scholarly journals Implication of miR-155-5p and miR-143-3p in the Vascular Insulin Resistance and Instability of Human and Experimental Atherosclerotic Plaque

2021 ◽  
Author(s):  
Paula González-López ◽  
Carla Ares-Carral ◽  
Andrea R. López-Pastor ◽  
Jorge Infante-Menéndez ◽  
Tamara Gonzalez-Illanes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Smooth Muscle ◽  
Atherosclerotic Plaques ◽  
Vascular Endothelial ◽  
Standard Type ◽  
Plaque Instability ◽  
Atherosclerotic Lesions ◽  
Human Atherosclerosis ◽  
Factor Type ◽  
First World

Abstract Background: Cardiovascular diseases (CVDs) are the main cause of death in first world countries, being atherosclerosis, a recurring process underlying their apparition. MicroRNAs (miRNAs) are small non-coding RNAs that modulate the expression of their target proteins. Therefore, they have emerged as key players in diseases like cancer, diabetes, or CVDs.Methods: Apolipoprotein E-deficient (ApoE-/-) mice fed a standard type diet (STD) or high fat diet (HFD) for 8 and 18 weeks was compared to wild type (WT) STD-fed groups for the same time. 18 miRNAs were selected (from pubmed and GEO database) for their possible role in promoting atherosclerosis and were analysed by RT-qPCR in the aorta from the experimental model. Afterwards, the altered miRNAs in the aorta from 18 weeks-ApoE-/- mice were studied in human healthy aortic samples, human early aortic atherosclerotic plaques, and human advanced carotid atherosclerotic plaques. Results: From the 18 miRNAs analyzed, miR-155-5p was overexpressed and miR-143-3p was downregulated in mouse and human atherosclerotic lesions. In addition, a significant decrease of protein kinase B (AKT), target of miR-155-5p, and an increase of insulin-like growth factor type II receptor (IGF-IIR), target of miR-143-3p, were noted in aortic roots from ApoE-/- mice and in carotid plaques from ACA patients. Finally, both miRNAs were studied on vascular endothelial and smooth muscle cell lines. The overexpression of miR-155-5p reduced AKT levels and its phosphorylation in vascular smooth muscle cells. MiR-143-3p overexpression decreased IGF-IIR reducing apoptosis in vascular cells. Conclusions: Our results suggest that miR-155-5p and miR-143-3p may be implicated in insulin resistance and plaque instability by the modulation of their targets AKT and IGF-IIR, contributing to the progression of experimental and human atherosclerosis.Trial Registration: authorization numbers PFS09-007 and PI1442016.

Abstract 593: Hypoxia is Present in the Macrophage-rich Center of Human Carotid Atherosclerotic Plaques

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Judith C Sluimer ◽  
Job L van Wanroij ◽  
Matthijs Groeneweg ◽  
Bradly G Wouters ◽  
Mat J Daemen ◽  
...  
Keyword(s):  
Hypoxic Exposure ◽  
Atherosclerotic Plaques ◽  
List Type ◽  
Strongly Correlated ◽  
Plaque Instability ◽  
Atherosclerotic Lesions ◽  
Hypoxia Marker ◽  
Diffuse Intimal Thickening ◽  
Human Atherosclerosis ◽  
The Media

Intraplaque neovascularization is linked to plaque instability and thought to be stimulated by hypoxia. However, hypoxia has not been demonstrated yet in human atherosclerosis. The hypoxia marker pimonidazole was administrated intravenously 2 hours prior to carotid endarterectomy in 6 symptomatic patients to evaluate the presence of hypoxia. Subsequent immunohistochemistry of the operatively removed atherosclerotic plaques demonstrated the presence of hypoxia, especially in the macrophage-rich center of the lesions. Notably, two hypoxic gradients were observed: hypoxia was very strong in the center of the plaque, but almost absent close to the main artery lumen and in the media. hypoxia was most intense in segments with advanced atheroma and almost absent in segments containing only diffuse intimal thickening. Hypoxia strongly correlated with CD68 immunoreactivity (ρ= 0.7, p=0.000), neovascularization (ρ= 0.6, p=0.000) and the presence of a thrombus (ρ= 0.4, p=0.009). In addition, hypoxia co-localized with expression of HIF1α and VEGF . To exclude that pimonidazole immunoreactivity in the atherosclerotic plaque was the result of surgery-induced ischemia, arterial wall segments were collected at two time-points: directly after incision of the carotid artery and directly following excision of the plaque. Pimonidazole immunoreactivity in these two pieces was not different, suggesting that hypoxia and pimonidazole adducts were already present in the plaques before surgery . To show that pimonidazole reactivity was hypoxia-specific and independent of reactive oxygen species, human THP-1 macrophages were exposed to normoxia (20% O 2 ), hypoxia (0.2% O 2 ) and/or H 2 O 2 (100 μM) in the presence of pimonidazole. Indeed, flow cytometry only showed pimonidazole-positive cells after hypoxic exposure. This is the first study proving direct evidence of the existence of hypoxia in advanced human atherosclerotic lesions, most prominently in the macrophage-rich center. Also, hypoxia was associated with the expression of HIF1α, VEGF and intraplaque microvessels, suggesting its involvement in the regulation of human intraplaque neovascularization.

