scholarly journals Inflammation during the life cycle of the atherosclerotic plaque

2021 ◽  
Author(s):  
Peter Libby
Keyword(s):  
Smooth Muscle ◽  
Life Cycle ◽  
Smooth Muscle Cells ◽  
Inflammatory Mediators ◽  
Healing Process ◽  
Muscle Cells ◽  
Endothelial Activation ◽  
Atherosclerotic Plaques ◽  
Fibrous Cap ◽  
Plaque Disruption

Abstract Inflammation orchestrates each stage of the life cycle of atherosclerotic plaques. Indeed, inflammatory mediators likely link many traditional and emerging risk factors with atherogenesis. Atheroma initiation involves endothelial activation with recruitment of leucocytes to the arterial intima, where they interact with lipoproteins or their derivatives that have accumulated in this layer. The prolonged and usually clinically silent progression of atherosclerosis involves periods of smouldering inflammation, punctuated by episodes of acute activation that may arise from inflammatory mediators released from sites of extravascular injury or infection or from subclinical disruptions of the plaque. Smooth muscle cells and infiltrating leucocytes can proliferate but also undergo various forms of cell death that typically lead to formation of a lipid-rich ‘necrotic’ core within the evolving intimal lesion. Extracellular matrix synthesized by smooth muscle cells can form a fibrous cap that overlies the lesion’s core. Thus, during progression of atheroma, cells not only procreate but perish. Inflammatory mediators participate in both processes. The ultimate clinical complication of atherosclerotic plaques involves disruption that provokes thrombosis, either by fracture of the plaque’s fibrous cap or superficial erosion. The consequent clots can cause acute ischaemic syndromes if they embarrass perfusion. Incorporation of the thrombi can promote plaque healing and progressive intimal thickening that can aggravate stenosis and further limit downstream blood flow. Inflammatory mediators regulate many aspects of both plaque disruption and healing process. Thus, inflammatory processes contribute to all phases of the life cycle of atherosclerotic plaques, and represent ripe targets for mitigating the disease.

scholarly journals Neointimal remodeling in carotid atherosclerosis: roles of matrix metalloproteinases-2 and -9 and different phenotypes of vascular smooth muscle cells

2020 ◽  
pp. 20-30
Author(s):  
Л.А. Богданов ◽  
Е.А. Великанова ◽  
Д.К. Шишкова ◽  
А.Р. Шабаев ◽  
А.Г. Кутихин
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Smooth Muscle Actin ◽  
Muscle Cells ◽  
Atherosclerotic Plaques ◽  
Double Positive ◽  
Fibrous Cap ◽  
The Media

