Foam Cell Formation Research Articles

Anticancer Chemotherapy-Induced Atherosclerotic Cardiovascular Disease: A Comprehensive Review

The introduction of anticancer agents has transformed oncology, significantly improving survival rates. However, these therapies have introduced unintended cardiovascular risks, with atherosclerovascular disease (ASCVD) emerging as a leading cause of morbidity and mortality among cancer survivors. The development of ASCVD in this population involves multifactorial mechanisms, including endothelial dysfunction, oxidative stress, systemic inflammation, and disrupted lipid metabolism. This review examines the various mechanisms through which anticancer chemotherapy contributes to ASCVD and highlights strategies for risk assessment and management. Each class of anticancer agents presents distinct cardiovascular challenges: anthracyclines induce oxidative stress and endothelial damage, promoting foam cell formation and plaque progression; taxanes and vascular endothelial growth factor (VEGF) inhibitors impair lipid metabolism and vascular stability; anti-metabolites exacerbate endothelial injury through reactive oxygen species; and mTOR inhibitors, hormonal therapies, tyrosine kinase inhibitors, and immune checkpoint inhibitors disrupt lipid profiles and inflammatory pathways, increasing the risk of plaque rupture and thrombosis. Mitigating chemotherapy-induced ASCVD necessitates a comprehensive, multidisciplinary approach. Detailed pre-treatment cardiovascular risk assessments must address traditional and cancer-specific risk factors, including demographics, pre-existing conditions, and modifiable behaviors such as smoking and inactivity. Pharmacological interventions like statins and angiotensin-converting enzyme (ACE) inhibitors, paired with lifestyle modifications, are essential to reducing ASCVD risk. In resource-limited settings, cost-effective strategies should be prioritized to enhance accessibility. Establishing cardio-oncology units facilitates care coordination, while long-term surveillance enables timely detection and intervention. These strategies collectively improve cardiovascular outcomes and survivorship in diverse patient populations.

Bone marrow mesenchymal stem cell-derived extracellular vesicles alleviate diabetes-exacerbated atherosclerosis via AMPK/mTOR pathway-mediated autophagy-related macrophage polarization

IntroductionBone marrow-derived mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) are widely used for therapeutic purposes in preclinical studies. However, their utility in treating diabetes-associated atherosclerosis remains largely unexplored. Here, we aimed to characterize BMSC-EV-mediated regulation of autophagy and macrophage polarization.MethodsEVs were isolated from the supernatant of cultured BMSCs and characterized with transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting. A diabetes-related atherosclerotic ApoE−/− mouse model was established through feeding with a high-fat diet (HFD) and streptozotocin (STZ). Histopathological analyses were carried out using Oil Red O, H&E, and Masson staining of the aorta. TEM and immunohistochemistry (IHC) were applied to evaluate autophagy, and immunofluorescence (IF) was used to identify macrophage polarization. RAW264.7 macrophages were induced with oxidized low-density lipoprotein (ox-LDL) and high glucose (HG), co-cultured with BMSC-EVs, and analyzed for macrophage proliferation, migration, and foam cell formation. RAW264.7 cells were transduced with autophagy marker mRFP-GFP-LC3 lentivirus and analyzed with IF and western blotting.ResultsDiabetic mice (DA group) had larger aortic plaque areas and lower collagen content than the HFD mice. BMSC-EV treatment significantly reduced blood glucose, LDL levels, and aortic plaque areas while increasing collagen content. BMSC-EV-treated aortas contained a higher number of autophagosomes/autolysosomes, with increased expression of LC3BII correlating with decreased P62 levels and a lower proportion of M1 macrophages. In vitro, BMSC-EVs inhibited proliferation, migration, and foam cell formation in ox-LDL and HG-induced activated RAW264.7 cells. These effects were reversed by the autophagy blocker bafilomycin A1. Consistent with the in vivo findings, BMSC-EVs elevated levels of the autophagy-related protein LC3BII/I and decreased P62 in ox-LDL and HG-induced RAW264.7 cells. These cells also expressed the M1 macrophage markers CD86 and iNOS, but showed reduced expression of the M2 marker Arg-1. Further, BMSC-EVs decreased AMPKα and mTOR phosphorylation levels, which were blocked by the AMPK inhibitor compound C.ConclusionsBMSC-EVs attenuate diabetes-exacerbated atherosclerosis by inhibiting vascular macrophage proliferation, migration, and foam cell formation via AMPK/mTOR signaling-regulated autophagy and macrophage polarization. BMSC-EVs thus hold promise as therapeutic agents for atherosclerosis.Graphical Extracellular vesicles derived from bone marrow mesenchymal stem cells may mitigate diabetes-aggravated atherosclerosis by regulating AMPK/mTOR-mediated autophagy-related macrophage polarization and inhibiting macrophage proliferation, migration, foam cell formation, and cholesterol transport.

