Subendothelial Accumulation Research Articles

Non-toxic concentrations of cadmium accelerate subendothelial retention of atherogenic lipoproteins in humanized atherosclerosis-susceptible mice

Aim: Cadmium is an important risk factor for cardiovascular disease (CVD). However, the underlying mechanism(s) are unclear. Cadmium has been shown to increase proteoglycan synthesis in vitro. Because proteoglycans mediate a critical step in atherosclerosis by trapping apoB-containing lipoproteins in the artery wall, we hypothesized that cadmium can increase proteoglycan mediated LDL binding and thereby promote subendothelial LDL accumulation. Here we tested the hypothesis that cadmium enhances the subendothelial accumulation of atherogenic lipoproteins in the setting of intimal hyperplasia and modest hypercholesterolemia.

Targeting mannose receptor expression on macrophages in atherosclerotic plaques of apolipoprotein E-knockout mice using 111In-tilmanocept

BackgroundAtherosclerotic plaque phenotypes are classified based on the extent of macrophage infiltration into the lesions, and the presence of certain macrophage subsets might be a sign for plaque vulnerability. The mannose receptor (MR) is over-expressed in activated macrophages. Tilmanocept is a tracer that targets MR and is approved in Europe and the USA for the detection of sentinel lymph nodes. In this study, our aim was to evaluate the potential of 111In-labelled tilmanocept for the detection of MR-positive macrophages in atherosclerotic plaques of apolipoprotein E-knockout (ApoE-KO) mouse model.MethodsTilmanocept was labelled with 111In. The labelling stability and biodistribution of the tracer was first evaluated in control mice (n = 10) 1 h post injection (p.i.). For in vivo imaging studies, 111In-tilmanocept was injected into ApoE-KO (n = 8) and control (n = 8) mice intravenously (i.v.). The mice were scanned 90 min p.i. using a dedicated animal SPECT/CT. For testing the specificity of 111In-tilmanocept uptake in plaques, a group of ApoE-KO mice was co-injected with excess amount of non-labelled tilmanocept. For ex vivo imaging studies, the whole aortas (n = 9 from ApoE-KO and n = 4 from control mice) were harvested free from adventitial tissue for Sudan IV staining and autoradiography. Cryosections were prepared for immunohistochemistry (IHC).Results111In radiolabelling of tilmanocept provided a yield of greater than 99%. After i.v. injection, 111In-tilmanocept accumulated in vivo in MR-expressing organs (i.e. liver and spleen) and showed only low residual blood signal 1 h p.i. MR-binding specificity in receptor-positive organs was demonstrated by a 1.5- to 3-fold reduced uptake of 111In-tilmanocept after co-injection of a blocking dose of non-labelled tilmanocept. Focal signal was detected in atherosclerotic plaques of ApoE-KO mice, whereas no signal was detected in the aortas of control mice. 111In-tilmanocept uptake was detected in atherosclerotic plaques on autoradiography correlating well with Sudan IV-positive areas and associating with subendothelial accumulations of MR-positive macrophages as demonstrated by IHC.ConclusionsAfter i.v. injection, 111In-tilmanocept accumulated in MR-expressing organs and was associated with only low residual blood signal. In addition, 111In-tilmanocept uptake was detected in atherosclerotic plaques of mice containing MR-expressing macrophages suggesting that tilmanocept represents a promising tracer for the non-invasive detection of macrophages in atherosclerotic plaques.

2016 Russell Ross Memorial Lecture in Vascular Biology: Molecular-Cellular Mechanisms in the Progression of Atherosclerosis.