Цель исследования - изучение распространенности и локализации сосудистых гладкомышечных клеток (СГМК) различного фенотипа в составе атеросклеротических бляшек сонной артерии, а также взаимосвязи различных клеточных популяций неоинтимы с экспрессией матриксных металлопротеиназ (ММП)-2 и ММП-9 в зависимости от степени стабильности бляшки. Методы. Проведено иммуногистохимическое исследование 16 атеросклеротических бляшек (8 клинически нестабильных и 8 стабильных), полученных при каротидной эндартерэктом в связи с гемодинамически значимым стенозом. Оценка сократительной способности СГМК проводилась при использовании метода иммуногистохимического типирования альфа-актина гладких мышц (α-SMA), синтетического, макрофагального и остеогенного фенотипов СГМК посредством типирования виметина, СВ68 и RUNX2 соответственно. Активность ремоделирования определялась посредством выявления ММП-2 и ММП-9. Результаты. Показано, что около трети каротидных бляшек характеризовались высокой экспрессией MMП-9 CD68-положительными клетками, что не коррелировало с их нестабильностью. Локализация, содержание и соотношение СГМК различного фенотипа и макрофагов значительно варьировали в зависимости от бляшки. Общей закономерностью было преимущественное послойное типирование на α-SMA в зоне интактных эластических волокон медии и, реже, в фиброзной покрышке или прилегающих участках. CD68-положительные клетки визуализировались в толще неоинтимы; некоторая их доля была колокализована с α-SMA, отражая СГМК макрофагального фенотипа. Положительное реакция на виментин наблюдалась на границе с эластическими волокнами медии, либо с основной клеточной массой неоинтимы и характеризовалась прилегающим бесклеточным экстрацеллюлярным матриксом, что свидетельствовало об активном синтезе его соответствующими клетками. Также в неоинтиме обнаруживались клетки положительные как на RUNX2 и α-SMA, так и исключительно RUNX2-положительные клетки. Заключение. Каротидные атеросклеротические бляшки характеризуются различной локализацией, содержанием и соотношением СГМК сократительного, синтетического, макрофагального и остеогенного фенотипов, при этом экспрессия ММП-2 и ММП-9 была ограничена CD68-положительными макрофагами и СГМК макрофагального фенотипа. Aim.To study prevalence and localization of different phenotypes of vascular smooth muscle cells (VSMCs) in carotid atherosclerotic plaques and to examine expression of matrix metalloproteinase (MMP)-2 and MMP-9 in relation to different cell populations within the neointima. Methods. The immunohistochemical examination was performed on 16 atherosclerotic plaques (8 unstable and 8 stable) excised during carotid endarterectomy for critical stenosis. VSMCs of contractile, synthetic, macrophagic, and osteogenic phenotypes were identified by staining for α-smooth muscle actin (α-SMA), vimentin, CD68, and RUNX2, respectively. Activity of neointimal remodeling was assessed by staining for MMP-2 and MMP-9. Results. Approximately one-third of atherosclerotic plaques was positively stained for MMP-9 exclusively expressed in CD68-positive cells, which however, did not correlate with plaque ruptures. Localization, content, and ratio of different VSCM phenotypes significantly varied in different plaques. Positive α-SMA staining was found mainly in the intact media and fibrous cap. In contrast, both CD68-positive and CD68/α-SMA double-positive cells were detected within the neointima but not in the media. Vimentin was expressed in the neointima between the medial layers and fibrous cap near the acellular extracellular matrix suggesting its active production by mesenchymal cells. Both RUNX2- and RUNX2 α-SMA double-positive cells indicative of VSMC osteogenic differentiation were also observed in the neointima. Conclusion. Carotid atherosclerotic plaques contained VSMCs of all phenotypes, which were differentially localized within the neointima; however, the MMP-2 and MMP-9 expression was restricted to CD68-positive macrophages and CD68/α-SMA-positive VSMCs of the macrophagal phenotype.

scholarly journals Maintenance of AMPK activation by metformin is beneficial for suppressing the progress of diabetes-accelerated atherosclerosis via inhibition of vascular smooth muscle cells migration

2020 ◽  
Author(s):  
Yi Yan ◽  
Ting Li ◽  
Zhonghao Li ◽  
Mingyuan He ◽  
Dejiang Wang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
High Fat Diet ◽  
Muscle Cells ◽  
Atherosclerotic Plaques ◽  
Ampk Activation ◽  
High Fat ◽  
Accelerated Atherosclerosis

