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Ankylosing Spondylitis (AS) stands as a chronic inflammatory arthritis within the spondyloarthritis spectrum, notably increasing cardiovascular (CV) risk and mortality through accelerated atherosclerosis compared to the non-affected population. While evidence in some studies supports a higher cardiovascular morbidity in AS patients, results from other studies reveal no significant disparities in atherosclerotic markers between AS individuals and healthy controls. This discrepancy may arise from the complex interaction between traditional CV risk factors and AS inflammatory burden. Endothelial dysfunction, a recognized antecedent of atherosclerosis prevalent among most individuals with AS, demonstrates the synergistic impact of inflammation and conventional risk factors on endothelial injury, consequently hastening the progression of atherosclerosis. Remarkably, endothelial dysfunction can precede vascular pathology in AS, suggesting a unique relationship between inflammation, atherosclerosis, and vascular damage. The role of adhesion molecules in the development of atherosclerosis, facilitating leukocyte adherence and migration into vascular walls, underscores the predictive value of soluble intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels for cardiovascular events. Despite significant progress in comprehending the pathogenesis of AS and its associated cardiovascular implications, the interplay among inflammation, endothelial dysfunction, and atherosclerosis remains partially elucidated. Investigations into the efficacy of therapeutic approaches involving angiotensin receptor blockers and statins have demonstrated reduced cardiovascular risk in AS patients, underscoring the imperative for additional research in this domain., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose of Review: This review seeks to provide important information on each of the major domains of social determinants of health (SDOH) in the context of atherosclerotic cardiovascular disease., Recent Findings: SDOH can be classified into five domains: social and community context, health care access and quality, neighborhood and built environment, economic stability, and education access and quality. SDOH are major drivers for cardiovascular health outcomes that exceed the impact from traditional risk factors, and explain inequities in health outcomes observed across different groups of individuals. SDOH profoundly impacts healthcare's receipt, delivery, and outcomes. Many patients fall within various disenfranchised groups (e.g., identify with minority race, low socioeconomic status, low educational attainment, LGBTQ+), which impact overall health status and care. Learning to understand, recognize, and address SDOH as the driving force of disparities are critical for achieving health equity in the prevention and adequate treatment of ASCVD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Dysregulation of the hematopoietic niche during hyperlipidemia facilitates pathologic leukocyte production, driving atherogenesis. Although definitive hematopoiesis occurs primarily in the bone marrow, during atherosclerosis this also occurs in the spleen. Cells of the bone marrow niche, particularly endothelial cells, have been studied in atherosclerosis, although little is known about how splenic endothelial cells respond to the atherogenic environment. Here we show unique dysregulated pathways in splenic compared to bone marrow endothelial cells during atherosclerosis, including perturbations of lipid metabolism and endocytic trafficking pathways. As part of this response, we identify the mixed lineage kinase domain-like (MLKL) protein as a repressor of splenic, but not bone marrow, myelopoiesis. Silencing MLKL in splenic endothelial cells results in inefficient endosomal trafficking and lipid accumulation, ultimately promoting the production of myeloid cells that participate in plaque development. These studies identify endocytic trafficking by MLKL as a key mechanism of splenic endothelial cell maintenance, splenic hematopoiesis and, subsequently, atherosclerosis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This study aimed at modelling the underlying predictor of ASCVD through the Bayesian network (BN). Data for the AZAR Cohort Study, which evaluated 500 healthcare providers in Iran, was collected through examinations, and blood samples. Two BNs were used to explore a suitable causal model for analysing the underlying predictor of ASCVD; Bayesian search through an algorithmic approach and knowledge-based BNs. Results showed significant differences in ASCVD risk factors across background variables' levels. The diagnostic indices showed better performance for the knowledge-based BN (Area under ROC curve (AUC) = 0.78, Accuracy = 76.6, Sensitivity = 62.5, Negative predictive value (NPV) = 96.0, Negative Likelihood Ratio (LR-) = 0.48) compared to Bayesian search (AUC = 0.76, Accuracy = 72.4, Sensitivity = 17.5, NPV = 93.2, LR- = 0.83). In addition, we decided on knowledge-based BN because of the interpretability of the relationships. Based on this BN, being male (conditional probability = 63.7), age over 45 (36.3), overweight (51.5), Mets (23.8), diabetes (8.3), smoking (10.6), hypertension (12.1), high T-C (28.5), high LDL-C (23.9), FBS (12.1), and TG (25.9) levels were associated with higher ASCVD risk. Low and normal HDL-C levels also had higher ASCVD risk (35.3 and 37.4), while high HDL-C levels had lower risk (27.3). In conclusion, BN demonstrated that ASCVD was significantly associated with certain risk factors including being older and overweight male, having a history of Mets, diabetes, hypertension, having high levels of T-C, LDL-C, FBS, and TG, but Low and normal HDL-C and being a smoker. The study may provide valuable insights for developing effective prevention strategies for ASCVD in Iran., (© 2024. The Author(s).)

Introduction: Achieving target low-density lipoprotein-cholesterol (LDL-C) levels remains challenging when treating homozygous familial hypercholesterolemia (HoFH). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are prescribed in addition to statins and ezetimibe, but patients' response varies and depends on residual low-density lipoprotein receptor (LDLR) function., Methods: A multicenter, retrospective observational analysis evaluated LDL-C target achievement in response to PCSK9i treatment in 28 patients with HoFH from the Middle East/North Africa region. Effect of genotype was investigated. Demographic and clinical information was retrospectively obtained from medical records. Patient response to PCSK9i treatment was assessed by calculating percentage changes in lipid levels from pre-PCSK9i treatment baseline to most recent follow-up visit where patients were recorded as receiving PCSK9i on top of standard of care lipid-lowering therapies (LLTs; i.e., statins/ezetimibe) and assessing European Atherosclerosis Society (EAS) target achievement up to January 31, 2022. Lowest LDL-C level while receiving PCSK9i was identified., Results: The cohort (n = 28) had a mean age (standard deviation; SD) of 22.8 (9.8) years (n = 28) and was 51% female (n = 27). Baseline LDL-C data were available in 24/28 (85.7%) patients (mean [SD] 14.0 [3.0] mmol/L). Median (interquartile range) duration of PCSK9i treatment was 12.0 months (4.0-19.1) months and mean (SD) % change in LDL-C after PCSK9i treatment was - 8.6% (12.1). LDL-C reduction from baseline was below 15% in 17/24 patients (70.8%). In the full cohort, mean (SD) minimum LDL-C during PCSK9i treatment was 11.9 (2.8; n = 28) mmol/L. No patient achieved EAS target LDL-C while receiving PCSK9i; genotype analysis suggested LDLR-null/null patients were most refractory to PCSK9i., Conclusion: Response to PCSK9i was minimal in this cohort of patients with HoFH. No patients achieved EAS LDL-C targets, and most failed to reach the EAS-recommended 15% LDL-C reduction for PCSK9i therapy continuation. These results suggest additional LLTs are necessary to achieve LDL-C targets in HoFH., (© 2023. The Author(s).)

