Abstract 13: Inhibition of Nudt6 Stabilizes Advanced Atherosclerotic Plaques

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Hong Jin ◽  
Yuhuang Li ◽  
Ekaterina Chernogubova ◽  
Alexandra Bäcklund ◽  
Stina Sellberg ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Atherosclerotic Plaque ◽  
Plaque Rupture ◽  
Survival Rates ◽  
Atherosclerotic Plaques ◽  
Protein Coding ◽  
Fibrous Cap ◽  
Asymptomatic Patients ◽  
Rupture Model

Natural antisense transcripts (NATs), a non-coding RNA subclass, being transcribed in antisense direction to protein coding genes, are an intriguing novel class of targetable modulators, exerting crucial effects on gene expression. Aim of the current study was to investigate the contribution of NATs to atherosclerotic plaque vulnerability. Using laser capture micro-dissection, we isolated fibrous caps tissue of carotid artery plaques from 20 symptomatic patients with ruptured lesions vs. 20 samples from asymptomatic patients with stable lesions. A human transcriptome array (HTA; GeneChip 2.0 ) was used to profile the expression of all currently annotated RNA transcripts. Nucleoside diphosphate-linked moiety X motif 6 (NUDT6) was identified as one of the most significantly up-regulated transcripts in fibrous caps of ruptured lesions. Interestingly, NUDT6 is an established antisense RNA targeting the fibroblast growth factor 2 (FGF2). Of importance, FGF2 was among the most significantly down-regulated transcripts in ruptured lesions, corresponding to elevated NUDT6 expression. In situ hybridization in both, human and mouse carotid atherosclerotic plaques, confirmed substantially higher expression levels of NUDT6 in ruptured lesions compared to stable. In addition, in situ hybridization revealed a distinct co-localization with smooth muscle cells (SMCs) in advanced plaques. Overexpression of NUDT6 in cultured human carotid artery SMCs effectively limited FGF2 on the mRNA as well as protein level. Furthermore, reduction of NUDT6 via siRNA stimulated proliferation and blocked apoptosis in SMCs. In an inducible atherosclerotic plaque rupture model using incomplete ligation and cuff placement on common carotid arteries of male apoE -/- mice, NUDT6 inhibition with gapmeRs was able to significantly improve SMC survival rates, leading to thicker fibrous caps, and to reduce the plaque rupture rate compared to scramble-gapmeR control-treated mice (22% vs . 63%, p = 0.03). The present study presents NUDT6 as a novel crucial antisense regulator of fibrous cap stability through steering SMC survival via targeting its sense RNA transcript FGF2.

Abstract 127: Induction of miR-21 Increases Fibrous Cap Stability in Vulnerable Atherosclerotic Lesions

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Hong Jin ◽  
Yuhuang Li ◽  
Alexandra Bäcklund ◽  
Albert Busch ◽  
Suzanne M Eken ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Cellular Proliferation ◽  
Plaque Rupture ◽  
Oxidized Ldl ◽  
Survival Rates ◽  
Experimental Models ◽  
Vascular Remodelling ◽  
Plaque Vulnerability ◽  
Plaque Instability ◽  
Asymptomatic Patients

The aim of the present study was to explore the role of miRNAs as potential regulators in patients with carotid artery stenosis and concordant vulnerable atherosclerotic plaques. A pre-determined miRNA-array of laser captured micro-dissected (LCM) tissue specimen from fibrous caps of 10 symptomatic patients (stroke or TIA within > 14 days and histo-morphologically identified ruptured lesion) compared to fibrous caps from 10 asymptomatic patients (stable lesions; high grade stenosis) discovered miR-21 as one of the two miRNAs (miRs-21 and -210) being substantially down-regulated in symptomatic patients. To functionally evaluate the contribution of miR-21 to plaque vulnerability, we created miR21 -/- / ApoE -/- mice on a C57BL/6 background. We explored the phenotype of these newly developed miR21 -/- /ApoE -/- mice in experimental models of vascular remodelling and plaque vulnerability. First, miR21 -/- mice revealed a complete lack of SMC proliferation in response to carotid ligation injury. In the second inducible plaque rupture model, using incomplete ligation of the common carotid artery with consecutive cuff placement proximal to the ligated region indicated that all miR21 -/- /ApoE -/- mice ( n =10) presented atherothombotic events and signs of severe plaque instability. The rupture rate in control miR21 +/+ /ApoE -/- mice was significantly lower at 56% ( n =9). In addition, miR21 -/- /ApoE -/- showed an increase in lesion area in the aortic root and substantially higher levels of macrophage infiltration in injured carotid arteries. Dynamic live cell imaging, using isolated aortic SMCs and peritoneal macrophages from miR21 -/- /ApoE -/- vs. miR2 +/+ /ApoE -/- mice displayed substantial lower cellular proliferation and survival rates (for SMCs), and distinct advanced inflammatory activity upon oxidized LDL (oxLDL) stimulation of macrophages. In the present study we identified miR-21 as a key modulator of pathologic processes in atherosclerosis-related vascular remodelling. Targeted, lesion-site specific overexpression of miR-21 could be a novel and powerful future strategy to stabilize vulnerable plaques by inducing pro-proliferative mechanisms in SMC-enriched fibrous caps.

