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Theranostics 2023Atherosclerosis (AS) is still the major cause of cardiovascular disease (CVD) as well as stroke. Endothelial metabolic disorder has been found to be activated and then...
Atherosclerosis (AS) is still the major cause of cardiovascular disease (CVD) as well as stroke. Endothelial metabolic disorder has been found to be activated and then promote endothelial cells (ECs) injury, which is regarded to initiate AS progression. N-acetylneuraminic acid (Neu5Ac), a metabolite produced by hexosamine-sialic acid pathway branching from glucose metabolism, was presented as a notable biomarker of CVD and is positively correlated with ECs function. However, few studies explain whether Neu5Ac regulate AS progression by affecting EC function as well as its involved mechanisms are still unknown. Here, we mimicked an animal model in mice which displaying similar plasma Neu5Ac levels with AS model to investigate its effect on AS progression. We found that Neu5Ac exacerbated plaques area and increased lipids in plasma in absence of HFD feeding, and ECs inflammatory injury was supposed as the triggering factor upon Neu5Ac treatment with increasing expression of IL-1β, ICAM-1, and promoting ability of monocyte adhesion to ECs. Mechanistic studies showed that Neu5Ac facilitated SLC3A2 binding to ubiquitin and then triggered P62 mediated degradation, further leading to accumulation of lipid peroxidation in ECs. Fer-1 could inhibit ECs injury and reverse AS progression induced by Neu5Ac in mice. Interestingly, mitochondrial dysfunction was also partly participated in ECs injury after Neu5Ac treatment and been reversed by Fer-1. Together, our study unveils a new mechanism by which evaluated metabolite Neu5Ac could promote SLC3A2 associated endothelial ferroptosis to activate ECs injury and AS plaque progression, thus providing a new insight into the role of Neu5Ac-ferroptosis pathway in AS. Also, our research revealed that pharmacological inhibition of ferroptosis may provide a novel therapeutic strategy for premature AS.
Topics: Animals; Mice; Atherosclerosis; Endothelial Cells; Ferroptosis; Plaque, Atherosclerotic; Mice, Knockout, ApoE; Fusion Regulatory Protein 1, Heavy Chain
PubMed: 37771765
DOI: 10.7150/thno.87968 -
Stroke Dec 2023The identification of a variant in the gene as a risk factor for large-artery atherosclerotic stroke, and subsequently coronary artery disease, has opened novel... (Review)
Review
The identification of a variant in the gene as a risk factor for large-artery atherosclerotic stroke, and subsequently coronary artery disease, has opened novel treatment pathways for stroke and more widely atherosclerotic disease. This article describes the pathway from gene discovery to novel therapeutic approaches that are now entering man. expression is elevated in human atherosclerotic plaque, while in animal and cellular models, reducing HDAC9 (histone deacetylase 9) protein is associated with reduced disease. Several mechanisms have been proposed to account for the association between HDAC9 and atherosclerosis including alterations in the inflammatory response and cholesterol efflux and endothelial-mesenchymal transition. The association raises the possibility that inhibiting HDAC9 may provide a novel treatment approach for atherosclerotic cardiovascular disease. This is supported by intervention studies demonstrating HDAC9 inhibition reduces atherosclerosis in animal and cellular models. Indirect data support such an approach in man. The antiseizure drug sodium valproate, which has nonspecific HDAC inhibitory properties, both inhibits atherosclerosis in animal models and is epidemiologically associated with reduced stroke and myocardial infarction risk in man. It is now being trailed in phase 2 studies in large-artery stroke, while more specific HDAC9 inhibitors are being developed.