Platelet membrane-modified exosomes targeting plaques to activate autophagy in vascular smooth muscle cells for atherosclerotic therapy.

Atherosclerosis is one of the leading causes of ischemic cardiovascular disease worldwide. Recent studies indicated that vascular smooth muscle cells (VSMCs) play an indispensable role in the progression of atherosclerosis. Exosomes derived from mesenchymal stem cells (MSCs) have demonstrated promising clinical applications in the treatment of atherosclerosis. However, there are still challenges and limitations persist in targeted therapy. This study aims to develop a bionic nano-delivery system by fusing platelet membranes with exosomes (MSC-ExoP) and explore the anti-atherosclerosis effect of MSC-ExoP by improving the targeting efficiency and participating in regulating the pathophysiological processes associated with VSMCs. The morphology, particle size, stability, and fusion efficiency of MSC-ExoP were assessed using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), immunofluorescence staining, and Western blotting, respectively. MSC-ExoP was administered intravenously into ApoE-/- mice via the tail vein. In vivo, immunofluorescence staining was used to assess the targeting efficacy of MSC-ExoP. The ORO staining, H&E staining, Masson staining, aortic root immunofluorescence staining, and Western blot were utilized to evaluate the VSMC autophagy and anti-atherosclerosis effects of MSC-ExoP. In vitro, the autophagy activation of MSC-ExoP on VSMCs was further assessed by immunofluorescence staining and Western blotting. The effects of MSC-ExoP on VSMCs proliferation, migration, and foam cell formation were detected by EdU experiment, Transwell experiment, wound healing experiment, ORO staining, and BODIPY staining. The TEM revealed that MSC-ExoP retained a ring nanostructure, which was similar to MSC-Exo in morphology. NTA analysis indicated the MSC-ExoP exhibited a slight increase after cell membrane fusion. Besides, the stability analysis of exosomes and MSC-ExoP resulted in no significant changes in particle size. Western blot analysis confirmed that MSC-ExoP simultaneously expressed platelet-specific markers (GPVI, GPIbα, CD62P) and exosome-specific markers (CD81, TSG101, and Alix). In ApoE-/- mice, the immunofluorescence of aorta and its roots was significantly enhanced after injection of DiI-labeled MSC-ExoP, indicating enhanced targeting of MSC-Exo to atherosclerotic plaques by platelets. In vivo experiments demonstrated that MSC-ExoP could significantly suppress the progression of atherosclerosis and reduce the area of atherosclerotic plaques by reducing lipid deposition and necrotic nucleus area and increasing collagen content. In vitro experiments further revealed that the uptake of MSC-ExoP by foam cells significantly increased, and their proliferation, migration, and foam formation were inhibited by autophagy activation. This study demonstrated successful fusion of platelet membranes with exosomes derived from MSCs. MSC-ExoP could significantly improve the targeting efficiency of atherosclerosis and play an anti-atherosclerosis effect by activating VSMC autophagy.

Lysosome Functions in Atherosclerosis: A Potential Therapeutic Target

Lysosomes in mammalian cells are recognized as key digestive organelles, containing a variety of hydrolytic enzymes that enable the processing of both endogenous and exogenous substrates. These organelles digest various macromolecules and recycle them through the autophagy–lysosomal system. Recent research has expanded our understanding of lysosomes, identifying them not only as centers of degradation but also as crucial regulators of nutrient sensing, immunity, secretion, and other vital cellular functions. The lysosomal pathway plays a significant role in vascular regulation and is implicated in diseases such as atherosclerosis. During atherosclerotic plaque formation, macrophages initially engulf large quantities of lipoproteins, triggering pathogenic responses that include lysosomal dysfunction, foam cell formation, and subsequent atherosclerosis development. Lysosomal dysfunction, along with the inefficient degradation of apoptotic cells and the accumulation of modified low-density lipoproteins, negatively impacts atherosclerotic lesion progression. Recent studies have highlighted that lysosomal dysfunction contributes critically to atherosclerosis in a cell- and stage-specific manner. In this review, we discuss the mechanisms of lysosomal biogenesis and its regulatory role in atherosclerotic lesions. Based on these lysosomal functions, we propose that targeting lysosomes could offer a novel therapeutic approach for atherosclerosis, shedding light on the connection between lysosomal dysfunction and disease progression while offering new insights into potential anti-atherosclerotic strategies.