Abstract 324: Pathological Quantitative Assessment of Plaque Instability in Patients Undergoing Carotid Endarterectomy

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Takao Konishi
Keyword(s):  
Logistic Regression ◽  
Carotid Endarterectomy ◽  
Atherosclerotic Plaque ◽  
Plaque Rupture ◽  
Multivariable Logistic Regression Analysis ◽  
Diagnostic Efficiency ◽  
Plaque Instability ◽  
Fibrous Cap ◽  
Multivariable Logistic Regression ◽  
Asymptomatic Patients

Introduction: Instability of carotid atherosclerotic plaques leads to cerebral thromboemboli and ischemic symptoms. However, there has been no specific pathological quantification for the instability of carotid atherosclerotic plaque. The purpose of this study was to quantify atherosclerotic plaque instability in patients undergoing carotid endarterectomy (CEA). Methods: Carotid plaques were collected after CEA from 67 symptomatic and 15 asymptomatic patients between May 2015 and August 2016. Samples were stained with hematoxylin/eosin and Elastica-Masson (E-Masson). Immunohistochemistry was performed by using an endothelial specific antibody to CD31, CD 34 and PDGFRβ. Plaques were assessed for histopathological characteristics. Results: Multivariable logistic regression analysis demonstrated that plaque instability was independently associated with the presence of plaque rupture (odds ratio [OR], 9.75, 95% confidence interval [CI]: 1.62 to 58.6, p = 0.013), the minimal fibrous cap thickness (FCT) (OR per 10 μm 0.70, 95% CI: 0.51 to 0.96, p = 0.025), the presence of microcalcification in the fibrous cap (OR 7.82, 95% CI: 1.35 to 45.4, p = 0.022) and the intraplaque microvessels (OR 1.91, 95% CI: 1.02 to 3.57, p = 0.043). If these four independent parameters were combined to a score using the equation derived from the multivariable logistic regression model (Logit(Score) = 0.179 + 2.277 * (insert 1 if plaque rupture present; else 0) - 0.355 * (insert minimal FCT in multiples of 10 μm) + 2.057 * (insert 1 if microcalcification in the fibrous cap present; else 0) + 0.646 * (insert intraplaque microvessels /mm 2 ), the diagnostic efficiency could be improved to an AUC 0.92 (95% CI: 0.85-0.99, optimal cut-off value 0.814, sensitivity 89.6%, specificity 86.7%, PPV 96.8%, NPV 65.0%, diagnostic accuracy 89.0%). Conclusions: This study suggested the diagnostic scoring was useful for the quantification of carotid plaque instability in patients undergoing CEA.

Association between physical activity and sedentary behaviour on carotid atherosclerotic plaques: an epidemiological and histological study in 90 asymptomatic patients

2019 ◽  
Vol 54 (8) ◽  
pp. 469-474
Author(s):  
Pauline Mury ◽  
Mathilde Mura ◽  
Nellie Della-Schiava ◽  
Stéphanie Chanon ◽  
Aurélie Vieille-Marchiset ◽  
...  
Keyword(s):  
Physical Activity ◽  
Carotid Artery ◽  
Sedentary Behaviour ◽  
Atherosclerotic Plaques ◽  
Physically Active ◽  
Lipid Core ◽  
Fibrous Cap ◽  
Intraplaque Haemorrhage ◽  
Asymptomatic Patients ◽  
Calcium Deposits

