability

2021 ◽  
Author(s):  
Yung‐Chih Chen ◽  
Karin Jandeleit‐Dahm ◽  
Karlheinz Peter
Keyword(s):  
Mouse Model ◽  
Sglt2 Inhibitor ◽  
Atherosclerotic Plaques ◽  
Plaque Instability ◽  
Nadph Oxidase 4 ◽  
Plaque Stabilization ◽  
Tandem Stenosis ◽  
Plaque Destabilization ◽  
The Right ◽  
Accelerate Atherosclerosis

Background Diabetes is known to accelerate atherosclerosis and increase plaque instability. However, there has been a lack of suitable animal models to study the effect of diabetes on plaque instability. We hypothesized that the tandem stenosis mouse model, which reflects plaque instability/rupture as seen in patients, can be applied to study the effects of diabetes and respective therapeutics on plaque instability/rupture. Methods and Results ApoE −/− mice at 7 weeks of age were rendered diabetic with streptozotocin and 5 weeks later were surgically subjected to tandem stenosis in the right carotid artery and fed with a high‐fat diet for 7 weeks. As a promising new antidiabetic drug class, a sodium glucose co‐transporter 2 inhibitor was tested in this new model. Diabetic mice showed an increase in the size of unstable atherosclerotic plaques and in the plaque instability markers MCP‐1, CD68, and necrotic core size. Mice treated with dapagliflozin demonstrated attenuated glucose and triglyceride levels. Importantly, these mice demonstrated plaque stabilization with enhanced collagen accumulation, increased fibrosis, increased cap‐to‐lesion height ratios, and significant upregulation of the vasculoprotective NADPH oxidase 4 expression. Conclusions The tandem stenosis mouse model in combination with the application of streptozotocin represents a highly suitable and unique mouse model for studying plaque destabilization under diabetic conditions. Furthermore, for the first time, we provide evidence of plaque‐stabilizing effects of sodium‐glucose co‐transporter 2 inhibitor. Our data also suggest that this newly developed mouse model is an attractive preclinical tool for testing antidiabetic drugs for the highly sought‐after potential to stabilize atherosclerotic plaques.

scholarly journals Dynamic Changes in Plasma Urotensin II and its Correlation with Plaque Stability

2020 ◽  
Author(s):  
Chunlin Yin ◽  
Xue Liu ◽  
Hongxia Wang ◽  
Mingcong Yan ◽  
Lijuan Guo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Vulnerable Plaque ◽  
Gene Transfection ◽  
Dynamic Change ◽  
High Cholesterol Diet ◽  
Atherosclerotic Plaques ◽  
Urotensin Ii ◽  
Plaque Instability ◽  
Coronary Syndrome ◽  
The Stability

Abstract Background: Urotensin II (UII) is involved in the formation of atherosclerosis, but its role in the stability of atherosclerotic plaque is undetermined. The purpose of this study was to observe the dynamic change of plasma UII and analyze its relationship with the stability of atherosclerotic plaques. Methods: The plasma UII concentration in patients with acute coronary syndrome (ACS) was detected. A vulnerable plaque model was established by local transfection of a recombinant P53 adenovirus into plaques of rabbits fed with a high-cholesterol diet and subjected to balloon injury, to evaluate the stability of the atherosclerotic plaques. Results: Our results showed that the level of plasma UII was increased in ACS patients compared with healthy subjects. However, it was significantly decreased in ST-segment elevation myocardial infarction patients (STEMI) and increased again in acute myocardial infarction (AMI) patients that were discharged after three months. UII dynamic change and its correlation with plaques stabilities were further verified in rabbit with atherosclerotic vulnerable plaque. The UII level in rabbits was significantly decreased after P53 gene transfection which can lead to of plaque instability. Conclusions: In conclusion, the level of plasma UII was significantly decreased in ACS with STEMI, which may serve as a reliable biological marker to reflect the progression and stability of atherosclerotic plaques.

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