Atherosclerosis remains a leading contributor to cardiovascular disease-associated morbidity and mortality. Interestingly, atherosclerosis-associated mortality rate is higher in men than women. This suggested a protective role for estrogen in the cardiovasculature. These effects of estrogen were initially thought to be mediated by the classic estrogen receptors, ER alpha, and beta. However, genetic knockdown of these receptors did not abolish estrogen's vasculoprotective effects suggesting that the other membranous Gprotein coupled estrogen receptor, GPER1, maybe the actual mediator. Indeed, in addition to its role in vasotone regulation, this GPER1 appears to play important roles in regulating vascular smooth cell phenotype, a critical player in the onset of atherosclerosis. Moreover, GPER1-selective agonists appear to reduce LDL levels by promoting the expression of LDL receptors as well as potentiating LDL re-uptake in liver cells. Further evidence also show that GPER1 can downregulate Proprotein Convertase Subtilisin/ Kexin type 9, leading to suppression of LDL receptor breakdown. Here, we review how selective activation of GPER1 might prevent or suppress atherosclerosis, with less side effects than those of the non-selective estrogen., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Mediterranean diet is frequently associated with longevity and a lower incidence of adverse cardiovascular events because of the biological activities and health effects of olives - its key component. Olive oil, olive leaf extract, fruits and different by-products contain many bioactive components that exert anti-oxidant, anti-inflammatory and anti-apoptotic activities. In this review, we focus on the recent studies exploring molecular mechanisms underlying the cardioprotective properties of different olive oils, olive leave extracts, and specific micro-constituents (such as oleuropein, tyrosol, hydroxytyrosol and others) in vitro on rodent models and in clinical trials on human subjects. Particularly, hydroxytyrosol and oleuropein were identified as the major bioactive compounds responsible for the antioxidant, anti-inflammatory, anti-platelet aggregation and anti-atherogenic activities of olive oil. In total, the discussed results demonstrated a positive association between the consumption of olive oil and improvement in outcomes in atherosclerosis, diabetes, myocardial infarction, heart failure, hypertension and obesity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cardiovascular disease (CDV) represents the major cause of death globally. Atherosclerosis, as the primary cause of CVD, is a chronic immune-inflammatory disorder with complex multifactorial pathophysiology encompassing oxidative stress, enhanced immune-inflammatory cascade, endothelial dysfunction, and thrombosis. An initiating event in atherosclerosis is the subendothelial accumulation of low-density lipoprotein (LDL), followed by the localization of macrophages to fatty deposits on blood vessel walls, forming lipid-laden macrophages (foam cells) that secrete compounds involved in plaque formation. Given the fact that foam cells are one of the key culprits that underlie the pathophysiology of atherosclerosis, special attention has been paid to the investigation of the efficient therapeutic approach to overcome the dysregulation of metabolism of cholesterol in macrophages, decrease the foam cell formation and/or to force its degradation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine proteinase that has emerged as a significant regulator of the lipid metabolism pathway. PCSK9 activation leads to the degradation of LDL receptors (LDLRs), increasing LDL cholesterol (LDL-C) levels in the circulation. PCSK9 pathway dysregulation has been identified as one of the mechanisms involved in atherosclerosis. In addition, microRNAs (miRNAs) are investigated as important epigenetic factors in the pathophysiology of atherosclerosis and dysregulation of lipid metabolism. This review article summarizes the recent findings connecting the role of PCSK9 in atherosclerosis and the involvement of various miRNAs in regulating the expression of PCSK9-related genes. We also discuss PCSK9 pathway-targeting therapeutic interventions based on PCSK9 inhibition, and miRNA levels manipulation by therapeutic agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cardiovascular Diseases (CVDs) pose a significant global health threat, with rising mortality rates attributed to factors like diabetes, obesity, and an aging population. This paper explores the evolving landscape of micro and nanoscale Drug Delivery Systems (DDSs) to enhance cardiovascular treatment efficacy. Various nanoagents, both organic (e.g., liposomes, dendrimers, polymeric nanoparticles) and inorganic (e.g., carbon nanotubes, silver nanoparticles, iron oxide nanoparticles), are classified and examined. The advantages, limitations, and preparation techniques of nanoagents are discussed, emphasizing their potential in targeted delivery, multifunctionality, minimal side effects, and enhanced efficiency. The anatomical details of the heart, layers of heart walls, and heart functions are presented for contextual understanding. The application of nanoagents in treating specific cardiovascular conditions, such as atherosclerosis, hypertension, myocardial infarction, and coronary artery disease, is thoroughly explored. Evaluation methods for nanoagents, including size and morphology analysis, surface charge determination, and molecular weight evaluation, are outlined. This paper concludes by emphasizing the promising role of nano-drug delivery systems in addressing CVD challenges, urging collaborative efforts for successful translational medicine implementation. Future research directions are proposed, highlighting the potential of peptides, antibodies, and selective nanodelivery systems in advancing cardiovascular care. Challenges like pharmaceutical scale-up, regulatory requirements, and patient preparation are acknowledged, underscoring the need for interdisciplinary collaboration to propel nanocardio medicine into clinical practice. [ABSTRACT FROM AUTHOR]

Flavonoids exert vasculoprotective effects in humans, but interindividual variability in their action has also been reported. This study aims to identify genes that are associated with vascular health effects of flavonoids and whose polymorphisms could explain interindividual variability in response to their intake. Applying the predetermined literature search criteria, we identified five human intervention studies reporting positive effects of flavonoids on vascular function together with global genomic changes analyzed using microarray methods. Genes involved in vascular dysfunction were identified from genome-wide association studies (GWAS). By extracting data from the eligible human intervention studies, we obtained 5807 differentially expressed genes (DEGs). The number of identified upstream regulators (URs) varied across the studies, from 227 to 1407. The search of the GWAS Catalog revealed 493 genes associated with vascular dysfunction. An integrative analysis of transcriptomic data with GWAS genes identified 106 candidate DEGs and 42 candidate URs, while subsequent functional analyses and a search of the literature identified 20 top priority candidate genes: ALDH2, APOE, CAPZA1, CYP11B2, GNA13, IL6, IRF5, LDLR, LPL, LSP1, MKNK1, MMP3, MTHFR, MYO6, NCR3, PPARG, SARM1, TCF20, TCF7L2, and TNF. In conclusion, this integrated analysis identifies important genes to design future nutrigenetic studies for development of precision nutrition for polyphenols. [ABSTRACT FROM AUTHOR]

Mesenteric ischemia diagnosis is challenging, with an overall mortality of up to 50% of cases despite advances in treatment. The main problem that affects the outcome is delayed diagnosis because of non-specific clinical presentation. Multi-Detector CT Angiography (MDCTA) is the first-line investigation for the suspected diagnosis of vascular abdominal pathologies and the diagnostic test of choice in suspected mesenteric bowel ischemia. MDCTA can accurately detect the presence of arterial and venous thrombosis, determine the extent and the gastrointestinal tract involved, and provide detailed information determining the subtype and the stage progression of the diseases, helping clinicians and surgeons with appropriate management. CT (Computed Tomography) can differentiate forms that are still susceptible to pharmacological or interventional treatment (NOM = non-operative management) from advanced disease with transmural necrosis in which a surgical approach is required. Knowledge of CT imaging patterns and corresponding vascular pathways is mandatory in emergency settings to reach a prompt and accurate diagnosis. The aims of this paper are 1. to provide technical information about the optimal CTA (CT Angiography) protocol; 2. to explain the CTA arterial and venous supply to the gastrointestinal tract and the relevant ischemic pattern; and 3. to describe vascular, bowel, and extraintestinal CT findings for the diagnosis of acute mesenteric ischemia. [ABSTRACT FROM AUTHOR]