NLRC5 in Macrophages Promotes Atherosclerosis in Acute Coronary Syndrome by Regulating STAT3 Expression.

The mortality rate of cardiovascular and cerebrovascular diseases ranks first among all causes. This study elucidated the role and potential mechanism of the NLRC5 gene in atherosclerosis (AS). We enrolled patients (number = 30) diagnosed with AS and healthy volunteers (number = 30) as controls from our hospital. In patients with AS, the levels of serum NLRC5 were up-regulated (Fig.1A) and positively correlated with CIMT/CRP. In a mouse model of AS, the expression of serum NLRC5 mRNA was increased at 6 or 12weeks after inducing AS. The expression of NLRC5 protein was found to be elevated in a mouse model of AS. The inhibition of NLRC5 reduced development of AS in ApoE-/- Mice. Reducing NLRC5 inhibited the polarization of M2 macrophages and shifted macrophages towards proinflammatory M1 phenotype. STAT3 was identified as a target of NLRC5, with NLRC5 protein expression shown to reduce STAT3 ubiquitination. Methylation promoted NLRC5 DNA stability in vitro model of AS. Sh-NLRC5 increased M1/M2 macrophage ratio, foam cell formation and ox-LDL uptake. STAT3 reduced the effects of sh-NLRC5-mediated M1/M2 macrophage ratio in model of AS. These data confirmed that NLRC5 in macrophages promotes atherosclerosis in acute coronary syndrome by regulating STAT3 expression. This suggests that NLRC5 could be a potential target for the treatment of premature AS.

Mycoplasma pneumoniae drives macrophage lipid uptake via GlpD-mediated oxidation, facilitating foam cell formation.

Cardiovascular diseases, primarily caused by atherosclerosis, are a major public health concern worldwide. Atherosclerosis is characterized by chronic inflammation and lipid accumulation in the arterial wall, leading to plaque formation. In this process, macrophages play a crucial role by ingesting lipids and transforming into foam cells, which contribute to plaque instability and cardiovascular events. Recent studies have suggested that various pathogens are involved in the development of atherosclerosis, with Mycoplasma pneumoniae considered one of the potential candidates. Therefore, this study investigated whether this bacterium induces lipid accumulation in macrophages, which play a crucial role in the development of atherosclerosis, using the Raw264.7 model. Our findings revealed that M. pneumoniae infection promotes lipid droplet formation in macrophages. Glycerol 3-phosphate oxidase, GlpD, in the bacterium is involved in this process by producing reactive oxygen species, which in turn causes the oxidation of low-density lipoprotein. Furthermore, the significant increase in the expression of oxidized lipid receptors involved in the uptake of this oxidized lipid indicates that the bacteria promote lipid uptake in infected macrophages. These results suggest that M. pneumoniae has a direct pro-atherogenic effect, promoting the formation of atherosclerotic lesions through foam cell formation. Understanding the mechanisms by which M. pneumoniae influences atherosclerosis provides valuable insights for devising new therapeutic strategies for the prevention and management of cardiovascular diseases.

Selenium-Doped Copper Formate Nanozymes with Antisenescence and Oxidative Stress Reduction for Atherosclerosis Treatment.

Atherosclerosis, resulting from chronic inflammation of the arterial wall, serves as the underlying cause of multiple major cardiovascular diseases. Current anti-inflammatory therapies often exhibit limited and unsatisfactory efficacy. To address this, we have designed a selenium-doped copper formate (Cuf-Se) nanozyme for the treatment of atherosclerosis, which possesses superoxide dismutase (SOD) and glutathione peroxidase (GPx)-like activities. The Cuf-Se can efficiently scavenge reactive oxygen species (ROS), inhibit cellular senescence, and prevent the formation of foam cells. It acts on macrophages to reduce cellular ROS levels and lipid oxidation, thereby significantly inhibiting inflammation-related processes. Notably, while inhibiting foam cell formation, Cuf-Se also alleviates endothelial cells senescence. After intravenous administration, Cuf-Se effectively inhibits the formation of atherosclerosis in mice through the synergistic effects of antisenescence and antioxidant properties, reducing plaque area by approximately 5-fold. This study provides an effective strategy for the treatment of atherosclerosis.