ObjectiveCarotid atherosclerotic plaques are a source of emboli for stroke. ‘Unstable’ carotid atherosclerotic plaques may have intraplaque haemorrhages, neovessels, prevalent macrophages, excessive calcium deposits, a large lipid core and a thin fibrous cap. Regular physical activity (PA) may lower the risk of plaques becoming unstable. We evaluated the association of both PA and sedentary behaviour (SB) with carotid plaque histopathology.Methods90 asymptomatic patients who were undergoing carotid endarterectomy for carotid artery narrowing identified on ultrasound reported their PA and SB by questionnaires. We calculated PA intensity in MET (metabolic equivalent of task)-min/week. For analysis, the population was divided into tertiles according to PA (T1PA: the less PA patients; T2PA: the intermediate PA patients; T3PA: the most physically active patients) (T1PA<T2PA<T3PA) and SB (T1SB: the less sedentary behaviour patients; T2SB: the intermediate sedentary behaviour patients; T3SB: the most sedentary behaviour patients) (T1SB<T2SB<T3SB). PA was categorised as one of four PA intensities (600, 900, 1600 and 3000 MET-min/week). We obtained the carotid artery plaque at surgery and performed histological analysis of intraplaque haemorrhages (present/absent), neovessels, macrophages, lipid core, calcium deposits and the fibrous cap.ResultsIntraplaque haemorrhage was less frequent in the most physically active tertile (T3PA, 48%) versus T1PA (74%) and in the least sedentary tertile T1SB (50%) versus T3SB (71%). The intraplaque haemorrhage was less frequent in those who exercised more than 900 MET-min/week (59% vs 47% for >900 and <900 MET-min/week, respectively). All the other features that associate with plaque instability (eg, neovessels, macrophages, etc) did not differ by level of PA or SB.ConclusionIn this cross-sectional study of asymptomatic patients who underwent endarterectomy (i) higher reported PA, (ii) intensity of PA and (iii) lower reported SB were associated with lower prevalence of intraplaque haemorrhage. This could be a mechanism whereby PA protects against cerebrovascular disease (stroke) and death.

Initial Stress in Biomechanical Models of Atherosclerotic Plaques

2011 ◽  
Author(s):  
L. Speelman ◽  
A. C. Akyildiz ◽  
J. J. Wentzel ◽  
E. H. van Brummelen ◽  
J. Jukema ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Finite Element ◽  
Initial Stress ◽  
Atherosclerotic Plaque ◽  
Initial Stresses ◽  
Atherosclerotic Plaques ◽  
Finite Element Models ◽  
Biomechanical Models ◽  
Fibrous Cap ◽  
Stress Studies

Rupture of the cap of an atherosclerotic plaque is instigated when the stresses in the cap due to the blood pressure exceed the local cap strength. Image based computational finite element models of atherosclerotic plaques are widely used to compute stresses in the fibrous cap. These models are often based on pressurized geometries. The shape of the plaque is determined by the blood pressure at the time of imaging, and thus contains initial stresses (IS) and strains, which are generally ignored in plaque stress studies.

Comparison of two murine models of thrombosis induced by atherosclerotic plaque injury

2011 ◽  
Vol 105 (S 06) ◽  
pp. S3-S12 ◽  
Author(s):  
Béatrice Hechler ◽  
Christian Gachet
Keyword(s):  
Atherosclerotic Plaque ◽  
Plaque Rupture ◽  
Vascular Lesions ◽  
Murine Models ◽  
Atherosclerotic Lesions ◽  
Human Pathology ◽  
Rupture Model ◽  
Atherosclerotic Plaque Rupture ◽  
Collagen Receptor

SummaryArterial thrombosis occurs at sites of erosion or rupture of atherosclerotic vascular lesions. To better study the pathophysiology of this complex phenomenon, there is a need for animal models of localised thrombosis at sites of atherosclerotic lesions with closer resemblance to the human pathology as compared to commonly used thrombosis models in healthy vessels. In the present study, we describe and compare a new model of thrombosis induced by atherosclerotic plaque rupture in the carotid artery from ApoE-/- mice using a suture needle to a milder model of ultrasound-induced plaque injury. Needle injury induces atherosclerotic plaque rupture with exposure of plaque material and formation of a thrombus that is larger, nearly occlusive and more stable as compared to that formed by application of ultrasounds. These two models have common features such as the concomitant involvement of platelet activation, thrombin generation and fibrin formation, which translates into sensitivity toward both antiplatelet drugs and anticoagulants. On the other hand, they display differences with respect to the role of the platelet collagen receptor GPVI, the plaque rupture model being less sensitive to its inhibition as compared to the ultrasound-induced injury, which may be related to the amount of thrombin generated. These models represent an improvement as compared to models in healthy vessels and may help identify specific plaque triggers of thrombosis. They should therefore be useful to evaluate new antithrombotic targets.