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This review paper examines the evolution of photodynamic therapy (PDT) as a novel, minimally invasive strategy for treating atherosclerosis, a leading global health concern. Atherosclerosis is characterized by the accumulation of lipids and inflammation within arterial walls, leading to significant morbidity and mortality through cardiovascular diseases such as myocardial infarction and stroke. Traditional therapeutic approaches have primarily focused on modulating risk factors such as hypertension and hyperlipidemia, with emerging evidence highlighting the pivotal role of inflammation. PDT, leveraging a photosensitizer, specific-wavelength light, and oxygen, offers targeted treatment by inducing cell death in diseased tissues while sparing healthy ones. This specificity, combined with advancements in nanoparticle technology for improved delivery, positions PDT as a promising alternative to traditional interventions. The review explores the mechanistic basis of PDT, its efficacy in preclinical studies, and the potential for enhancing plaque stability and reducing macrophage density within plaques. It also addresses the need for further research to optimize treatment parameters, mitigate adverse effects, and validate long-term outcomes. By detailing past developments, current progress, and future directions, this paper aims to highlight PDT's potential in revolutionizing atherosclerosis treatment, bridging the gap from experimental research to clinical application. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a chronic inflammatory disease which associated with a maladaptive immune response driven by macrophages. In the development of AS, macrophages have gradually become new therapeutic targets due to their involvement in numerous inflammatory-related pathological processes in AS. However, despite significant breakthroughs in the development of macrophages targeting nanocarriers, unsatisfactory drug loading, and inexact drug release limited the development of nano-therapy. Therefore, developing a high drug-loading nanocarrier that can accurately release drugs at AS lesions is quite essential. Herein, we optimized double moieties coupled mPEG-PLA copolymer micelles via phenylboronic acid (PBA)-terminated on the hydrophobic chain and cRGD coupled in hydrophilic chain to enhance AS therapy. The micelles loaded with andrographolide (AND) exhibited advanced drug loading capacity, as PBA could form a reversible boronic ester with AND at physiological pH. The cRGD-modified AND-loaded micelles (RPPPA) could be efficaciously internalized by macrophages and efficiently prevent macrophages from differentiating to foam cells. After intravenous administration, RPPPA could accumulate in plaques and exert therapeutic effects. The optimistic therapeutic results of atherosclerosis were shown in RPPPA, included the fewer plaques, a smaller necrotic core, a more stabilized fibrous cap, and lower macrophages and MMP-9, compared with the control group. To sum up, the proposed encouraging therapy can contribute to high drug loading, exact target, and precise drug release as well as reduce inflammation for AS treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: In this study, we performed RNA sequencing (RNA-seq) on the abdominal aorta tissue of New Zealand rabbits and investigated the potential association of lncRNA TCONS_02443383 with the development of AS through bioinformatics analysis of the sequencing data. The obtained results were further validated using quantitative real-time polymerase chain reaction (qRT-PCR)., Method: We induced an AS model in New Zealand rabbits by causing balloon injury to the abdominal aorta vascular wall and administering a high-fat diet. We then upregulated the expression level of the lncRNA TCONS_02443383 by injecting lentiviral plasmids through the ear vein. RNA sequencing (RNA-seq) was performed on the abdominal aorta tissues. We conducted Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway and Gene Ontology (GO) analyses., Result: The overexpression of the lncRNA TCONS_02443383 led to an upregulation of peroxisome proliferator-activated receptor (PPAR) signaling pathways as well as genes related to cell adhesion., Conclusion: The overexpression of the lncRNA TCONS_02443383 can inhibit the occurrence and development of AS by upregulating peroxisome proliferator-activated receptor (PPAR) signaling pathways and genes related to cell adhesion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Atherosclerosis (AS) is a chronic inflammatory disease characterized by the formation of atherosclerotic plaques that consist of numerous cells including smooth muscle cells, endothelial cells, immune cells, and foam cells. The most abundant innate and adaptive immune cells, including neutrophils, monocytes, macrophages, B cells, and T cells, play a pivotal role in the inflammatory response, lipoprotein metabolism, and foam cell formation to accelerate atherosclerotic plaque formation. In this review, we have discussed the underlying mechanisms of activated immune cells in promoting AS and reviewed published clinical trials for the treatment of AS by suppressing immune cell activation. We have also presented some crucial shortcomings of current clinical trials. Lastly, we have discussed the therapeutic potential of novel compounds, including herbal medicine and dietary food, in alleviating AS in animals. Despite these limitations, further clinical trials and experimental studies will enhance our understanding of the mechanisms modulated by immune cells and promote widespread drug use to treat AS by suppressing immune system-induced inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Atherosclerosis (AS) is the main cause of coronary heart disease, cerebral infarction, and peripheral vascular disease. QingRe HuoXue Formula (QRHXF), a common prescription of traditional Chinese medicine, has a definite effect on the clinical treatment of AS, but its mechanism remains to be further explored., Purpose: The current study aimed to demonstrate the effectiveness of the QRHXF in the treatment of AS and further reveal its potential pharmacological mechanisms., Methods: Explore the potential mechanisms of QRHXF in treating AS through network pharmacology, machine learning, transcriptome analysis, and molecular docking, then validate them through animal experiments and PCR experiments., Results: The results indicate that through network pharmacology and machine learning methods, 10 genes including COL1A1 and CCR7 have been identified as potential candidate genes for QRHXF treatment of atherosclerosis. Molecular docking indicates that the key active compounds of QRHXF have good binding affinity with the predicted genes. Two key genes, COL1A1 and CCR7, were identified through transcriptome sequencing analysis of the aortic tissue of APOE -/- mice in the AS model. Finally, the animal and PCR experiment found that QRHXF can effectively reduce the formation of aortic plaques in APOE -/- mice of the AS model, lower blood lipid levels in mice, and upregulate the mRNA expression level of COL1A1, promoting the formation of fibrosis within plaques., Conclusions: We revealed the inflammatory and immune pathways underlying QRHXF treatment for AS, and verified through transcriptome sequencing and experiments that QRHXF can promote the expression of COL1A1, thereby increasing the stability of AS plaques., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Atherosclerosis (AS), the leading cause of cardiovascular diseases, is heavily influenced by inflammation, lipid accumulation, autophagy, and aging. The expression of glycoprotein non-metastatic melanoma B (GPNMB) has been observed to correlate with lipid content, inflammation, and aging, progressively increasing as atherosclerosis advances through its various stages, from baseline to early and advanced phases. However, the interaction between GPNMB and AS is controversial. Knockout of GPNMB has been shown to increase atherosclerotic plaque burden in mice. Conversely, targeted elimination of GPNMB-positive cells reduced atherosclerotic burden. These seemingly contradictory findings underscore the complexity of the issue and highlight the need for further research to reconcile these discrepancies and to elucidate the precise role of GPNMB in the pathogenesis of AS., Competing Interests: Declaration of competing interest On behalf of all authors, the corresponding author states that there are no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Targeting senescent cells has recently emerged as a promising strategy for treating age-related diseases, such as atherosclerosis, which significantly contributes to global cardiovascular morbidity and mortality. This review elucidates the role of senescent cells in the development of atherosclerosis, including persistently damaging DNA, inducing oxidative stress and secreting pro-inflammatory factors known as the senescence-associated secretory phenotype. Therapeutic approaches targeting senescent cells to mitigate atherosclerosis are summarized in this review, which include the development of senotherapeutics and immunotherapies. These therapies are designed to either remove these cells or suppress their deleterious effects. These emerging therapies hold potential to decelerate or even alleviate the progression of AS, paving the way for new avenues in cardiovascular research and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Low-dose aspirin remains the most commonly used antiplatelet agent among patients with atherosclerotic cardiovascular disease. Aspirin hypersensitivity occurs in 1% to 5% of patients and is among the most frequent causes for prohibiting the use of aspirin, posing a significant dilemma on how to manage these patients in clinical practice. Aspirin hypersensitivity is often misinterpreted and confused with aspirin intolerance, with treatment approaches being often unclear and lacking specific recommendations. Aspirin desensitization and low-dose aspirin challenge have emerged as pragmatic, effective, and safe approaches in patients with suspected or confirmed aspirin hypersensitivity who require aspirin therapy, but they are underused systematically in clinical practice. Furthermore, there is confusion over alternative antiplatelet agents to be used in these patients. The pathophysiological mechanisms and classification of aspirin hypersensitivity, as well as alternative strategies and practical algorithms to overcome the need for aspirin use in patients with atherosclerotic cardiovascular disease with suspected aspirin hypersensitivity, are discussed., Competing Interests: Funding Support and Author Disclosures Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, and the Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Zhishi Xiebai Guizhi Decoction (ZSXBGZD) is a traditional herbal manuscript used to treat cardiovascular disease, including atherosclerosis and coronary heart disease. The decoction has demonstrated its capability to protect arteries and resist atherosclerosis. Its mechanisms for anti-atherosclerosis effect, nevertheless, remain unknown., Aims of the Study: The goal of the present study is to explore the effectiveness of ZSXBGZD acting on atherosclerosis and its key components based on experimental verification and network pharmacology analysis., Materials and Methods: The ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and databases were used to identify chemical components in ZSXBGZD. Network pharmacological analysis and molecular docking were implemented in order to reveal the possible therapeutic targets of ZSXBGZD. To form the model of atherosclerosis, we gave Apolipoprotein E knocked out mice a high-fat diet. H&E staining was performed to observe the effects of ZSXBGZD on