Mechanisms of inflammatory microenvironment formation in cardiometabolic diseases: molecular and cellular perspectives.

Cardiometabolic diseases (CMD) are leading causes of death and disability worldwide, with complex pathophysiological mechanisms in which inflammation plays a crucial role. This review aims to elucidate the molecular and cellular mechanisms within the inflammatory microenvironment of atherosclerosis, hypertension and diabetic cardiomyopathy. In atherosclerosis, oxidized low-density lipoprotein (ox-LDL) and pro-inflammatory cytokines such as Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) activate immune cells contributing to foam cell formation and arterial wall thickening. Hypertension involves the activation of the renin-angiotensin system (RAS) alongside oxidative stress-induced endothelial dysfunction and local inflammation mediated by T cells. In diabetic cardiomyopathy, a high-glucose environment leads to the accumulation of advanced glycation end products (AGEs), activating the Receptor for Advanced Glycation Endproducts (RAGE) and triggering inflammatory responses that further damage cardiac and microvascular function. In summary, the inflammatory mechanisms in different types of metabolic cardiovascular diseases are complex and diverse; understanding these mechanisms deeply will aid in developing more effective individualized treatment strategies.

Tianxiangdan suppresses foam cell formation by enhancing lipophagy and reduces the progression of atherosclerosis.

The aim of this study is to assess the impact of Tianxiangdan (TXD) on lipophagy in foam cells and its underlying mechanism in treating atherosclerosis, particularly focusing on its efficacy in lowering blood lipids. In vivo, ApoE-/- atherosclerosis mouse models were established for group intervention. Blood lipid levels of the mice were measured, lipid deposition and autophagy levels in atherosclerotic plaques were assessed, and co-localization of lipid droplets and autophagosomes was examined. In vitro, human THP-1 cells were induced into macrophages and then transformed into foam cells using ox-LDL induction. Different intervention groups were established. Total cellular cholesterol (TC), free cholesterol (FC), and autophagy levels were assessed, while the morphology and distribution of lipid droplets and autophagosomes in cells were observed using transmission electron microscopy. Western blot analysis was performed to evaluate the expression levels of PI3K, Akt, mTOR, TFEB, LC3II/I, ULK1, ABCA1, and p62. TXD effectively lowers blood lipid levels in ApoE-/- atherosclerotic mice, enhances lipophagy, and reduces lipid accumulation in foam cells and arterial lipid plaques. It achieves this by suppressing the expression of p85, Akt, and mTOR, while activating downstream autophagy signals such as TFEB, LC3II/I, and ULK1. Additionally, TXD reduces the expression of p62 and enhances the expression of the cholesterol transport molecule ABCA1. Our findings indicate that TXD activates lipophagy via the PI3K/Akt/mTOR pathway, leading to a reduction in lipid deposition within foam cells and plaques, thereby mitigating atherosclerosis.

The Role of Inflammatory Cytokines and lncRNAs in the Pathogenesis of Atherosclerosis and Other Inflammatory Diseases: Focus on Sarcoidosis and Alzheimer’s Disease

Introduction Atherosclerosis, a chronic inflammatory disease of the arterial wall, remains a leading cause of morbidity and mortality worldwide. Recent advances highlight the role of inflammatory cytokines and long non-coding RNAs (lncRNAs) in its pathogenesis. Aim of the Study This study synthesizes current knowledge on the interplay between cytokines and lncRNAs across these conditions, emphasizing their potential as biomarkers and therapeutic targets. Materials and Methods Through a systematic review of recent studies, we identify key pathways and discuss translational implications for novel interventions. Description of the State of Knowledge Inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), orchestrate immune responses that exacerbate endothelial dysfunction, foam cell formation, and plaque instability. Concurrently, lncRNAs regulate gene expression through transcriptional and post-transcriptional mechanisms, influencing cellular processes such as macrophage polarization and smooth muscle cell proliferation. Beyond atherosclerosis, these mediators are implicated in the pathogenesis of other inflammatory diseases, including sarcoidosis and Alzheimer's disease. Conclusion Our findings underscore the critical need for integrated approaches targeting both inflammatory mediators and epigenetic regulators to mitigate the burden of these diseases.

HIF-1α and VEGF Immunophenotypes as Potential Biomarkers in the Prognosis and Evaluation of Treatment Efficacy of Atherosclerosis: A Systematic Review of the Literature.