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

Regression of atherosclecrotic lesions: medicinal and alimentary factors

2016 ◽  
Vol 94 (9) ◽  
pp. 668-671
Author(s):  
S. V. Magaeva ◽  
A. A. Kubatiev ◽  
E. A. Shirokov ◽  
V. B. Simonenko
Keyword(s):  
Smooth Muscle ◽  
Clinical Studies ◽  
Cerebral Arteries ◽  
Foam Cells ◽  
Atherosclerotic Plaques ◽  
Long Period ◽  
Atherosclerotic Lesions

The article reports results of clinical studies aimed to elucidate the influence of medicines on the size and density of atherosclerotic plaques in the walls of coronary and cerebral arteries. The phenomenon of regression of atherosclerotic lesions in the survivors of Leningrad siege during a long period of starvation is analyzed. The influence of inhibitors of angiotensinconverting enzyme on apoptosis of smooth muscle and foam cells of atherosclerotic plaques in the sanological mechanisms of atherosclerosis is discussed. The concept of natural regression of atherosclerosis is formulated and the necessity of development of the methods for is pharmacological activation are formulated.

scholarly journals AMPA-Type Glutamate Receptors Associated With Vascular Smooth Muscle Cell Subpopulations in Atherosclerosis and Vascular Injury

2021 ◽  
Vol 8 ◽  
Author(s):  
Alessandro L. Gallina ◽  
Urszula Rykaczewska ◽  
Robert C. Wirka ◽  
April S. Caravaca ◽  
Vladimir S. Shavva ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Glutamate Receptors ◽  
Mrna Level ◽  
Phenotypic Modulation ◽  
Atherosclerotic Lesions ◽  
Clinical Events ◽  
Human Atherosclerosis ◽  
Type Receptor ◽  
Human Carotid

Objectives and Aims: Vascular smooth muscle cells (VSMCs) are key constituents of both normal arteries and atherosclerotic plaques. They have an ability to adapt to changes in the local environment by undergoing phenotypic modulation. An improved understanding of the mechanisms that regulate VSMC phenotypic changes may provide insights that suggest new therapeutic targets in treatment of cardiovascular disease (CVD). The amino-acid glutamate has been associated with CVD risk and VSMCs metabolism in experimental models, and glutamate receptors regulate VSMC biology and promote pulmonary vascular remodeling. However, glutamate-signaling in human atherosclerosis has not been explored.Methods and Results: We identified glutamate receptors and glutamate metabolism-related enzymes in VSMCs from human atherosclerotic lesions, as determined by single cell RNA sequencing and microarray analysis. Expression of the receptor subunits glutamate receptor, ionotropic, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA)-type subunit 1 (GRIA1) and 2 (GRIA2) was restricted to cells of mesenchymal origin, primarily VSMCs, as confirmed by immunostaining. In a rat model of arterial injury and repair, changes of GRIA1 and GRIA2 mRNA level were most pronounced at time points associated with VSMC proliferation, migration, and phenotypic modulation. In vitro, human carotid artery SMCs expressed GRIA1, and selective AMPA-type receptor blocking inhibited expression of typical contractile markers and promoted pathways associated with VSMC phenotypic modulation. In our biobank of human carotid endarterectomies, low expression of AMPA-type receptor subunits was associated with higher content of inflammatory cells and a higher frequency of adverse clinical events such as stroke.Conclusion: AMPA-type glutamate receptors are expressed in VSMCs and are associated with phenotypic modulation. Patients suffering from adverse clinical events showed significantly lower mRNA level of GRIA1 and GRIA2 in their atherosclerotic lesions compared to asymptomatic patients. These results warrant further mapping of neurotransmitter signaling in the pathogenesis of human atherosclerosis.