Atherosclerosis is initiated by the subendothelial accumulation of apoB-lipoproteins, which initiates a sterile inflammatory response dominated by monocyte-macrophages but including all classes of innate and adaptive immune cells. These inflammatory cells, together with proliferating smooth muscle cells and extracellular matrix, promote the formation of subendothelial lesions or plaques. In the vast majority of cases, these lesions do not cause serious clinical symptoms, which is due in part to a resolution-repair response that limits tissue damage. However, a deadly minority of lesions progress to the point where they can trigger acute lumenal thrombosis, which may then cause unstable angina, myocardial infarction, sudden cardiac death, or stroke. Many of these clinically dangerous lesions have hallmarks of defective inflammation resolution, including defective clearance of dead cells (efferocytosis), necrosis, a defective scar response, and decreased levels of lipid mediators of the resolution response. Efferocytosis is both an effector arm of the resolution response and an inducer of resolution mediators, and thus its defect in advanced atherosclerosis amplifies plaque progression. Preclinical causation/treatment studies have demonstrated that replacement therapy with exogenously administered resolving mediators can improve lesional efferocytosis and prevent plaque progression. Work in this area has the potential to potentiate the cardiovascular benefits of apoB-lipoprotein-lowering therapy.

The morphological changes in the myocardial tissue after sudden cardiac death from alcoholic cardiomyopathy

This paper was designed to report the results of the retrospective analysis of the protocols of 180 forensic medical autopsy sections stored in the archives of Sankt-Petersburg Bureau of Forensic Medical Expertise and the data of the histological studies of myocardial tissues obtained after sudden cardiac death from alcoholic cardiomyopathy. The study revealed the following most pathognomonic histological criteria for alcoholic heart lesions: the alternation of hypertrophic and atrophic cardiomyocytes in the state of severe parenchymatous degeneration, pronounced mesenchymal fatty dystrophy in combination with pathological changes of the vascular walls (vascular wall plasmatization), sub-endothelial accumulation of the PAS-positive tissue compounds, microcirculatory disorders in the form of erythrocyte stasis with the manifestations of the blood "sludge" phenomenon, and precapillary fibrosis. The signs of severe parenchymatous and stromal vascular dystrophy of the myocardial histohematic barrier (HHB) are supposed to reflect the toxic effects of ethanol and its metabolites that are directly involved in the mechanisms underlying the disturbances of intracellular metabolism and dyscirculatory events leading to the development of heart muscle hypoxia.

SIV/SHIV Infection Triggers Vascular Inflammation, Diminished Expression of Krüppel-like Factor 2 and Endothelial Dysfunction.

Human immunodeficiency virus (HIV) infection is associated with increased risk of thromboembolic and cardiovascular comorbid conditions. Although systemic inflammation is linked to cardiovascular risk, direct evidence of vascular inflammation and endothelial dysfunction is lacking. We examined by immunofluorescence microscopy thoracic aortas from 16 simian immunodeficiency virus (SIV)- or simian-human immunodeficiency virus (SHIV)-infected and 16 uninfected rhesus macaques. Focal endothelial proliferation and subendothelial inflammatory cells were found in sections of all infected animals, compared with minimal changes in sections from the 16 uninfected controls. In the infected animals, we detected increased endothelial levels of bacterial 16s ribosomal DNA as well as increased subendothelial accumulation of CD68(+) monocytes/macrophages (P< .001) and CD8(+) T lymphocytes (P< .001). Endothelial dysfunction was manifested by decreased levels of endothelial nitric oxide synthase (P< .005) and Krüppel-like factor 2 (KLF2) (P< .005). KLF2 expression was decreased in primary human aortic endothelial cells exposed to bacterial lipopolysaccharide or to oxidized low-density lipoprotein in vitro, and this could be prevented by simvastatin. SIV and SHIV infection lead to endothelial inflammation, dysfunction, and decreased KLF2 expression reflecting early atherosclerotic changes. Translocated bacterial components and lipid oxidation products may induce endothelial dysfunction in HIV infection that could be prevented by statin treatment.

Regulatory T cells in atherosclerosis: critical immune regulatory function and therapeutic potential.