Hypoxia-inducible factor 1 alpha (HIF-1α) and its related vascular endothelial growth factor (VEGF) may play a significant role in atherosclerosis and their targeting is a strategic approach that may affect multiple pathways influencing disease progression. This study aimed to perform a systematic review to reveal current evidence on the role of HIF-1α and VEGF immunophenotypes with other prognostic markers as potential biomarkers of atherosclerosis prognosis and treatment efficacy. We performed a systematic review of the current literature to explore the role of HIF-1α and VEGF protein expression along with the relation to the prognosis and therapeutic strategies of atherosclerosis. We used the terms {"Atherosclerosis" [OR] "Atheroma" [OR] "atheromatous plaque" [OR] "plaque atherosclerotic"} [AND] {"HIF-1α"} [AND] {"VEGF"} from 2009 up to May 2024 and the Medline/Embase/PubMed database. We used methodological approaches to assess unbiased data [ROBIS (Risk of Bias in Systematic) tool]. We used study eligibility criteria, and data were collected and evaluated from original articles by two independent teams, judged by an independent reviewer, and reported by PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) 2020. We included 34 original studies investigating 650 human specimens, 21 different cell lines, and 9 animal models. Increased HIF-1α in vascular smooth muscle cells, macrophages, or endothelial cells, under hypoxia, chronic loss of nitric oxide (NO), or reduced micro ribonucleic acid (miRNA)-17 and miR-20, is associated with the upregulation of pro-inflammatory molecules, such as interleukin-1 beta (IL-1β) or tumor necrosis factor-alpha (TNF-α), increased migration inhibitory factor of macrophages, glycolytic flux, lipid accumulation, necroptosis via miR-383, and adverse effects in atherosclerosis and plaque vulnerability. However, increased HIF-1α in lymphocytes is associated with decreased interferon-gamma (IFN-γ) and a favorable prognosis. Increased VEGF in a coronary artery, activated macrophages, or chronic exposure to methamphetamine is associated with elevated levels of serum inflammatory cells (interleukin-18; IL18), p38 mitogen-activated protein kinase (MAPK) phosphorylation, lipopolysaccharide-induced tumor necrosis factor-alpha factor (LITAF), and signal transducer and activator of transcription 6 isoform B (STAT6B) overexpression, leading to atherosclerosis progression and plaque break. However, VEGF overexpression in serum is marginally associated with an elevated risk for atherosclerosis. In contrast, stable overexpression of VEGF in macrophages correlates with reduced hyperplasia after arterial injury, reduced foam cell formation, and attenuation of atherosclerosis progression. HIF-1α/VEGF immunophenotypes reflect atherosclerosis treatment efficacy using, among others, HIF-inhibitors, statins, polyphenols, miR-497-5p, methylation modification, adenosine receptor antagonists, natural products, or glycosides. We present an overview of HIF-1α/VEGF expression in chronic inflammatory-related atherosclerosis disease. Exploring pathogenetic mechanisms and therapeutic options, we included several studies using variable methods to evaluate HIF-1α/VEGF immunophenotypes with controversial and innovative results. Data limitations may include the use of different survival methods. Our data support HIF-1α/VEGF immunophenotypes as potential biomarkers of atherosclerosis prognosis and treatment efficacy.

Antibodies to low-density lipoproteins modified by malonic dialdehyde: contents in blood and role in atherogenesis

In this work, we determined the content of antibodies to low-density lipoproteins modified by malondialdehyde, the concentration of circulating immune complexes cholesterol and oxidized low-density lipoproteins in the blood of healthy individuals and patients with various manifestations of atherosclerosis. In addition, the effect of antibodies to low-density lipoproteins modified with malondialdehyde on the interaction of such lipoproteins with macrophages was studied. 253 persons were examined: healthy individuals (59 people), patients with preclinical atherosclerosis (25 people) and patients with coronary artery disease (169 people). It was found that the concentration of circulating immune complexes cholesterol in plasma was increased in patients with coronary artery disease compared with healthy individuals and patients with preclinical atherosclerosis, while oxidized low-density lipoproteins content did not differ between patients groups. At the same time, a positive correlation oxidized low-density lipoproteins plasma concentration with circulating immune complexes cholesterol content was found in patients with atherosclerosis. The plasma level of IgG antibodies to malondialdehyde-modified lipoproteins was significantly reduced in patients with coronary artery disease compared with healthy people and patients with preclinical atherosclerosis. While the level of IgM antibodies to malondialdehyde low-density lipoproteins practically did not change in patients with atherosclerosis independently of disease severity. It was shown that specific antibodies vastly reduced malondialdehyde low density lipoproteins cytotoxicity and ability to induce cholesterol esters accumulation in macrophages derived from human peripheral blood mononuclear cells. Thus, the data obtained indicate that anti-lipoprotein antibodies may have a protective effect by preventing cell death and reducing the accumulation of cholesterol esters in macrophages when they interact with modified low-density lipoproteins, i.e. prevent the foam cells formation.