Abstract 14463: A Novel Mouse Model of the Effect of Acute Kidney Injury on Neointima After Injury of an Artery

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yanpeng Diao ◽  
Yuanqing Lu ◽  
Mark S Segal
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Smooth Muscle ◽  
Mouse Model ◽  
Kidney Injury ◽  
Permanent Change ◽  
Atherosclerotic Lesions ◽  
Increased Risk ◽  
Renal Vessels ◽  
Human Atherosclerosis

Introduction and Hypothesis: Acute kidney injury (AKI), even if renal function returns to normal, is associated with an increased risk of cardiovascular disease. We have developed a novel, mouse model that allows investigation into the mechanism of this clinical scenario. We hypothesized that AKI, particular at a severe level, may result in a permanent change to the vasculature that would promote atherosclerotic lesions. Methods and Results: AKI was induced by clamping the bilateral renal vessels of male, C57/BL mice for 28-30 minutes. The creatinine (Cr) was measured two days later to determine the severity of the AKI. An increase in the Cr of at least three-fold, was defined as severe damage, corresponding to Kidney Disease Improving Global Outcomes (KDIGO) AKI Stage 3. If the Cr increased less than three times, this was defined as mild/moderate AKI. Ten weeks after AKI, the Cr was measured to determine if renal function returned to baseline and the femoral artery was injured by repeated introduction of a guidewire. After four weeks, the animals were sacrificed and the neointima lesions were analyzed. Immunohistochemistry for smooth muscle myosin heavy chain revealed that the neointima was mostly composed of smooth muscle cells. The re-endothelialization was almost complete, as determined by anti-CD31 staining. More interestingly, the narrowing rate of the injured artery in animals who suffered severe AKI was higher than in the mild/moderate AKI animals (53.2% vs 27.2%; P= 0.04). There is no difference between the sham-AKI animals and the mild/moderate AKI animals (34.9 % vs 27.2%, see picture). Conclusions: Severe AKI induces a permanent change to the vasculature and/or the immune cells that hastens the development of neointima even after renal function recovers. This work has implications for the development of human atherosclerosis in the clinical setting after AKI. Potential mechanisms for this increased propensity will be discussed.

Expression of cytokeratin 8 in human aortic smooth muscle cells

1991 ◽  
Vol 261 (4) ◽  
pp. 72-77 ◽  
Author(s):  
Marina A. Glukhova ◽  
Boris V. Shekhonin ◽  
Howard Kruth ◽  
Victor E. Koteliansky
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Prenatal Development ◽  
Atherosclerotic Plaques ◽  
Immunofluorescence Method ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Atherosclerotic Lesions

An immunofluorescence method was used to study the expression of cytokeratin 8 in human aortic smooth muscle cells (SMCs) during prenatal development and in atherosclerotic plaques. Aortic SMCs from a 10-wk-old fetus contained cytokeratin 8 in additional to vimentin and a small amount of desmin, whereas, in the cells from a 25-wk-old fetus, cytokeratin 8 was not detected. Cytokeratin 8 was found in the SMCs from intimal thickenings, fatty streaks, and atherosclerotic fibrous plaques. Clusters of cytokeratin 8-positive cells were more abundant in rather advanced lesions (fibrous plaques) that contained at least some amount of lipid. Expression of cytokeratin 8 in the cells of human atherosclerotic lesions probably reflects general rearrangement of gene expression in the intimal cells. cytodifferentiation; fetal phenotype; lipid accumulation

scholarly journals SIRT6 Protects Smooth Muscle Cells from Senescence and Reduces Atherosclerosis

2020 ◽  
Author(s):  
Mandy Grootaert ◽  
Alison Finigan ◽  
Nichola Figg ◽  
Anna Katarzyna Uryga ◽  
Martin Bennett
Keyword(s):  
Dna Damage ◽  
Smooth Muscle ◽  
Ubiquitin Ligase ◽  
Oxidative Dna Damage ◽  
Telomere Maintenance ◽  
Atherosclerotic Plaques ◽  
Dependent Manner ◽  
Plaque Instability ◽  
Damage Response ◽  
Human And Mouse