Atherosclerosis is a chronic inflammatory disease that is mediated by innate and adaptive immune responses. The disease is characterized by sub-endothelial accumulation and modification of lipids in the artery wall triggering an inflammatory reaction which promotes lesion progression and eventual plaque rupture, thrombus formation, and the respective clinical sequelae such as myocardial infarction or stroke. During the past decade, T-cell-mediated immune responses, especially control of pro-inflammatory signals by regulatory T cells (Tregs), have increasingly attracted the interest of experimental and clinical researchers. By suppression of T cell proliferation and secretion of anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-β, Tregs exert their atheroprotective properties. Atherosclerosis-prone, hyperlipidemic mice harbor systemically less Tregs compared to wild-type mice, suggesting an imbalance of immune cells which affects local and systemic inflammatory and potentially metabolic processes leading to atherogenesis. Restoring or increasing Treg frequency and enhancing their suppressive capacity by various modulations may pose a promising approach for treating inflammatory conditions such as cardiovascular diseases. In this review, we briefly summarize the immunological basics of atherosclerosis and introduce the role and contribution of different subsets of T cells. We then discuss experimental data and current knowledge pertaining to Tregs in atherosclerosis and perspectives on manipulating the adaptive immune system to alleviate atherosclerosis and cardiovascular disease.

Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility.

Leukocyte migration is critical for the infiltration of monocytes and accumulation of monocyte-derived macrophages in inflammation. Considering that Hck and Fgr are instrumental in this process, their impact on atherosclerosis and on lesion inflammation and stability was evaluated. Hematopoietic Hck/Fgr-deficient, LDLr(-/-) chimeras, obtained by bone marrow transplantation, had smaller but, paradoxically, less stable lesions with reduced macrophage content, overt cap thinning, and necrotic core expansion as the most prominent features. Despite a Ly6C(high)-skewed proinflammatory monocyte phenotype, Hck/Fgr deficiency led to disrupted adhesion of myeloid cells to and transmigration across endothelial monolayers in vitro and atherosclerotic plaques in vivo, as assessed by intravital microscopy, flow cytometry, and histological examination of atherosclerotic arteries. Moreover, Hck/Fgr-deficient macrophages showed blunted podosome formation and mesenchymal migration capacity. In consequence, transmigrated double-knockout macrophages were seen to accumulate in the fibrous cap, potentially promoting its focal erosion, as observed for double-knockout chimeras. The hematopoietic deficiency of Hck and Fgr led to attenuated atherosclerotic plaque formation by abrogating endothelial adhesion and transmigration; paradoxically, it also promoted plaque instability by causing monocyte subset imbalance and subendothelial accumulation, raising a note of caution regarding src kinase-targeted intervention in plaque inflammation.

Hiperplasia em túnicas de artérias coronárias de beijupirás criados em sistema offshore

As lesões coronarianas já foram relatadas em espécies de peixes anádromos, com características semelhantes às observadas em aterosclerose humana, mas não em peixes cultivados sem interferência de padrões reprodutivos. Objetivou-se descrever lesões coronarianas em beijupirá (Rachycentron canadum) criado em sistema offshore, em 54 exemplares coletados ao longo do cultivo de oito meses. Amostras de tecido cardíaco de alevinos e juvenis foram submetidas à análise histopatológica e à microscopia eletrônica de transmissão (MET), para visualização de lesões coronarianas, sendo as lâminas histológicas coradas pela técnica de hematoxilina-eosina, ácido periódico de Schiff, alcian blue e reticulina de Gomori. Exames realizados pela fotomicroscopia de luz evidenciaram lesões arteriais caracterizadas por hiperplasia das túnicas íntima e média de artérias coronárias em, respectivamente, 29,63% e 79,63% dos animais, com redução do lúmen arterial. Na MET, foram observadas alterações na estrutura das coronárias com espessamento do endotélio e membrana basal, proliferação de fibroblastos e fibras colágenas, com acúmulo de material lipídico subendotelial, resíduos celulares aderidos à membrana basal e vesículas pinocitóticas com presença de lisossomos isolados. Constatou-se que os peixes da espécie Rachycentron canadum criados em cativeiro desenvolvem lesão arterial do tipo crônica degenerativa inflamatória.