Biomimetic Cerium-Assisted Supra-Carbon Dots Assembly for Reactive Oxygen Species-Activated Atherosclerosis Theranostic.

Theranostic applications in atherosclerosis plaque microenvironment-triggered nanoplatforms are significantly compromised by the complex synthesis procedure, non-specific distribution, and limited therapeutic function. Therefore, development of a facile and feasible method to construct a pathology-based stimuli-responsive nanoplatform with satisfactory theranostic performance remains a demanding and highly anticipated goal. Herein, a novel class of multifunctional supra-carbon dots (CDs), denoted as MM@Ce-CDs NPs, by a simple nanoassembly and a subsequent coating with macrophage membrane (MM), is developed for the targeted reactive oxygen species-trigged theranostic and positive regulation of the pathological plaque microenvironment in AS. The harvested MM@Ce-CDs NPs exhibit activatable fluorescence properties, photoacoustic characteristics, and cascade enzyme performances, which can be effectively activated under ROS stimulation in the plaque pathological microenvironment, enabling precise control over theranostic functions, while markedly enhancing diagnostic accuracy and therapeutic efficacy for AS management. Besides, MM@Ce-CDs NPs can effectively manipulate the plaque microenvironment by reducing ROS levels and inflammation, alleviating M1 macrophage infiltration, and inhibiting foam cell formation, all together suppressing the pathological plaque development through the synergistic mechanisms. In addition, MM@Ce-CDs NPs inherit the biomimetic biological functions from MM, facilitating a highly specific target delivery to AS.

Floralozone attenuates atherosclerotic vascular injury by regulating AMPKα/SREBP-1c pathway and down-regulating miR-33-5p.

Severe disruption of lipid metabolism in vivo is one of the central mechanisms in the development of atherosclerotic vascular injury (AVI). Reverse cholesterol transport (RCT) plays a pivotal role in eliminating excess cholesterol, preventing lipid deposition in the aorta, and reducing plaque formation associated with AVI. Floralozone (FL) reduces endothelial cell injury in AVI rats by regulating sphingosine-1-phosphate (S1P) expression. However, FL's potential to prevent AVI by modulating cholesterol metabolism remains unknown. In this study, network pharmacology and molecular docking predicted FL's potential targets in AVI protection. AVI rats were induced with a high-sugar, high-fat diet and vitamin D3 injection. FL intervention's effects on aortic pathology and lipid levels were assessed. The expression levels of SREBP-1c, PPARγ, ABCA1, and ABCG1 were evaluated. Raw264.7 macrophages were induced to form foam cells with ox-LDL, and FL's effects on the AMPKα/SREBP-1c pathway and miR-33-5p were investigated. FL reduced lipid levels and SREBP-1c expression, increased HDL-C, promoted ABCA1- and ABCG1-mediated cholesterol efflux, and reduced aortic cholesterol accumulation. The AMPKα inhibitor dorsomorphin blocked FL's inhibition of intracellular cholesterol accumulation and SREBP1 down-regulation in foam cells. FL decreased miR-33-5p expression but up-regulated PPARγ, promoting ABCA1- and ABCG1-mediated cholesterol efflux. However, miR-33-5p mimic reduced FL-induced cholesterol efflux, while miR-33-5p inhibitor increased it. FL may promote foam cell cholesterol efflux by modifying the AMPKα/SREBP-1c pathway and down-regulating miR-33-5p, which targets cholesterol metabolism genes (PPARγ, ABCA1, and ABCG1). These findings provide a new insight into the protective effect of FL on AVI.

Reduced Uptake of Oxidized Low-Density Lipoprotein by Macrophages Using Multiple Aptamer Combinations.