atherosclerosis. Immunofluorescence and Western blot were used to investigate whether ZSXBGZD could affect autophagy, apoptosis, AGE-RAGE signaling pathway and other related mechanisms., Results: In total, 30 core compounds were screened through intersecting UPLC-Q-TOF-MS and the databases. The anti-atherosclerotic effect of ZSXBGZD might relate to the AGE-RAGE signaling pathway via network pharmacology analysis. ZSXBGZD could inhibit apoptosis, activate autophagy and ease inflammation by modifying AGE-RAGE signaling pathway to reduce the area of atherosclerotic plaque., Conclusion: ZSXBGZD could treat atherosclerosis by regulating autophagy and apoptosis via adjusting the AGE-RAGE signaling pathway., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interests regarding the publication of this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the impact of the glucagon-like peptide-1 (GLP-1) receptor agonist Exendin-4 on the proportion of myeloid-derived suppressor cells (MDSCs) in male ApoE -/- mice, and investigate alterations in the concentrations of inflammatory factors in plasma and spleen tissues and assess their correlation with MDSCs., Methods: Thirty male ApoE -/- mice were randomly divided into five groups (n = 6 per group): control group (CON), model group (MOD), Exendin-4 intervention group (MOD/Ex-4), Exendin-9-39 intervention group (MOD/Ex-9-39), and Exendin-4 + Exendin-9-39 combined intervention group (MOD/Ex-4 + Ex-9-39). After 4 weeks of drug intervention, changes in aortic plaque were observed using Oil Red O staining and H&E staining. Flow cytometry was employed to detect the content of myeloid-derived suppressor cells (MDSCs) in bone marrow and peripheral blood. ELISA was utilized to measure the concentrations of inflammatory factors in mouse peripheral blood plasma, while RT-qPCR was employed to quantify the expression levels of inflammatory factors in the spleen. Pearson correlation analysis was conducted to assess the relationship between MDSCs and inflammatory factors., Results: Mice in the MOD group had significantly higher body weight compared to the CON group, with a statistically significant difference (P<0.05). Following Exendin-4 intervention, body weight was reduced compared to the MOD group (P<0.05). Additionally, Exendin-4 treatment led to a significant reduction in atherosclerotic plaque compared to the MOD group (P<0.001). After Exendin-4 intervention, the proportion of MDSCs in the bone marrow was higher than in the MOD group (P<0.001), and the proportion of MDSCs in peripheral blood was significantly higher than in the MOD group (P<0.05). Further investigation revealed that Exendin-4 could regulate lipid levels in mice, decreasing concentrations of TG (P<0.01), TC (P<0.0001), and LDL-C (P<0.0001), while increasing HDL-C concentrations (P<0.01). Moreover, after Exendin-4 treatment, the level of the cytokine IL-6 in peripheral plasma was significantly lower compared to the MOD group (P<0.0001), while levels of IL-10 and TGF-β were significantly higher compared to the MOD group (P<0.0001). In the spleen, levels of the cytokines IL-10 (P<0.0001) and TGF-β (P<0.001) were significantly increased compared to the MOD group. Pearson correlation analysis showed that the proportion of MDSCs in peripheral blood was positively correlated with IL-10 and TGF-β levels in both the spleen and peripheral blood. Additionally, the proportion of MDSCs in the bone marrow was positively correlated with IL-10 and TGF-β levels in the spleen and peripheral blood., Conclusion: Exendin-4 alleviates the severity of atherosclerosis. This process may be achieved by promoting the secretion of myeloid-derived suppressor cells (MDSCs) in the bone marrow and peripheral blood of atherosclerotic ApoE -/- mice, regulating the ratio of inflammatory factors in the body, reducing mouse body weight, and lowering blood lipids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Atherosclerosis (AS) and its related cardiovascular diseases (CVDs) remain the most frequent cause of morbidity and mortality worldwide. Researches showed that bisphenol A (BPA) exposure might exacerbate AS progression. However, as an analogue of BPA, little is known about the cardiovascular toxicity of bisphenol S (BPS), especially whether BPS exposure has the pro-atherogenic effects in mammals is still unknown. Here, we firstly constructed an apolipoprotein E knockout (ApoE -/- ) mouse model and cultured cells to investigate the risk of BPS on AS and explore the underlying mechanisms. Results showed that prolonged exposure to 50 μg/kg body weight (bw)/day BPS indeed aggravated AS lesions both in the en face aortas and aortic sinuses of ApoE -/- mice. Moreover, BPS were found to be implicated in the AS pathological process: 1) stimulates adhesion molecule expression to promote monocyte-endothelial cells (ECs) adhesion with 3.6 times more than the control group in vivo; 2) increases the distribution of vascular smooth muscle cells (VSMCs) with 9.3 times more than the control group in vivo, possibly through the migration of VSMCs; and 3) induces an inflammatory response by increasing the number of macrophages (MACs), with 3.7 times more than the control group in vivo, and the release of inflammatory mediators. Furthermore, we have identified eight significant AS-related genes induced by BPS, including angiopoietin-like protein 7 (Angptl17) and lipocalin-2 (Lcn2) in ECs; matrix metalloproteinase 9 (Mmp13), secreted phosphoprotein 1 (Spp1), and collagen type II alpha 1 (Col2a1) in VSMCs; and kininogen 1 (Kng1), integrin alpha X (Itgax), and MAC-expressed gene 1 (Mpeg1) in MACs. Overall, this study firstly found BPS exposure could exacerbate mammalian AS and might also provide a theoretical basis for elucidating BPS and its analogues induced AS and related CVDs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Exposure to metals, a newly recognized risk factor for cardiovascular disease (CVD), could be related to atherosclerosis progression., Objectives: The authors hypothesized that higher urinary levels of nonessential (cadmium, tungsten, uranium) and essential (cobalt, copper, zinc) metals previously associated with CVD would be associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of CVD in MESA (Multi-Ethnic Study of Atherosclerosis)., Methods: We analyzed data from 6,418 MESA participants with spot urinary metal levels at baseline (2000-2002) and 1 to 4 repeated, continuous measures of CAC over a 10-year period. We used linear mixed-effect models to assess the association of baseline urinary metal levels with baseline CAC and cumulative change in CAC over a 10-year period. Urinary metals (μg/g creatinine) and CAC were log transformed. Models were adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors., Results: At baseline, the median CAC was 6.3 (Q1-Q3: 0.7-58.2). Comparing the highest to lowest quartile of urinary cadmium, CAC levels were 51% (95% CI: 32%, 74%) higher at baseline and 75% (95% CI: 47%, 107%) higher over the 10-year period. For urinary tungsten, uranium, and cobalt, the corresponding CAC levels over the 10-year period were 45% (95% CI: 23%, 71%), 39% (95% CI: 17%, 64%), and 47% (95% CI: 25%, 74%) higher, respectively, with no difference for models with and without adjustment for clinical factors. For copper and zinc, the corresponding estimates dropped from 55% to 33% and from 85% to 57%, respectively, after adjustment for clinical factors. The associations of metals with CAC were comparable in magnitude to those for classical CVD risk factors., Conclusions: Exposure to metals was generally associated with extent of coronary calcification at baseline and follow-up. These findings support that metals are associated with the progression of atherosclerosis, potentially providing a novel strategy for the prevention and treatment of atherosclerosis progression., Competing Interests: Funding Support and Author Disclosures The Multi-Ethnic Study of Atherosclerosis (MESA) is supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute; and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). This publication was developed under the Science to Achieve Results (STAR) research assistance agreements, No. RD831697 (MESA Air) and RD-83830001 (MESA Air Next Stage), awarded by the U.S. Environmental Protection Agency (EPA). It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. Work in the authors’ laboratories is also supported in part by NIH grants P42ES023716, P42ES010349, P42ES033719, P30ES009089, T32ES007322, R01ES029967, R01HL155576, R01ES029967, and R01ES028758. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The cardiovascular system effects of environmental low-dose radiation exposure on radiation practitioners remain uncertain and require further investigation. The aim of this study was to initially investigate and explore the mechanisms by which low-dose radiation may contribute to atherosclerosis through a multi-omics joint comprehensive basic experiment., Methods: We used WGCNA and differential analyses to identify shared genes and potential pathways between radiation injury and atherosclerosis sequencing datasets, as well as tissue transcriptome immune infiltration level extrapolation and single-cell transcriptome data correction using the CIBERSORT deconvolution algorithm. Animal models were constructed by combining a high-fat diet with 5 Gy γ-ray whole-body low-dose ionizing radiation. The detection of NETs release was validated by enzyme-linked immunosorbent assay., Results: Analysis reveals shared genes in both datasets of post-irradiation and atherosclerosis, suggesting that immune system neutrophils may be a key node connecting radiation to atherosclerosis. NETs released by neutrophil death can influence the development of atherosclerosis. Animal experiments showed that the number of neutrophils decreased (P < 0.05) and the concentration of NETs reduced after low-dose radiation compared with the control group, and the concentration of NETs significantly increased (P < 0.05) in the HF group. Endothelial plaques were significantly increased in the high-fat feed group and significantly decreased in the low-dose radiation group compared with the control group., Conclusions: Long-term low-dose ionizing radiation exposure stimulates neutrophils and inhibits their production of NETs, resulting in inhibition of atherosclerosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Wenzhou Medical University. Published by Elsevier B.V. All rights reserved.)