Image-based computational simulation of sub-endothelial LDL accumulation in a human right coronary artery

Accumulation of low density lipoproteins (LDL) in the vessel wall is suggested as the initiator of atherosclerosis and coronary stenosis. This process is associated with the performance of endothelium layer that regulates entering of macromolecules to the vessel wall. Therefore, the present study aims to investigate sub-endothelial accumulation of LDL molecules in a coronary tree and predict atherosclerosis prone sites. Non-Newtonian blood flow is simulated for normal and hypertensive conditions through the lumen of a right coronary artery reconstructed from computed tomography (CT) images. A three-pore model is implemented as the endothelium boundary condition and hence, plasma flow and LDL transport are simulated within the arterial wall. Based on the pore model, endothelium pathways divide into normal junctions, vesicles and leaky junctions. Most of LDL molecules pass through the leaky junctions that arise at locations with low wall shear stress (WSS). Results indicate that increase in the number of leaky junctions at branch points with low WSS can lead to both elevated levels of sub-endothelial LDL accumulation and atherosclerosis risk. Findings reveal that at the branch points with disturbed flow, sub-endothelial concentration of LDL for the hypertensive condition is higher than the normal condition, however for the rest of regions with uniform geometry and unidirectional flow, this is reversed. Comparisons of non-Newtonian and Newtonian flows show mean increases of 34% and 13% in the sub-endothelial concentrations of Newtonian flows during the normal and hypertensive conditions, respectively.

Sialyltransferase Activity and Atherosclerosis

Leukocyte accumulation within the vascular wall is a major feature of atherosclerotic disease and plays crucial roles in the inception, progression, and complications of atherosclerosis. Several coordinated steps converge to promote subendothelial and perivascular accumulation of leukocytes. For example, hyperlipidemia triggers both medullary and extramedullary (spleen) hematopoiesis and induces leukocyte mobilization from these sites to the circulating blood.1–3 Concomitantly, hyperlipidemia induces an inflammatory response in the vascular wall (endothelial and smooth muscle cells) to promote recruitment of the mobilized circulating leukocytes.4 These events are controlled by the induction of selective chemoattractants and adhesion molecules, which interact with specific receptors and ligands expressed on leukocytes to tightly coordinate leukocyte mobilization and the sequential steps of leukocyte rolling, adhesion, and transmigration across the inflamed endothelium (reviewed in references 5 and 6). More particularly, extensive experimental work based on selective gene-targeting studies revealed specific roles for chemokine receptors (Ccr2, Ccr5, Cxcr2, and Cx3cr1), selectins (E- and P-selectins), and adhesion molecules (vascular cell adhesion molecule [Vcam-1]) in promoting intravascular leukocyte accumulation and atherosclerotic lesion development, whereas an antiatherogenic role has been assigned to specific chemokine receptors (Ccr1)7,8 and selectins (L-selectin).9 Importantly, although some of these recruitment pathways may be either redundant or active in selective arterial sites,10 other pairs of chemokines and chemokine receptors have been shown to act in parallel and play additive roles to ensure optimal mobilization of leukocytes and recruitment into the developing arterial lesions. This is the case for Ccr2, Ccr5, and Cx3cr1 pathways whose simultaneous blockade in mice leads to 90% reduction in lesion size.11 Thus, in depth study of the cellular, biochemical, and molecular events leading to activation of these recruitment pathways is of major importance to our understanding of the mechanisms of atherosclerotic lesion development. Article, see …

Imaging Atherosclerotic Plaque Inflammation via Folate Receptor Targeting Using a Novel 18 F-Folate Radiotracer

Folate receptor β (FR-β) is overexpressed on activated, but not resting, macrophages involved in a variety of inflammatory and autoimmune diseases. A pivotal step in atherogenesis is the subendothelial accumulation of macrophages. In nascent lesions, they coordinate the scavenging of lipids and cellular debris to define the likelihood of plaque inflammation and eventually rupture. In this study, we determined the presence of FR-β-expressing macrophages in atherosclerotic lesions by the use of a fluorine-18-labeled folate-based radiotracer. Human endarterectomized specimens were used to measure gene expression levels of FR-β and CD68. Increased FR-β and CD68 levels were found in atherosclerotic plaques compared to normal artery walls by quantitative real-time polymerase chain reaction. Western blotting and immunohistochemistry demonstrated prominent FR-β protein levels in plaques. FR-β-positive cells colocalized with activated macrophages (CD68) in plaque tissue. Carotid sections incubated with 3'-aza-2'-[18F]fluorofolic acid displayed increased accumulation in atherosclerotic plaques through in vitro autoradiography. Specific binding of the radiotracer correlated with FR-β-expressing macrophages. These results demonstrate high FR-β expression in atherosclerotic lesions of human carotid tissue correlating with CD68-positive macrophages. Areas of high 3'-aza-2'-[18F]fluorofolic acid binding within the lesions represented FR-β-expressing macrophages. Selectively targeting FR-β-positive macrophages through folate-based radiopharmaceuticals may be useful for noninvasive imaging of plaque inflammation.