The accumulation of oxidized low-density lipoprotein (oxLDL) in macrophages leads to the formation of foam cells and atherosclerosis development. Reducing the uptake of oxLDL in macrophages decreases the incidence and progression of atherosclerosis. Four distinct single-strand DNA sequences, namely, AP07, AP11, AP25, and AP29, were selected that demonstrated specific binding to distinct regions of oxidized apolipoprotein B100 (apoB100; the protein component of oxLDL) with low HDOCK scores. These four DNA sequences were combined to generate aptamers that selectively bound to labeled Dil-oxLDL, and were subsequently added to murine RAW 264.7 macrophages to test their inhibitory effects using fluorescence spectrometry. The four combined aptamers at 10 μM reduced oxLDL uptake by 79 ± 4% compared to that of the untreated aptamer group. Flow cytometry data demonstrated that macrophages treated with aptamers reached only 32.6% of the Dil-oxLDL signal, a 50% reduction in fluorescence emission relative to that of the untreated group (64.4% Dil-oxLDL signal). Binding the four combined aptamers to the oxLDL surface disrupted the interaction between oxLDL and CD36 via cyclic voltammetry, effectively decreasing the level of uptake of oxLDL by macrophages. Results suggested that these aptamers could be used as alternative compounds to prevent the formation of foam cells, hence providing antiatherosclerosis activity.

An intimal-lumen model in a microfluidic device: potential platform for atherosclerosis-related studies.

Atherosclerosis is a chronic inflammatory vascular disorder driven by factors such as endothelial dysfunction, hypertension, hyperlipidemia, and arterial calcification, and is considered a leading global cause of death. Existing atherosclerosis models have limitations due to the absence of an appropriate hemodynamic microenvironment in vitro and interspecies differences in vivo. Here, we develop a simple but robust microfluidic intimal-lumen model of early atherosclerosis using interconnected dual channels for studying monocyte transmigration and foam cell formation at an arterial shear rate. To the best of our knowledge, this is the first study that creates a physiologically relevant microenvironment under an arterial shear rate to modulate lipid-laden foam cells on a microfluidic platform. As a proof of concept, we use murine endothelial cells to develop a vascular lumen in one channel and collagen-embedded murine smooth muscle cells to mimic the subendothelial intimal layer in another channel. The model successfully triggers endothelial dysfunction upon TNF-α stimulation, initiating monocyte adhesion to the endothelial monolayer under the arterial shear rate. Unlike existing in vitro models, native low-density lipoprotein (LDL) is added in the culture media instead of ox-LDL to stimulate subendothelial lipid accumulation, thereby mimicking more accurate physiology. The subendothelial transmigration of adherent monocytes and subsequent foam cell formation is also achieved under flow conditions in the model. The model also investigates the inhibitory effect of aspirin in monocyte adhesion and transmigration. The model exhibits a significant dose-dependent reduction in monocyte adhesion and transmigration upon aspirin treatment, making it an excellent tool for drug testing.

Ferulic acid and protocatechuic acid alleviate atherosclerosis by promoting UCP1 expression to inhibit the NLRP3-IL-1β signaling pathway.

Dietary phenolic acids can combat metabolic diseases like obesity and non-alcoholic fatty liver by enhancing adipose tissue's thermogenic function. Uncoupling protein 1 (UCP1), a key thermogenic protein, is linked to atherosclerosis (AS) development. Whether dietary phenolic acids inhibit AS by boosting thermogenic function remains unknown. This study aims to identify phenolic acids that can enhance the thermogenic capacity of fat and investigate their roles and mechanisms in alleviating AS. Here, we utilized C3H10T1/2 cells and UCP1-luciferase gene knock-in mice to screen dietary phenolic acids, namely ferulic acid and protocatechuic acid, which could enhance the thermogenic capacity of the organism. Treating ApoE-/- mice with these phenolic acids reduced aortic plaques and suppressed pro-inflammatory gene expression (il-1β, il-6, tnf-α), while simultaneously promoting thermogenic functionality in interscapular brown adipose tissue and perivascular adipose tissue. Furthermore, applying conditioned media from brown adipose cells whose thermogenic capacity was activated by the phenolic acids to foam cells substantially inhibited the NLRP3-IL-1β inflammatory pathway and suppressed foam cell formation. These studies reveal that ferulic acid and protocatechuic acid can inhibit AS, at least in part, by upregulating UCP1 in adipose tissue, thereby suppressing the NLRP3-IL-1β inflammatory pathway and inhibiting foam cell formation in AS plaques. This validates the potential therapeutic function of phenolic acid compounds selected using UCP1 as a target for treating AS. Our work provides a theoretical basis for the precise utilization of food resources rich in phenolic acid compounds.