Abstract Background: Our previous work revealed that augmented AMPK activation inhibit cell migration by phosphorylating its substrate Pdlim5. As medial VSMCs contribute to the major composition of atherosclerotic plaques, a hypothesis is raised that modulation of AMPK-Pdlim5 signal pathway could retard the development of atherosclerosis through inhibiting migration of VSMCs. Therefore, we initiate the present study to investigate whether AMPK agonist like metformin is beneficial for suppressing diabetes-accelerated atherosclerosis in a diabetic mouse model induced by streptozotocin and high fat diet.Methods: For cell experiment, vascular smooth muscle cells (VSMCs) were overexpressed flag fused Pdlim5 and Pdlim5 mutant. Then the engineered VSMCs were introduced with metformin or control drug before determination of phosphorylated Pdlim5 with immunoblotting. For animal work, 8-week-old male ApoE−/−mice were induced diabetes with streptozotocin and then were randomly divided into 8 groups: control group, metformin hydrochloride (300 mg/kg/day) group, wildtype-Pdlim5 (Pdlim5 WT) carried adenovirus (Ad) group, Ad Pdlim5 WT and Met group, Ad Pdlim5 S177A group, Ad Pdlim5 S177A and Met group, Ad Pdlim5 S177D group, Ad Pdlim5 S177D and Met group. All mice were fed with high fat diet after virus infection. At the end, mice were sacrificed to observe atherosclerotic plaques and deposition of VSMCs in plaques. Moreover, 12–15-week-old Myh11-cre-EGFP male mice were accepted ligation of the left carotid artery and randomly divided into control and metformin treatment group. Finally, the injured vessel of Myh11-cre-EGFP mice were isolated to analyze the relationship between AMPK activation and neointima formation.Results: It was found that AMPK directly phosphorylate Pdlim5 at Ser177 in vitro, and metformin, an AMPK agonist, could induce phosphorylation of Pdlim5 indirectly and inhibition of cell migration as a result. Exogenous expression of phosphomimetic S177D-Pdlim5 inhibits lamellipodia formation and migration in VSMCs. It was also demonstrated that VSMCs contribute to the major composition of injury-induced neointimal lesions, while metformin could alleviate the occlusion of carotid artery in a wire-injury mice model. In order to investigate the function of AMPK-Pdlim5 pathway in the context of pathological condition, ApoE−/− male mice were divided randomly into control, streptozocin and high fat diet-induced diabetes mellitus, STZ + HFD together with metformin or Pdlim5 mutant carried adenovirus treatment groups. The results showed increased plasma lipids and aggravated vascular smooth muscle cells infiltration into the atherosclerotic lesion in diabetic mice compared with control mice. However, metformin alleviated diabetes-induced metabolic disorders and atherosclerosis, as well as decreased VSMCs infiltration in atherosclerotic plaques, while Pdlim5 phospho-abolished mutant carried adenovirus S177A-Pdlim5 undermine this protective function.Conclusions: The activation of AMPK-Pdlim5 pathway by chemicals like Metformin could inhibit formation of migratory machine of VSMCs and alleviate the progress of atherosclerotic plaques in diabetic mice. The maintenance of AMPK activity is beneficial for suppressing diabetes-accelerated atherosclerosis or metabolic syndrome.

Statins inhibit in vitro calcification of human vascular smooth muscle cells induced by inflammatory mediators

2004 ◽  
Vol 93 (5) ◽  
pp. 1011-1019 ◽  
Author(s):  
Akane Kizu ◽  
Atsushi Shioi ◽  
Shuichi Jono ◽  
Hidenori Koyama ◽  
Yasuhisa Okuno ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Inflammatory Mediators ◽  
Muscle Cells

scholarly journals The Role of Smooth Myocytes and Macrophages in Development of Complicated Forms of Arterial Atherosclerosis

Kardiologiia ◽  
2019 ◽  
Vol 59 (1) ◽  
pp. 57-61
Author(s):  
S. S. Todorov
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Immunohistochemical Study ◽  
Muscle Cells ◽  
External Carotid ◽  
Atherosclerotic Plaques ◽  
Unstable Atherosclerotic Plaque ◽  
Immunohistochemical Studies ◽  
Smooth Myocytes

Purpose:to conduct morphohistochemical and immunohistochemical study of arterial unstable atherosclerotic plaques for assessment of the state of smooth muscle cells (SMC) and macrophages.Materials and methods.The surgical material of the peripheral arteries (femoral, popliteal, external carotid) was obtained from 50 patients aged over 60 years, followed by morphohistochemical, immunohistochemical studies.Results.Hyperplasia of secretory smooth muscle cells (SMC), and new formation of thin-walled capillary vessels was noted in unstable atherosclerotic plaques. Macrophagic infiltration was detected in the intima of arteries, in places of accumulation of foam cells.Conclusion.Unstable atherosclerotic plaque is a cellular-intercellular process with the participation of lipids, macrophages, and with predominance of SMC and newly formed vessels.

scholarly journals Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

2020 ◽  
Vol 127 (11) ◽  
pp. 1437-1455 ◽  
Author(s):  
Marie A.C. Depuydt ◽  
Koen H.M. Prange ◽  
Lotte Slenders ◽  
Tiit Örd ◽  
Danny Elbersen ◽  
...  
Keyword(s):  
T Cells ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Single Cell ◽  
Association Studies ◽  
Myeloid Cells ◽  
Muscle Cells ◽  
Atherosclerotic Plaques ◽  
Genome Wide Association Studies ◽  
Mesenchymal Transition