Endothelial Cell MicroRNA Expression in Human Late-Onset Fuchs' Dystrophy

MicroRNAs (miRNAs) are a class of endogenous noncoding RNA and post transcriptionally modulate gene expression during development and disease. Our study investigated the differential miRNA expression in human Fuchs' endothelial corneal dystrophy (FECD) compared with normal endothelium to identify miRNA sequences that are involved in the pathogenesis of FECD. Comparative miRNA expression profiles of endothelial samples obtained from FECD patients during lamellar corneal transplant surgery and from normal donor globes were generated using OpenArray plate technology. Differential expression of individual miRNAs was validated in the original and in independent samples using stem-loop RT qPCR assays. Expression of miRNA target genes was assessed using qPCR and tissue microarray (TMA) immunolabeling. Our results demonstrate downregulation of 87 miRNAs in FECD compared with normal endothelium (>3-fold change; P < 0.01). Correspondingly, DICER1, (encoding an endoribonuclease critical to miRNA biogenesis) showed a moderate but significant decrease in FECD samples (P < 0.05). Significant repression of three miR-29 family members (miR-29a-3p, miR-29b-2-5p, and miR-29c-5p) was paralleled by upregulation of their extracellular matrix associated mRNA targets collagen I and collagen IV. Tissue microarray immunolabeling showed histologically verifiable subendothelial collagen I and collagen IV deposition and increased endothelial laminin protein expression in FECD samples. The present study provides the first miRNA profile in FECD and normal endothelial cells and demonstrates widespread miRNA downregulation in FECD. Decreased endothelial expression of miR-29 family members may be associated with increased subendothelial extracellular matrix accumulation in FECD.

Interaction between insulin-like growth factor-1 and atherosclerosis and vascular aging.

The process of vascular aging encompasses alterations in the function of endothelial (ECs) and vascular smooth muscle cells (VSMCs) via oxidation, inflammation, cell senescence and epigenetic modifications, increasing the probability of atherosclerosis. Aged vessels exhibit decreased endothelial antithrombogenic properties, increased reactive oxygen species generation, inflammatory signaling and migration of VSMCs to the subintimal space, impaired angiogenesis and increased elastin degradation. The key initiating step in atherogenesis is subendothelial accumulation of apolipoprotein B-containing low-density lipoproteins resulting in activation of ECs and recruitment of monocytes. Activated ECs secrete 'chemokines' that interact with cognate chemokine receptors on monocytes and promote directional migration. Recruitment of immune cells establishes a proinflammatory status, further causing elevated oxidative stress, which in turn triggers a series of events including apoptotic or necrotic death of vascular and nonvascular cells. Increased oxidative stress is also considered to be a key factor in mechanisms of aging-associated changes in tissue integrity and function. Experimental evidence indicates that insulin-like growth factor-1 exerts antioxidant, anti-inflammatory and pro-survival effects on the vasculature, reducing atherosclerotic plaque burden and promoting features of atherosclerotic plaque stability.

Myeloperoxidase oxidized LDL interferes with endothelial cell motility through miR-22 and heme oxygenase 1 induction: possible involvement in reendothelialization of vascular injuries.