Background: Atherosclerosis is a dynamic process. There is little evidence regarding whether quantification of atherosclerosis extent and progression, particularly in the carotid artery, in asymptomatic individuals predicts all-cause mortality., Objectives: This study sought to evaluate the independent predictive value (beyond cardiovascular risk factors) of subclinical atherosclerosis burden and progression and all-cause mortality., Methods: A population of 5,716 asymptomatic U.S. adults (mean age 68.9 years, 56.7% female) enrolled between 2008 and 2009 in the BioImage (A Clinical Study of Burden of Atherosclerotic Disease in an At Risk Population) study underwent examination by vascular ultrasound to quantify carotid plaque burden (cPB) (the sum of right and left carotid plaque areas) and by computed tomography for coronary artery calcium (CAC). Follow-up carotid vascular ultrasound was performed on 732 participants a median of 8.9 years after the baseline exam. All participants were followed up for all-cause mortality, the primary outcome. Trend HRs are the per-tertile increase in each variable., Results: Over a median 12.4 years' follow-up, 901 (16%) participants died. After adjustment for cardiovascular risk factors and background medication, baseline cPB and CAC score were both significantly associated with all-cause mortality (fully adjusted trend HR: 1.23; 95% CI: 1.16-1.32; and HR: 1.15; 95% CI: 1.08-1.23), respectively (both P < 0.001), thus providing additional prognostic value. cPB performed better than CAC score. In participants with a second vascular ultrasound evaluation, median cPB progressed from 29.2 to 91.3 mm 3 . cPB progression was significantly associated with all-cause mortality after adjusting for cardiovascular risk factors and baseline cPB (HR: 1.03; 95% CI: 1.01-1.04 per absolute 10-mm 3 change; P = 0.01)., Conclusions: Subclinical atherosclerosis burden (cPB and CAC) in asymptomatic individuals was independently associated with all-cause mortality. Moreover, atherosclerosis progression was independently associated with all-cause mortality., Competing Interests: Funding Support and Author Disclosures The High-Risk Plaque BioImage initiative was a precompetitive industry collaboration funded by BG Medicine, Abbott Vascular, AstraZeneca, Merck & Co., Philips, and Takeda. These funders had no role in the present study. Dr Ibanez was supported by the European Commission (grant numbers H2020-HEALTH 945118 and ERC-CoG 819775), La Caixa Foundation (HR22-00533, DIREQT2Heart), the Spanish Ministry of Science and Innovation (PID2022-140176OB-I00), and the Red Madrileña de Nanomedicina en Imagen Molecular–Comunidad de Madrid (2022/BMD-7403 RENIM-CM). Dr García-Álvarez was supported by the Instituto de Salud Carlos III (PI20/00742 and PI23/01341) and La Fundació la Marató TV3 (202314-30/31). Dr Devesa is an Alfonso Martin Escudero fellow and was scientifically supported by la La Caixa Foundation. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MICIU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIU/AEI/10.13039/501100011033). Dr Sánchez-González is an employee of Philips. Dr Muntendam is CEO of SQ innovation. Philips and SQ innovation had no role in the present study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: The process of atherosclerosis (AS) is complicated. Transcriptomics technology can assist in discovering the underlying mechanisms and exploring the key targets of Traditional Chinese Medicine (TCM) against atherosclerosis., Aim: This study aimed to investigate targets and signaling pathways significantly related to AS and the potential intervention targets of Xuefu Zhuyu decoction by transcriptomics., Materials and Methods: AS models were established by subjecting ApoE -/- mice to an 8-week high-fat diet. Structural changes and plaque formation in the aortic root were observed using hematoxylin-eosin staining (HE staining), while Oil Red O staining was employed to visualize lipid deposition within the aortic root plaque. Movat staining and immunohistochemical staining were conducted to examine the components present in the aortic root plaque. Macrophage content within the plaque was observed through immunofluorescence. Additionally, mRNA sequencing was performed on aortic tissues to identify differentially expressed genes. Enrichment analysis was performed using GO and KEGG analysis. Visualization of the protein-protein interaction (PPI) network was achieved using Cytoscape 3.7.1 and STRING. Western blotting (WB) was employed to assess the protein expression of major differentially expressed genes in the aortic tissue. The drug freeze-dried powder of Xuefu Zhuyu decoction was prepared and the RAW264.7 cells were induced by lipopolysaccharide (LPS) to build an in vitro model. Real-time quantitative PCR was employed to measure the mRNA expression of major differential genes., Results: After ApoE -/- mice were fed with an 8-week high-fat diet, observable changes included the thinning of the aortic root wall, the accumulation of foam cells within the plaque, and the formation of cholesterol crystals in the model group. Treatment with Xuefu Zhuyu (XFZY) decoction for 12 weeks significantly reduced the lipid deposition and the number of macrophages (P < 0.05) and significantly increased the collagen content within the plaque (P < 0.01). Enrichment analysis revealed a high enrichment of the Cytokine-cytokine receptor interaction pathway and Chemokine signaling pathway. Noteworthy genes involved in this response included Ccl12, Ccl22, Cx3cr1, Ccr7, Ccr2, Tnfrsf25, and Gdf5. Xuefu Zhuyu decoction significantly downregulated the expression of CX3CL1 and CX3CR1 (P < 0.05) and upregulated the expression of GDF5 (P < 0.01). Compared with control group, in cell models, the mRNA expressions of Ccl12, Ccl22, and Ccr2 were significantly upregulated (P < 0.05 or P < 0.01). Xuefu Zhuyu decoction significantly downregulated the expression of Ccl12, Ccl22, Cx3cr1, Ccr7 and Ccr2 (P < 0.05 or P < 0.01)., Conclusion: Xuefu Zhuyu decoction demonstrates effective regulation of plaque components, retarding plaque progression and preserving plaque stability by modulating lipid metabolism and inflammatory responses. Subsequent transcriptome analysis identified the Cytokine-cytokine receptor interaction and Chemokine signaling pathway as potential key pathways for the therapeutic effects of Xuefu Zhuyu decoction. This insight not only provides crucial avenues for further exploration into the mechanisms underlying Xuefu Zhuyu decoction but also offers valuable perspectives and hypotheses for enhancing disease prevention and treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aims: CCN4/WISP-1 regulates various cell behaviours that contribute to atherosclerosis progression, including cell adhesion, migration, proliferation and survival. We therefore hypothesised that CCN4 regulates the development and progression of atherosclerotic plaques., Methods: We used a high fat fed ApoE -/- mouse model to study atherosclerotic plaque progression in the brachiocephalic artery and aortic root. In protocol 1, male ApoE -/- mice with established plaques were given a CCN4 helper-dependent adenovirus to see the effect of treatment with CCN4, while in protocol 2 male CCN4 -/- ApoE -/- were compared to CCN4 +/+ ApoE -/- mice to assess the effect of CCN4 deletion on plaque progression., Results: CCN4 overexpression resulted in reduced occlusion of the brachiocephalic artery with less apoptosis, fewer macrophages, and attenuated lipid core size. The amount of plaque found on the aortic root was also reduced. CCN4 deficiency resulted in increased apoptosis and occlusion of the brachiocephalic artery as well as increased plaque in the aortic root. Additionally, in vitro cells from CCN4 -/- ApoE -/- mice had higher apoptotic levels. CCN4 deficiency did not significantly affect blood cholesterol levels or circulating myeloid cell populations., Conclusions: We conclude that in an atherosclerosis model the most important action of CCN4 is the effect on cell apoptosis. CCN4 provides pro-survival signals and leads to reduced cell death, lower macrophage number, smaller lipid core size and reduced atherosclerotic plaque burden. As such, the pro-survival effect of CCN4 is worthy of further investigation, in a bid to find a therapeutic for atherosclerosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Macrophage polarization and the resulting phenotype have versatile roles in atherosclerosis. The study aims to decipher the role of SIRT1 in regulating macrophage phenotypes and atherosclerosis development., Methods: Two mouse lines of SIRT1 △Mac /ApoE -/- and SIRT1 fl/fl /ApoE -/- were fed with high-fat diet to generate atherosclerotic lesion. Mouse peritoneal macrophages were isolated and transfected with SIRT1-overexpressing vector or vector-null., Results: The SIRT1 △Mac /ApoE -/- mice exhibited greater atherosclerotic lesions, stronger immunofluorescence staining for M1-like macrophage marker, iNOS, and weaker immunofluorescence staining for M2-like macrophage marker, Arginase-1, than the SIRT1 fl/fl /ApoE -/- littermates. The gene expressions of M1 markers (IL-1β, IL-6, and iNOS) were increased and those of M2 markers (IL-10 and Arg-1) decreased in both aortic roots and peritoneal macrophages