Multifunctional Prussian blue nanozymes alleviate atherosclerosis through inhibiting the inflammation feedback loop.

Atherosclerosis (AS) is a lipid-driven chronic inflammatory disease characterized by the presence of numerous proinflammatory cytokines, massive reactive oxygen species (ROS) and excess lipids, which together result in an overall inflammatory positive feedback loop in the plaque focus. Due to its excellent enzyme-like activity in ROS scavenging and inflammation inhibition, as well as its photothermal effects in the lipid efflux ability of foam cells, Prussian blue (PB) has greater potential in preventing inflammatory factor loops for enhanced treatment of AS than traditional nanozymes. In this study, the multifunctional nanozyme BSA@PB/Cur was synthesized by self-assembly of bovine serum albumin (BSA) with PB and further encapsulation of the anti-inflammatory drug curcumin (Cur). The in vitro results showed that BSA@PB/Cur could effectively scavenge ROS and inhibit the expression of the inflammatory cytokines TNF-α and IL-1β as well as enhance the expression of ABCA1 and ABCG1 in foam cells, promote cholesterol efflux and inhibit foam cell formation. The in vivo experimental results demonstrated that BSA@PB/Cur could target plaque locations, significantly efflux the lipid content, and decrease the matrix metalloproteinase expression. This research provides a potential strategy for alleviating the persistent inflammatory feedback loop within the plaque microenvironment for AS treatment.

Metal-organic framework-based nanoplatforms for synergistic anti-atherosclerosis therapy by regulating the PI3K/AKT/MSR1 pathway in macrophages.

Atherosclerosis is the main pathogenic factor of various cardiovascular diseases. During the pathogenesis of atherosclerosis, macrophages play a major role, mainly by secreting pro-inflammatory cytokines and taking in lipids to form foam cells. Thiamine pyrophosphate (TPP) is an antagonist of the P2Y6 receptor, which is overexpressed on macrophages during atherosclerosis and facilitates the lipid phagocytosis of macrophages. However, the excessive accumulation of TPP may interfere with some vital metabolic processes like the tricarboxylic acid cycle, oxidative phosphorylation and the pentose phosphate pathway. Herein, we designed and constructed a nanoparticle ZIF-8@TPP for the treatment of atherosclerosis. The as-established ZIF-8@TPP nanoplatform exhibited specific cytotoxicity towards macrophages in vitro. Meanwhile, histological analysis confirmed the excellent therapeutic efficacy of ZIF-8@TPP in vivo. Mechanistic studies indicated that ZIF-8@TPP potentially lowered lipid phagocytosis and lipid metabolism of macrophages via the PI3K/AKT/MSR1 pathway. This study also demonstrated that the anti-atherosclerotic effect of TPP was enhanced after combination with a prototypical metal-organic framework (MOF), ZIF-8. This synergistic controlled-release drug delivery system may provide a novel idea for anti-atherosclerosis therapy by combining reagents that can inhibit lipid phagocytosis of macrophages with MOFs.

LOX-1-Based Assembly Layer on Devices Surface to Promote Endothelial Repair and Reduce Complications for In Situ Interventional Plaque.

Rapid endothelialization and functional recovery are considered as promising methods to extend the long-term effectiveness of cardiovascular implant materials. LOX-1 participates in the initiation and development of atherosclerosis and is highly expressed in a variety of cells involved in atherosclerosis, hence it is feasible to accelerate the recovery of endothelial function and inhibit the development of existing plaques by regulating LOX-1. Herein, the surface is modified with Poly I, a LOX-1 inhibitor, using rich amino dendritic macromolecules (PAMAM) as the linker coating, to against the pathological microenvironment. Poly I modified surface resisted endothelial damage caused by oxidative stress through the LOX-1-NADPH signaling pathway and inhibited endothelial inflammation via the LOX-1-NF-κB signaling pathway. It also promoted endothelial cell migration and inhibited platelet adhesion. Moreover, the Poly I modified surface can inhibit oxLDL-induced macrophage foam cell formation and alleviate inflammation by modulating macrophage phenotypes. Poly I modified surface significantly reduced plaque burden after treatment of atherosclerotic model rats, most importantly, it significantly inhibited post-implantation-induced restenosis and thrombosis. In vivo and in vitro evaluations confirmed its safety and therapeutic efficacy against atherosclerosis. Overall, the multifunctional Poly I with pathological microenvironment regulation exhibits potential application value in the surface engineering of cardiovascular devices.