Cardiovascular disease linked to atherosclerosis is the leading cause of death worldwide. Atherosclerosis is mainly linked to dysfunction in vascular endothelial cells and subendothelial accumulation of oxidized forms of LDL. In the present study, we investigated the role of myeloperoxidase oxidized LDL (Mox-LDL) in endothelial cell dysfunction. We studied the effect of proinflammatory Mox-LDL treatment on endothelial cell motility, a parameter essential for normal vascular processes such as angiogenesis and blood vessel repair. This is particularly important in the context of an atheroma plaque, where vascular wall integrity is affected and interference with its repair could contribute to progression of the disease. We investigated in vitro the effect of Mox-LDL on endothelial cells angiogenic properties and we also studied the signalling pathways that could be affected by analysing Mox-LDL effect on the expression of angiogenesis-related genes. We report that Mox-LDL inhibits endothelial cell motility and tubulogenesis through an increase in miR-22 and heme oxygenase 1 expression. Our in vitro data indicate that Mox-LDL interferes with parameters associated with angiogenesis. They suggest that high LDL levels in patients would impair their endothelial cell capacity to cope with a damaged endothelium contributing negatively to the progression of the atheroma plaque.

The effects of miR-467b on lipoprotein lipase (LPL) expression, pro-inflammatory cytokine, lipid levels and atherosclerotic lesions in apolipoprotein E knockout mice

Atherosclerosis is a lipid disorder disease characterized by chronic blood vessel wall inflammation driven by the subendothelial accumulation of macrophages. Studies have shown that lipoprotein lipase (LPL) participates in lipid metabolism, but it is not yet known whether post-transcriptional regulation of LPL gene expression by microRNAs (miRNAs) occurs in vivo. Here, we tested that miR-467b provides protection against atherosclerosis by regulating the target gene LPL which leads to reductions in LPL expression, lipid accumulation, progression of atherosclerosis and production of inflammatory cytokines in apolipoprotein E knockout (apoE−/−) mice. Treatment of apoE−/− mice with intra-peritoneal injection of miR-467b agomir led to decreased blood plasma levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β and monocyte chemotactic protein-1 (MCP-1). Using Western blots and real time PCR, we determined that LPL expression in aorta and abdominal cavity macrophages were significantly down-regulated in the miR-467b agomir group. Furthermore, systemic treatment with miR-467b antagomir accelerated the progression of atherosclerosis in the aorta of apoE−/− mice. The present study showed that miR-467b protects apoE−/− mice from atherosclerosis by reducing lipid accumulation and inflammatory cytokine secretion via downregulation of LPL expression. Therefore, targeting miR-467b may offer a promising strategy to treat atherosclerotic vascular disease.

Abstract 17984: Protective Role of Dicer in Macrophages During Atherogenesis

Atherosclerotic lesion development is characterized by the subendothelial accumulation of lipid-laden macrophages. It is known that microRNAs (miRs) are generated by the RNase Dicer and play important roles in macrophage function by negatively regulating post-transcriptional gene expression. Previously, we found that macrophage-derived miR-342-5p enhances atherosclerosis by fostering inflammatory macrophage activation. However, the impact of Dicer-dependent miR expression in macrophages during atherosclerosis is unclear. To study the role of Dicer in macrophages in atherosclerosis, we fed Apoe-/- mice with a myeloid cell-specific deletion of Dicer (LysMCre-Dicerflox) and littermate controls (LysMCre-DicerWT) a high cholesterol diet (HCD) for 3 months. Dicer deletion in myeloid cells was confirmed in bone marrow-derived macrophages isolated from LysMCre-Dicerflox mice by real-time PCR. The lipid deposition in the aortas was increased by 50% in LysMCre-Dicerflox (3.3±0.3%) compared to LysMCre-Dicerwt mice (2.1±0.3%) (p = 0.01, n = 13). The differential blood counts and the serum cholesterol and triglyceride levels were not altered between two groups. We found that 79 miRs, including those highly expressed in macrophages (e.g., miR-146a and miR-223), were down-regulated in LysMCre-Dicerflox aortas compared to controls after 3 months of a HCD (p &lt; 0.05, n = 3) using a miR real-time PCR array. In aortas from LysMCre-Dicerflox mice, 471 genes were up-regulated as determined by whole-genome gene expression profiling using Agilent Mouse Microarrays (p &lt; 0.05, n = 3-4). Genes involved in fatty acid and lipid metabolism were enriched among the up-regulated genes as analyzed by GeneGo MetaCore. Up-regulation of Plg, Ptges2, Eci1, Impa2, Acox2, Thrsp, and the lipid droplet-related genes plin-1, -2, -5 and Cidea was confirmed by real-time PCR. Whereas Plg was predicted to be a target of miR-223 by Targetscan, plin-1, -2, and Ptges2 were identified as potential targets of miR-146a using miRanda. These data indicate a protective role of Dicer during atherogenesis by inhibiting lipid metabolism in lesional macrophages through miRs. Thus, regulation of the lipid metabolism in macrophages might be a critical step in the development of atherosclerosis.