Rationale: Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed. Objective: Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis. Methods and Results: We performed single-cell RNA and single-cell ATAC sequencing on human carotid atherosclerotic plaques to define the cells at play and determine their transcriptomic and epigenomic characteristics. We identified 14 distinct cell populations including endothelial cells, smooth muscle cells, mast cells, B cells, myeloid cells, and T cells and identified multiple cellular activation states and suggested cellular interconversions. Within the endothelial cell population, we defined subsets with angiogenic capacity plus clear signs of endothelial to mesenchymal transition. CD4 + and CD8 + T cells showed activation-based subclasses, each with a gradual decline from a cytotoxic to a more quiescent phenotype. Myeloid cells included 2 populations of proinflammatory macrophages showing IL (interleukin) 1B or TNF (tumor necrosis factor) expression as well as a foam cell-like population expressing TREM2 (triggering receptor expressed on myeloid cells 2) and displaying a fibrosis-promoting phenotype. ATACseq data identified specific transcription factors associated with the myeloid subpopulation and T cell cytokine profiles underlying mutual activation between both cell types. Finally, cardiovascular disease susceptibility genes identified using public genome-wide association studies data were particularly enriched in lesional macrophages, endothelial, and smooth muscle cells. Conclusions: This study provides a transcriptome-based cellular landscape of human atherosclerotic plaques and highlights cellular plasticity and intercellular communication at the site of disease. This detailed definition of cell communities at play in atherosclerosis will facilitate cell-based mapping of novel interventional targets with direct functional relevance for the treatment of human disease.

Abstract 353: Elastase-Activated Stress Response of Vascular Cells

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Irina Grechowa ◽  
Bernhard Dorweiler ◽  
Anja Wallrath ◽  
Sven Horke
Keyword(s):  
Flow Cytometry ◽  
Endothelial Cells ◽  
Cell Death ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Apoptotic Cell ◽  
Muscle Cells ◽  
Apoptotic Cell Death ◽  
Atherosclerotic Plaques ◽  
Vascular Cells

Introduction: Rupture of atherosclerotic plaques is the most abundant cause for stroke. The serine protease elastase plays an important role as it induces death of endothelial cells (ECs) and smooth muscle cells (SMCs), and breaks down the fibrous cap of atherosclerotic plaques. Increased elastase concentrations were found in patients with symptomatic stenosis. We previously showed that elastase activates the endoplasmic reticulum (ER) stress signaling pathway unfolded protein response (UPR) in rupture-prone plaques of human carotid artery. However, signaling pathways elicited by elastase in vascular cells were largely unknown. We hypothesized that elastase induces cell-type dependent responses in ECs, SMCs and macrophages (M[[Unable to Display Character: &#1060;]]). Methods and Results: Different forms of cell death and UPR activation were analyzed in primary and immortalized endothelial cells, coronary artery smooth muscle cells (HCASMCs) and M[[Unable to Display Character: &#1060;]] after treatment with human neutrophil elastase. To discriminate between the involved cell death types, three independent assays were performed. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-assay by confocal microscopy (p < .01), caspase3/7 activity by chemiluminescence-assays (p < .01) and cell-cycle analysis by flow cytometry revealed that an autophagic/apoptotic cell death was induced upon elastase treatment. This appeared specific for ECs, as it was absent in M[[Unable to Display Character: &#1060;]]. Necrosis (as determined by chemiluminescent lactate dehydrogenase-release assay) and necroptosis (assessed by flow cytometry) played only minor roles. The involvement of the UPR was investigated on protein and / or gene expression level. The high levels of GRP78, phospho-PERK, phospho-eIF2α, spliced XBP1 and CHOP indicate a strongly activated UPR that may give rise to the subsequent induced autophagic/apoptotic cell death. Conclusion: Elastase plays a significant role in plaque stability and cell survival likely through activation of a UPR/autophagic type of endothelial cell death. This may explain underlying molecular links how elastase destabilizes atherosclerotic plaques.

Sign in / Sign up

Export Citation Format

Share Document