from SIRT1 △Mac /ApoE -/- mice, whereas SIRT1 overexpression rectified the changes in M1/M2 expression. A declined expression of TIMP3 with an increased expression of ADAM17 was noted in SIRT1 △Mac /ApoE -/- macrophages, whereas SIRT1 overexpression rescued TIMP3 expression and inhibited ADAM17 expression., Conclusion: Our data suggest that SIRT1 deficiency may promote macrophage M1 polarization and regulate the TIMP3/ADAM17 pathway thus favoring atherosclerosis development, indicating an anti-atherosclerotic role of macrophage SIRT1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Lysyl oxidase (LOX) catalyzes the crosslinking of collagen and elastin to maintain tensile strength and structural integrity of the vasculature. Excessive LOX activity increases vascular stiffness and the severity of occlusive diseases. Herein, we investigated the mechanisms by which LOX controls atherogenesis and osteogenic differentiation of vascular smooth muscle cells (SMC) in hyperlipidemic mice., Methods: Gene inactivation of Lox in SMC was achieved in conditional knockout mice after tamoxifen injections. Atherosclerosis burden and vascular calcification were assessed in hyperlipidemic conditional [Lox f/f Myh11-CreER T2 ApoE -/- ] and sibling control mice [Lox wt/wt Myh11-CreER T2 ApoE -/- ]. Mechanistic studies were performed with primary aortic SMC from Lox mutant and wild type mice., Results: Inactivation of Lox in SMCs decreased > 70 % its RNA expression and protein level in the aortic wall and significantly reduced LOX activity without compromising vascular structure and function. Moreover, LOX deficiency protected mice against atherosclerotic burden (13 ± 2 versus 23 ± 1 %, p < 0.01) and plaque calcification (5 ± 0.4 versus 11.8 ± 3 %, p < 0.05) compared to sibling controls. Interestingly, gene inactivation of Lox in SMCs preserved the contractile phenotype of vascular SMC under hyperlipidemic conditions as demonstrated by single-cell RNA sequencing and immunofluorescence. Mechanistically, the absence of LOX in SMC prevented excessive collagen crosslinking and the subsequent activation of the pro-osteogenic FAK/β-catenin signaling axis., Conclusions: Lox inactivation in SMC protects mice against atherosclerosis and plaque calcification by reducing SMC modulation and FAK/β-catenin signaling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Microplastics and nanoplastics (MNPs) originating from plastic pollution pose potential threats to cardiovascular health, with prior studies linking MNPs to atherosclerosis. Our earlier research elucidated how nanoplastics enhance macrophages' phagocytic activity, leading to the formation of foam cells and an elevated risk of atherosclerosis. However, the specific influence of MNPs on smooth muscle cells (SMCs) in the context of MNP-induced atherosclerosis remains poorly understood. In this study, ApoE knockout (ApoE -/- ) male mice with a high-fat diet were orally exposed to environmentally realistic concentrations of 2.5-250 mg/kg polystyrene nanoplastics (PS-NPs, 50 nm) for consecutive 19 weeks. Cardiovascular toxicity was comprehensively assessed through histopathological, transcriptomic, and proteomic analyses, while mechanisms underlying this toxicity were explored through in vitro studies. Herein, hematoxylin and eosin staining revealed accelerated atherosclerotic plaque development in ApoE -/- mice exposed to PS-NPs. Multi-omics analysis identified kinesin family member 15 (KIF15) as a pivotal target molecule. Both in vitro and in vivo experiments affirmed the specific upregulation of KIF15 in mouse aortic SMCs exposed to PS-NPs. Furthermore, in vitro experiments demonstrated that PS-NPs can promote the migration ability of MOVAS cells. Knockdown of Kif15 revealed its role in reducing MOVAS cell migration, with subsequent exposure to PS-NPs reversing the increased migration ability. This suggests that PS-NPs promote SMC migration by upregulating KIF15, and the migration of SMCs is closely associated with atherosclerosis outcomes. This study significantly advances our understanding of MNP-induced cardiovascular toxicity, providing valuable insights for risk assessment of human MNP exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Part of the figures were created with biorender.com., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Atherosclerotic cardiovascular disease complicated by diabetes mellitus (DM) is the leading cause of death in diabetic patients, and it is strongly associated with macrophages and inflammasomes. It has been found that activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is closely associated with phosphatidylinositol 4-phosphate (PI4P) on the trans-Golgi. However, how PI4P and NLRP3 regulate macrophage function and its role in diabetic atherosclerotic plaques is unclear., Methods: The expression of Pi4p and Nlrp3-inflammasome-related proteins in atherosclerosis in apolipoprotein E-deficient (Apoe -/- ) and Apoe -/- DM mice was investigated. Then, Pi4p levels were affected by shRNA-Pi4kb or cDNA-Sac1 plasmid to investigate the effects of changes in Pi4p-related metabolic enzymes on macrophage function. Finally, genetically modified macrophages were injected into diabetic Apoe -/- mice to explore the effects on atherosclerosis., Results: DM promoted plaque progression in atherosclerotic mice and increased expression of Pi4p and Nlrp3 in plaques. In addition, impaired macrophage function induced by high glucose was reversed by transfected shRNA-Pi4kb or cDNA-Sac1 plasmid. Furthermore, decreased levels of Pi4p reduced plaque area in diabetic Apoe -/- mice., Conclusions: Our data suggests that Pi4p/Nlrp3 in macrophages play an important role in the exacerbation of atherosclerosis in diabetic mice. Pi4p-related metabolizing enzymes (PI4KB and SAC1) may be a potential therapeutic strategy for diabetic atherosclerosis, and macrophage therapy is also a potential treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Identifying controllable risk factors for large-artery atherosclerosis (LAA) stroke is crucial due to its significant role as a leading cause of ischemic stroke. We aimed to validate the correlation of serum vitamin B 12 with LAA stroke., Methods: Inpatients with LAA stroke and healthy controls were retrospectively collected for a case-control study from January 2020 to May 2022. Serum vitamin B 12 concentration and other blood indicators, demographic, lifestyle factors and comorbidities were investigated. Logistic regression analysis was used to identify the correlation of serum vitamin B 12 concentrations with LAA stroke, meanwhile adjusted for confounding factors., Results: Patients with LAA stroke had significantly lower serum vitamin B 12 concentrations in comparison to those of controls. In the fully adjusted model, vitamin B 12 (per 1 interquartile range increase, odds ratio [OR] = 0.84, 95 % confidence interval [CI]: 0.77-0.91), vitamin B 12  < 200 pg/mL (OR=7.70, 95 %CI: 2.19-27.03) and vitamin B 12  < 300 pg/mL (OR=4.19, 95 %CI: 1.82-9.66) were independently factors for LAA stroke. Furthermore, the optimal cut-off values for vitamin B 12 to predict LAA stroke were 305.25 pg/mL (area under the curve [AUC] = 0.71) when unadjusted and 308.25 pg/mL when adjusted for age and sex (AUC=0.68). Lower vitamin B 12 concentrations were significantly associated with male sex, smoking, older age, higher neutrophil count, higher creatinine, lower folate and higher total homocysteine., Conclusion: Results indicate that low concentration of serum vitamin B 12 may be a strong predictor for the risk of LAA stroke., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Neuregulin-1(NRG-1) is a protein that belongs to the group of epidermal growth factors. It plays vital roles in anti-fibrotic effects on the myocardium. The current paper explores the role of NRG-1 in type 2 diabetes mellitus (T2DM) and its relation to atherogenic index as a factor for increasing cardiovascular disease(CVD) risk., Material and Methods: In this study, 79 diabetes mellitus patients are independent insulin. These patients consisted of 53 females and 26 males their age were ranged 40-67 years. They were divided into two groups depending on the atherogenic index of plasma (AIP). Group I including48 diabetic patient with high risk of CVD and group II including 31 diabetic patients without risk CVD. Forty healthy individuals were included as control., Result: When compared to the control group, the serum levels of NRG-1 were significantly lower (p = 0.01). Additionally, group I had a much lower NRG-1level than group II. The results of multiple stepwise regression showed that the only independent predictor for NRG-1 level prediction was AIP (β =  - 0.600, P = 0.040). When comparing the diabetic patients with high risk factors for CVD to the healthy subject group, the AUC was outstanding (AUC = 0.889, P = 0.001) and had a high diagnosis., Conclusions: We proved low NRG-1 levels in diabetic patients and the association of highest NRG-1 amounts to a better AIP. Moreover, the measurement of NRG-1 levels could be beneficial as laboratory markers to monitor for increasing CVD risk in type 2 diabetes mellitus., (© 2024. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Background and Aims: Dysregulated cholesterol metabolism is a hallmark of atherosclerotic cardiovascular diseases, yet our understanding of how endogenous cholesterol synthesis affects atherosclerosis is not clear. The energy sensor AMP-activated protein kinase (AMPK) phosphorylates and inhibits the rate-limiting enzyme in the mevalonate pathway HMG-CoA reductase (HMGCR). Recent work demonstrated that when AMPK-HMGCR signaling was compromised in an Apoe -/- model of hypercholesterolemia, atherosclerosis was exacerbated due to elevated hematopoietic stem and progenitor cell mobilization and myelopoiesis. We sought to validate the significance of the AMPK-HMGCR signaling axis in atherosclerosis using a non-germline hypercholesterolemia model with functional ApoE., Methods: Male and female HMGCR S871A knock-in (KI) mice and wild-type (WT) littermate controls were made atherosclerotic by intravenous injection of a gain-of-function Pcsk9 D374Y -adeno-associated virus followed by high-fat and high-cholesterol atherogenic western diet feeding for 16 weeks., Results: AMPK activation suppressed endogenous cholesterol synthesis in primary bone marrow-derived macrophages from WT but not HMGCR KI mice, without changing other parameters of cholesterol regulation. Atherosclerotic plaque area was unchanged between WT and HMGCR KI mice, independent of sex. Correspondingly, there were no phenotypic differences observed in hematopoietic progenitors or differentiated immune cells in the bone marrow, blood, or spleen, and no significant changes in systemic markers of inflammation. When lethally irradiated female mice were transplanted with KI bone marrow, there was similar plaque content relative to WT., Conclusions: Given previous work, our study demonstrates the importance of preclinical atherosclerosis model comparison and brings into question the importance of AMPK-mediated control of cholesterol synthesis in atherosclerosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Ganoderma lucidum is a unique form of fungus utilized in Chinese medicine for various therapies as it exhibits a wide range of pharmacological activity. In this study, the purpose is to evaluate the possible drug-like qualities of the metabolites of G. lucidium as well as the impact that these metabolites have on the pathways involved in atherosclerosis. Throughout our research, a total of 17 compounds were chosen based on their drug-like properties. These compounds were then utilized in the subsequent networking and docking simulations. According to the findings, the compound ganodone has a maximum binding energy of -7.243 Kcal/mol. In terms of the binding energy, it has been discovered that the compound cianidanol has the lowest value. Based on the findings of the molecular docking investigations, it was determined that TNF, AKT1, SRC, and STAT3 exhibited a higher affinity for the complex. To determine this, molecular dynamics simulation was performed for about 100 nanoseconds. Following the completion of the GO functional analysis, it was discovered that the target genes were involved in the processes of protein binding, ATP binding, enzyme binding, and protein tyrosine kinase activity. Overall, the study results provide a view of possible metabolites that may have an impact on disease progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Macrophage lipid accumulation indicates a pathological change in atherosclerosis. Ilexgenin A (IA), a pentacyclic triterpenoid compound, plays a role in preventing inflammation, bacterial infection, and fatty liver and induces a potential anti-atherogenic effect. However, the anti-atherosclerotic mechanism remains unclear. The present study investigated the effects of IA on lipid accumulation in macrophage-derived foam cells and atherogenesis in apoE -/- mice. Our results indicated that the expression of adenosine triphosphate-binding cassette transporter A1 (ABCA1) was up-regulated by IA, promoting cholesterol efflux and reducing lipid accumulation in macrophages, which may be regulated by the protein tyrosine phosphatase non-receptor type 2 (PTPN2)/ERK1/2 signalling pathway. IA attenuated the progression of atherosclerosis in high-fat diet-fed apoE -/- mice. PTPN2 knockdown with siRNA or treatment with an ERK1/2 agonist (Ro 67-7476) impeded the effects of IA on ABCA1 upregulation and cholesterol efflux in macrophages. These results suggest that IA inhibits macrophage lipid accumulation and alleviates atherosclerosis progression via the PTPN2/ERK1/2 signalling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism commonly exists in the East Asian populations and is associated with high risks of cardiovascular disease (CVD). However, the cellular and molecular mechanisms that underlie the ALDH2 rs671 mutant-linked high CVD remain elusive. Here, we show that macrophages derived from human ALDH2 rs671 carriers and ALDH2 knockout mice exhibited an enhanced pro-inflammatory macrophage phenotype and an impaired anti-inflammatory macrophage phenotype. Transplanting bone marrow from ALDH2 -/- ApoE -/- to ApoE -/- mice significantly increased atherosclerotic plaque growth and pro-inflammatory macrophage polarization in vivo. Mechanistically, ALDH2 inhibited activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in macrophages. Pharmacological inhibition of cGAS by RU.521 completely neutralized ALDH2-deficiency-induced macrophage polarization. In-depth mechanistic investigation showed that ALDH2 accelerated cGAS K48-linked polyubiquitination degradation at lysine 282 in macrophages by reducing the interaction between ubiquitin-specific protease 14 (USP14) and cGAS, mainly through its enzymatic role in mitigating 4-hydroxy-2-nonenal (4-HNE) accumulation. Consistently, USP14 knockdown in bone marrow cells alleviated proinflammatory responses in macrophages and protected against atherosclerosis. Our findings provide new mechanistic insights of ALDH2 deficiency-associated proinflammation and atherosclerosis and new therapeutic and preventive paradigms for treatment of atherosclerosis-associated CVD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The subendothelial retention of circulating lipoproteins on extracellular matrix proteins and proteoglycans is one of the earliest events in the development of atherosclerosis. Multiple factors, including the size, type, composition, surrounding pH, and chemical modifications to lipoproteins, influence the electrostatic interactions between relevant moieties of the apolipoproteins on lipoproteins and the glycosaminoglycans of proteoglycans. The length and chemical composition of glycosaminoglycan chains attached to proteoglycan core proteins determine the extent of initial lipoprotein binding and retention in the artery wall. The phenomena of hyperelongation of glycosaminoglycan chains is associated with initial lipid retention and later atherosclerotic plaque formation. This review includes a summary of the current literature surrounding cellular mechanisms leading to GAG chain modification and lipid retention and discusses potential therapeutic strategies to target lipoprotein:proteoglycan interactions to prevent the development and progression of atherosclerosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is a chronic inflammatory disease mainly affecting the peripheral diarthrodial joints symmetrically and also presenting many extra-articular manifestations. Morbidity and mortality in RA patients are higher compared to the general population. Cardiovascular (CV) disease is one of the most common causes of death in these patients. Classical or traditional risk factors for atherosclerosis development occur more frequently in RA patients compared to those without this condition. Studies have showed that RA patients often present comorbidities such as hypertension, dyslipidemia, diabetes mellitus and obesity. However, the high incidence of CV events occurring in RA patients is not explained by the presence of traditional risk factors. Systemic inflammation, as it is expressed with the presence of proinflammatory cytokines and increased acute phase reactants, may contribute to the development of premature atherosclerosis in these patients. In this review, we explore the risk factors for CV disease, the generation of dyslipidemia, the lipid paradox and the role of systemic inflammation in the atherosclerotic process in RA. We discuss also the role of early therapeutic intervention that suppresses inflammation which may have beneficial effects on CV disease in RA patients., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Cardiovascular disease (CVD) is a global health concern, presenting significant risks to human health. Atherosclerosis is among the most prevalent CVD, impacting the medium and large arteries in the kidneys, brain, heart, and other vital organs, as well as the lower limbs. As the disease progresses, arterial obstruction can result in heart attacks and strokes. Therefore, patients with atherosclerosis should receive accurate diagnosis and timely therapeutic intervention. With the advancements in nanomedicine, researchers have proposed new research strategies and methods for atherosclerosis imaging. This paper summarizes some current research findings on the use of nanomaterials in diagnosing atherosclerosis and offers insights for optimizing the imaging applications of nanomaterials in the future.