The microRNA-342-5p Fosters Inflammatory Macrophage Activation Through an Akt1- and microRNA-155 –Dependent Pathway During Atherosclerosis

Atherosclerosis is a chronic inflammatory vascular disease driven by the subendothelial accumulation of macrophages. The mechanism regulating the inflammatory response in macrophages during atherogenesis remains unclear. Because microRNAs (miRNAs) play a crucial role in cellular signaling by posttranscriptional regulation of gene expression, we studied the miRNA expression profiles during the progression of atherosclerosis. Using an miRNA real-time polymerase chain reaction array, we found that macrophage-derived miR-342-5p and miR-155 are selectively upregulated in early atherosclerotic lesions in Apoe(-/-) mice. miR-342-5p directly targets Akt1 through its 3'-untranslated region. Akt1 suppression by miR-342-5p induces proinflammatory mediators such as Nos2 and II6 in macrophages via the upregulation of miR-155. The local application of an miR-342-5p antagomir inhibits the development of atherosclerosis in partially ligated carotid arteries. In atherosclerotic lesions, the miR-342-5p antagomir upregulated Akt1 expression and suppressed the expression of miR-155 and Nos2. This reduced Nos2 expression was associated with a diminished generation of nitrotyrosine in the plaques. Furthermore, systemic treatment with an inhibitor of miR-342-5p reduced the progression of atherosclerosis in the aorta of Apoe(-/-) mice. Macrophage-derived miR-342-5p promotes atherosclerosis and enhances the inflammatory stimulation of macrophages by suppressing the Akt1-mediated inhibition of miR-155 expression. Therefore, targeting miR-342-5p may offer a promising strategy to treat atherosclerotic vascular disease.

Patient-specific computational modeling of subendothelial LDL accumulation in a stenosed right coronary artery: effect of hemodynamic and biological factors

Atherosclerosis is a systemic disease with local manifestations. Low-density lipoprotein (LDL) accumulation in the subendothelial layer is one of the hallmarks of atherosclerosis onset and ignites plaque development and progression. Blood flow-induced endothelial shear stress (ESS) is causally related to the heterogenic distribution of atherosclerotic lesions and critically affects LDL deposition in the vessel wall. In this work we modeled blood flow and LDL transport in the coronary arterial wall and investigated the influence of several hemodynamic and biological factors that may regulate LDL accumulation. We used a three-dimensional model of a stenosed right coronary artery reconstructed from angiographic and intravascular ultrasound patient data. We also reconstructed a second model after restoring the patency of the stenosed lumen to its nondiseased state to assess the effect of the stenosis on LDL accumulation. Furthermore, we implemented a new model for LDL penetration across the endothelial membrane, assuming that endothelial permeability depends on the local lumen LDL concentration. The results showed that the presence of the stenosis had a dramatic effect on the local ESS distribution and LDL accumulation along the artery, and areas of increased LDL accumulation were observed in the downstream region where flow recirculation and low ESS were present. Of the studied factors influencing LDL accumulation, 1) hypertension, 2) increased endothelial permeability (a surrogate of endothelial dysfunction), and 3) increased serum LDL levels, especially when the new model of variable endothelial permeability was applied, had the largest effects, thereby supporting their role as major cardiovascular risk factors.

Improving the treatment of atherosclerosis by linking anti-inflammatory and lipid modulating strategies

Atherosclerotic vascular disease manifests as a progressive narrowing of the vessel wall, and underlies coronary artery disease (CAD) and cerebrovascular disease. With consequences such as myocardial infarction and stroke, atherosclerosis...

Circulation Research Thematic Synopsis

<i>Circulation Research</i> Thematic Synopsis