Rationale: Vascular smooth muscle cell (VSMC) senescence promotes atherosclerosis and features of plaque instability, in part through lipid-mediated oxidative DNA damage and telomere dysfunction. Sirtuin 6 (SIRT6) is a nuclear deacetylase involved in DNA damage response signaling, inflammation and metabolism; however, its role in regulating VSMC senescence and atherosclerosis is unclear. Objective: We examined SIRT6 expression in human VSMCs (hVSMCs), the role, regulation and downstream pathways activated by SIRT6, and how VSMC SIRT6 regulates atherogenesis. Methods and Results: SIRT6 protein, but not mRNA, expression was markedly reduced in VSMCs in human and mouse atherosclerotic plaques, and in hVSMCs derived from plaques or undergoing replicative or palmitate-induced senescence vs. healthy aortic VSMCs. The ubiquitin ligase CHIP promoted SIRT6 stability, but CHIP expression was reduced in human and mouse plaque VSMCs and by palmitate in a p38- and c-Jun N-terminal kinase-dependent manner. SIRT6 bound to telomeres, while SIRT6 inhibition using shRNA or a deacetylase-inactive mutant (SIRT6 H133Y ) shortened hVSMC lifespan and induced senescence, associated with telomeric H3K9 hyperacetylation and 53BP1 binding, indicative of telomere damage. In contrast, SIRT6 overexpression preserved telomere integrity, delayed cellular senescence, and reduced inflammatory cytokine expression and changes in VSMC metabolism associated with senescence. SIRT6, but not SIRT6 H133Y , promoted proliferation and lifespan of mouse VSMCs, and prevented senescence-associated metabolic changes. ApoE -/- mice were generated that overexpress SIRT6 or SIRT6H133Y in VSMCs only. SM22alpha-hSIRT6/ApoE -/- mice had reduced atherosclerosis, markers of senescence and inflammation compared to littermate controls, while plaques of SM22alpha-hSIRT6 H133Y /ApoE -/- mice showed increased features of plaque instability. Conclusions: SIRT6 protein expression is reduced in human and mouse plaque VSMCs and is positively regulated by CHIP. SIRT6 regulates telomere maintenance and VSMC lifespan, and inhibits atherogenesis, all dependent on its deacetylase activity. Our data shows that endogenous SIRT6 deacetylase is an important and unrecognized inhibitor of VSMC senescence and atherosclerosis.

scholarly journals Possibilities of Ultrasound Dopplerography in Detecting Instability of Atherosclerotic Plaque of Carotid Arteries

2019 ◽  
Vol 6 (3) ◽  
pp. 36-43
Author(s):  
D. E. Zaitsev ◽  
G. E. Trufanov
Keyword(s):  
Atherosclerotic Plaque ◽  
Carotid Arteries ◽  
Imaging Techniques ◽  
Detailed Examination ◽  
Atherosclerotic Plaques ◽  
Imaging Method ◽  
Plaque Instability ◽  
Atherosclerotic Lesions ◽  
Ischemic Attack ◽  
Design And Methods

Background. Studying the possibilities of ultrasound diagnosis of atherosclerotic lesions of the carotid arteries to determine the treatment tactics of patients with various types of atherosclerotic plaques.Objective. Assessment of the possibilities of ultrasonic triplex research in identifying signs of instability of atherosclerotic plaques of the carotid arteries.Design and methods. The study included 360 patients aged from 28 to 95 years old who were admitted to the St. Petersburg State Budgetary Health Institution “Mariinskaya Hospital” with diagnoses of transient ischemic attack and acute cerebrovascular accident. All patients underwent an ultrasound visualization of the brachiocephalic arteries. Results. Most patients had atherosclerotic plaques of the carotid arteries with a stenosis of up to 75 % and had signs of instability with varying degrees of severity (according to triplex ultrasound). However, it was not possible to reliably assess the presence of hemorrhage in the plaque using a single imaging method.Conclusion. The data obtained indicate the complexity and ambiguity of the studied question. Further detailed examination of the signs of atherosclerotic plaque instability is required using various diagnostic imaging techniques.

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