scholarly journals Analysis of MicroRNAs Associated With Carotid Atherosclerotic Plaque Rupture With Thrombosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Nie ◽  
Fan Yang ◽  
Fang Wan ◽  
Shuxuan Jin ◽  
Jun Pu
Keyword(s):  
Carotid Artery ◽  
Atherosclerotic Plaque ◽  
Plaque Rupture ◽  
Vascular Wall ◽  
Intraplaque Hemorrhage ◽  
Control Group ◽  
Left Carotid Artery ◽  
Mirna Microarray ◽  
Post Surgery ◽  
Atherosclerotic Plaque Rupture

Atherosclerosis is a progressive vascular wall inflammatory disease, and the rupture of atherosclerotic vulnerable plaques is the leading cause of morbidity and mortality worldwide. This study intended to explore the potential mechanisms behind plaque rupture and thrombosis in ApoE knockout mice. The spontaneous plaque rupture models were established, and left carotid artery tissues at different time points (1-, 2-, 4-, 6-, 8-, 12-, and 16-week post-surgery) were collected. By the extent of plaque rupture, plaque was defined as (1) control groups, (2) atherosclerotic plaque group, and (3) plaque rupture group. Macrophage (CD68), MMP-8, and MMP-13 activities were measured by immunofluorescence. Cytokines and inflammatory markers were measured by ELISA. The left carotid artery sample tissue was collected to evaluate the miRNAs expression level by miRNA-microarray. Bioinformatic analyses were conducted at three levels: (2) vs. (1), (3) vs. (2), and again in seven time series analysis. The plaque rupture with thrombus and intraplaque hemorrhage results peaked at 8 weeks and decreased thereafter. Similar trends were seen in the number of plaque macrophages and lipids, the expression of matrix metalloproteinase, and the atherosclerotic and plasma cytokine levels. MiRNA-microarray showed that miR-322-5p and miR-206-3p were specifically upregulated in the atherosclerotic plaque group compared with those in the control group. Meanwhile, miR-466h-5p was specifically upregulated in the plaque rupture group compared with the atherosclerotic plaque group. The highest incidence of plaque rupture and thrombosis occurred at 8 weeks post-surgery. miR-322-5p and miR-206-3p may be associated with the formation of atherosclerotic plaques. miR-466h-5p may promote atherosclerotic plaque rupture via apoptosis-related pathways.

scholarly journals Development of a Collagen Fibre Remodelling Rupture Risk Metric for Potentially Vulnerable Carotid Artery Atherosclerotic Plaques

2021 ◽  
Vol 12 ◽  
Author(s):  
Milad Ghasemi ◽  
Robert D. Johnston ◽  
Caitríona Lally
Keyword(s):  
Carotid Artery ◽  
Atherosclerotic Plaque ◽  
Mechanical Response ◽  
Plaque Rupture ◽  
Collagen Fibre ◽  
Local Stress ◽  
Patient Specific ◽  
Collagen Fibres ◽  
Magnetic Resonance Imaging Mri ◽  
Risk Metric

Atherosclerotic plaque rupture in carotid arteries can lead to stroke which is one of the leading causes of death or disability worldwide. The accumulation of atherosclerotic plaque in an artery changes the mechanical properties of the vessel. Whilst healthy arteries can continuously adapt to mechanical loads by remodelling their internal structure, particularly the load-bearing collagen fibres, diseased vessels may have limited remodelling capabilities. In this study, a local stress modulated remodelling algorithm is proposed to explore the mechanical response of arterial tissue to the remodelling of collagen fibres. This stress driven remodelling algorithm is used to predict the optimum distribution of fibres in healthy and diseased human carotid bifurcations obtained using Magnetic Resonance Imaging (MRI). In the models, healthy geometries were segmented into two layers: media and adventitia and diseased into four components: adventitia, media, plaque atheroma and lipid pool (when present in the MRI images). A novel meshing technique for hexahedral meshing of these geometries is also demonstrated. Using the remodelling algorithm, the optimum fibre patterns in various patient specific plaques are identified and the role that deviations from these fibre configurations in plaque vulnerability is shown. This study provides critical insights into the collagen fibre patterns required in carotid artery and plaque tissue to maintain plaque stability.