Background: Macrophage-derived foam cell formation is a hallmark of atherosclerosis and is retained during plaque formation. Strategies to inhibit the accumulation of these cells hold promise as viable options for treating atherosclerosis. Plexin D1 (PLXND1), a member of the Plexin family, has elevated expression in atherosclerotic plaques and correlates with cell migration; however, its role in macrophages remains unclear. We hypothesize that the guidance receptor PLXND1 negatively regulating macrophage mobility to promote the progression of atherosclerosis., Methods: We utilized a mouse model of atherosclerosis based on a high-fat diet and an ox-LDL- induced foam cell model to assess PLXND1 levels and their impact on cell migration. Through western blotting, Transwell assays, and immunofluorescence staining, we explored the potential mechanism by which PLXND1 mediates foam cell motility in atherosclerosis., Results: Our study identifies a critical role for PLXND1 in atherosclerosis plaques and in a low-migration capacity foam cell model induced by ox-LDL. In the aortic sinus plaques of ApoE -/- mice, immunofluorescence staining revealed significant upregulation of PLXND1 and Sema3E, with colocalization in macrophages. In macrophages treated with ox-LDL, increased expression of PLXND1 led to reduced pseudopodia formation and decreased migratory capacity. PLXND1 is involved in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK. Additionally, FAK inhibitors counteract the ox-LDL-induced migration suppression by modulating the phosphorylation states of FAK, Paxillin and their downstream effectors CDC42 and PAK., Conclusion: Our findings indicate that PLXND1 plays a role in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK to promoting atherosclerosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tetrahydroxy stilbene glucoside (TSG) is a water-soluble natural product that has shown potential in treating atherosclerosis (AS). However, its underlying mechanisms remain unclear. Here, we demonstrate that an 8-week TSG treatment (100 mg/kg/d) significantly reduces atherosclerotic lesions and alleviates dyslipidemia symptoms in ApoE -/- mice. 1 H nuclear magnetic resonance metabolomic analysis reveals differences in both lipid components and water-soluble metabolites in the livers of AS mice compared to control groups, and TSG treatment shifts the metabolic profiles of AS mice towards a normal state. At the transcriptional level, TSG significantly restores the expression of fatty acid metabolism-related genes (Srepb-1c, Fasn, Scd1, Gpat1, Dgat1, Pparα and Cpt1α), and regulates the expression levels of disturbed cholesterol metabolism-related genes (Srebp2, Hmgcr, Ldlr, Acat1, Acat2 and Cyp7a1) associated with lipid metabolism. Furthermore, at the cellular level, TSG remarkably polarizes aortic macrophages to their M2 phenotype. Our data demonstrate that TSG alleviates arthrosclerosis by dual-targeting to hepatic lipid metabolism and aortic M2 macrophage polarization in ApoE -/- mice, with significant implications for translational medicine and the treatment of AS using natural products., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Atherosclerosis is a chronic inflammatory disease of the arterial wall caused by an imbalance of lipid metabolism and a maladaptive inflammatory response. A variety of harmful cellular changes associated with atherosclerosis include endothelial dysfunction, the migration of circulating inflammatory cells to the arterial wall, the production of proinflammatory cytokines, lipid buildup in the intima, local inflammatory responses in blood vessels, atherosclerosis-associated apoptosis, and autophagy. PTEN inhibits the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT)/mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity. Previous studies have shown that PTEN is closely related to atherosclerosis. This article reviews the role of PTEN in atherosclerosis from the perspectives of autophagy, apoptosis, inflammation, proliferation, and angiogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The ability of a 1-time measurement of non-high-density lipoprotein cholesterol (non-HDL-C) or low-density lipoprotein cholesterol (LDL-C) to predict the cumulative exposure to these lipids during early adulthood (age 18-40 years) and the associated atherosclerotic cardiovascular disease (ASCVD) risk after age 40 years is not clear., Objectives: The objectives of this study were to evaluate whether a 1-time measurement of non-HDL-C or LDL-C in a young adult can predict cumulative exposure to these lipids during early adulthood, and to quantify the association between cumulative exposure to non-HDL-C or LDL-C during early adulthood and the risk of ASCVD after age 40 years., Methods: We included CARDIA (Coronary Artery Risk Development in Young Adults Study) participants who were free of cardiovascular disease before age 40 years, were not taking lipid-lowering medications, and had ≥3 measurements of LDL-C and non-HDL-C before age 40 years. First, we assessed the ability of a 1-time measurement of LDL-C or non-HDL-C obtained between age 18 and 30 years to predict the quartile of cumulative lipid exposure from ages 18 to 40 years. Second, we assessed the associations between quartiles of cumulative lipid exposure from ages 18 to 40 years with ASCVD events (fatal and nonfatal myocardial infarction and stroke) after age 40 years., Results: Of 4,104 CARDIA participants who had multiple lipid measurements before and after age 30 years, 3,995 participants met our inclusion criteria and were in the final analysis set. A 1-time measure of non-HDL-C and LDL-C had excellent discrimination for predicting membership in the top or bottom quartiles of cumulative exposure (AUC: 0.93 for the 4 models). The absolute values of non-HDL-C and LDL-C that predicted membership in the top quartiles with the highest simultaneous sensitivity and specificity (highest Youden's Index) were >135 mg/dL for non-HDL-C and >118 mg/dL for LDL-C; the values that predicted membership in the bottom quartiles were <107 mg/dL for non-HDL-C and <96 mg/dL for LDL-C. Individuals in the top quartile of non-HDL-C and LDL-C exposure had demographic-adjusted HRs of 4.6 (95% CI: 2.84-7.29) and 4.0 (95% CI: 2.50-6.33) for ASCVD events after age 40 years, respectively, when compared with each bottom quartile., Conclusions: Single measures of non-HDL-C and LDL-C obtained between ages 18 and 30 years are highly predictive of cumulative exposure before age 40 years, which in turn strongly predicts later-life ASCVD events., Competing Interests: Funding Support and Author Disclosures This work was supported by National Heart, Lung, and Blood Institute R01HL146844. Dr Wilkins has served as a consultant for 3M (nonmedical division) that is not relevant to the content of this manuscript. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)