scholarly journals Reduction of TMAO level enhances the stability of carotid atherosclerotic plaque through promoting macrophage M2 polarization and efferocytosis

2021 ◽  
Author(s):  
Weihao Shi ◽  
Yijun Huang ◽  
Zhou Yang ◽  
Liang Zhu ◽  
Bo Yu
Keyword(s):  
Carotid Artery ◽  
Atherosclerotic Plaque ◽  
Raw264.7 Cells ◽  
Carotid Atherosclerotic Plaque ◽  
Obvious Effect ◽  
Carotid Artery Plaque ◽  
Fibrous Cap ◽  
M2 Polarization ◽  
Significant Difference ◽  
The Stability

It has been demonstrated that trimethylamine N-oxide (TMAO) serves as a driver of atherosclerosis, suggesting that reduction of TMAO level might be a potent method to prevent the progression of atherosclerosis. Herein, we explored the role of TMAO in the stability of carotid atherosclerotic plaques, and disclosed the underlying mechanisms. The unstable carotid artery plaque models were established in C57/BL6 mice. L-carnitine (LCA) and methimazole (MMI) administration were applied to increase and reduce TMAO levels. Hematoxylin and eosin (H&E) staining, Sirius red , Perl’s staining, Masson trichrome staining and immunohistochemical staining with CD68 staining were used to for histopathology analysis of the carotid artery plaque. M1 and M2 macrophagocyte markers were assessed by RT-PCR to determine the polarization of RAW264.7 cells. MMI administration for 2 weeks significantly decreased the plaque area, increased the thickness of the fibrous cap and reduced the size of the necrotic lipid cores, whereas 5-week of administration of MMI induced intraplate hemorrhage. LCA treatment further deteriorated the carotid atherosclerotic plaque, but with no significant difference. In mechanism, we found that TMAO treatment impaired the M2 polarization and efferocytosis of RAW264.7 cells, with no obvious effect on the M1 polarization. In conclusion, this study demonstrated that TMAO reduction enhanced the stability of carotid atherosclerotic plaque through promoting macrophage M2 polarization and efferocytosis.

scholarly journals SP-8356, a Novel Inhibitor of CD147-Cyclophilin A Interactions, Reduces Plaque Progression and Stabilizes Vulnerable Plaques in apoE-Deficient Mice

2019 ◽  
Vol 21 (1) ◽  
pp. 95 ◽  
Author(s):  
Kisoo Pahk ◽  
Chanmin Joung ◽  
Hwa Young Song ◽  
Sungeun Kim ◽  
Won-Ki Kim
Keyword(s):  
Carotid Artery ◽  
Atherosclerotic Plaque ◽  
Plaque Rupture ◽  
Cyclophilin A ◽  
Atherogenic Diet ◽  
Therapeutic Effects ◽  
Plaque Progression ◽  
Artery Ligation ◽  
Apoe Ko Mice ◽  
Apoe Ko

Interactions between CD147 and cyclophilin A (CypA) promote plaque rupture that causes atherosclerosis-related cardiovascular events, such as myocardial infarction and stroke. Here, we investigated whether SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one), a novel drug, can exert therapeutic effects against plaque progression and instability through disruption of CD147-CypA interactions in apolipoprotein E-deficient (ApoE KO) mice. Immunocytochemistry and immunoprecipitation analyses were performed to assess the effects of SP-8356 on CD147-CypA interactions. Advanced plaques were induced in ApoE KO mice via partial ligation of the right carotid artery coupled with an atherogenic diet, and SP-8356 (50 mg/kg) orally administrated daily one day after carotid artery ligation for three weeks. The anti-atherosclerotic effect of SP-8356 was assessed using histological and molecular approaches. SP-8356 interfered with CD147-CypA interactions and attenuated matrix metalloproteinase-9 activation. Moreover, SP-8356 induced a decreased in atherosclerotic plaque size in ApoE KO mice and stabilized plaque vulnerability by reducing the necrotic lipid core, suppressing macrophage infiltration, and enhancing fibrous cap thickness through increasing the content of vascular smooth muscle cells. SP-8356 exerts remarkable anti-atherosclerotic effects by suppressing plaque development and improving plaque stability through inhibiting CD147-CypA interactions. Our novel findings support the potential utility of SP-8356 as a therapeutic agent for atherosclerotic plaque.

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