Topics: Animals; Humans; Stroke; Atherosclerosis; Plaque, Atherosclerotic; Risk Factors; Histone Deacetylases; Repressor Proteins
PubMed: 37942644
DOI: 10.1161/STROKEAHA.123.044862 -
Current Problems in Cardiology Nov 2023Traditional atherosclerosis imaging modalities are limited to late stages of disease, prior to which patients are frequently asymptomatic. Positron emission tomography... (Review)
Review
Traditional atherosclerosis imaging modalities are limited to late stages of disease, prior to which patients are frequently asymptomatic. Positron emission tomography (PET) imaging allows for the visualization of metabolic processes underscoring disease progression via radioactive tracer, allowing earlier-stage disease to be identified. 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) uptake largely reflects the metabolic activity of macrophages, but is unspecific and limited in its utility. By detecting areas of microcalcification, 18F-Sodium Fluoride (18F-NaF) uptake also provides insight into atherosclerosis pathogenesis. Gallium-68 DOTA-0-Tyr3-Octreotate (68Ga-DOTATATE) PET has also shown potential in identifying vulnerable atherosclerotic plaques with high somatostatin receptor expression. Finally, 11-carbon (11C)-choline and 18F-fluoromethylcholine (FMCH) tracers may identify high-risk atherosclerotic plaques by detecting increased choline metabolism. Together, these radiotracers quantify disease burden, assess treatment efficacy, and stratify risk for adverse cardiac events.
Topics: Humans; Plaque, Atherosclerotic; Radiopharmaceuticals; Positron-Emission Tomography; Atherosclerosis; Choline
PubMed: 37392979
DOI: 10.1016/j.cpcardiol.2023.101925 -
Frontiers in Immunology 2023The role of complement component 1q (C1Q) related genes on human atherosclerotic plaques (HAP) is less known. Our aim is to establish C1Q associated hub genes using...
An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis.
BACKGROUND
The role of complement component 1q (C1Q) related genes on human atherosclerotic plaques (HAP) is less known. Our aim is to establish C1Q associated hub genes using single-cell RNA sequencing (scRNA-seq) and bulk RNA analysis to diagnose and predict HAP patients more effectively and investigate the association between C1Q and HAP (ischemic stroke) using bidirectional Mendelian randomization (MR) analysis.
METHODS
HAP scRNA-seq and bulk-RNA data were download from the Gene Expression Omnibus (GEO) database. The C1Q-related hub genes was screened using the GBM, LASSO and XGBoost algorithms. We built machine learning models to diagnose and distinguish between types of atherosclerosis using generalized linear models and receiver operating characteristics (ROC) analyses. Further, we scored the HALLMARK_COMPLEMENT signaling pathway using ssGSEA and confirmed hub gene expression through qRT-PCR in RAW264.7 macrophages and apoE-/- mice. Furthermore, the risk association between C1Q and HAP was assessed through bidirectional MR analysis, with C1Q as exposure and ischemic stroke (IS, large artery atherosclerosis) as outcomes. Inverse variance weighting (IVW) was used as the main method.
RESULTS
We utilized scRNA-seq dataset (GSE159677) to identify 24 cell clusters and 12 cell types, and revealed seven C1Q associated DEGs in both the scRNA-seq and GEO datasets. We then used GBM, LASSO and XGBoost to select C1QA and C1QC from the seven DEGs. Our findings indicated that both training and validation cohorts had satisfactory diagnostic accuracy for identifying patients with HPAs. Additionally, we confirmed SPI1 as a potential TF responsible for regulating the two hub genes in HAP. Our analysis further revealed that the HALLMARK_COMPLEMENT signaling pathway was correlated and activated with C1QA and C1QC. We confirmed high expression levels of C1QA, C1QC and SPI1 in ox-LDL-treated RAW264.7 macrophages and apoE-/- mice using qPCR. The results of MR indicated that there was a positive association between the genetic risk of C1Q and IS, as evidenced by an odds ratio (OR) of 1.118 (95%CI: 1.013-1.234, P = 0.027).
CONCLUSION
The authors have effectively developed and validated a novel diagnostic signature comprising two genes for HAP, while MR analysis has provided evidence supporting a favorable association of C1Q on IS.
Topics: Humans; Mice; Animals; Complement C1q; Mendelian Randomization Analysis; Transcriptome; Mice, Knockout, ApoE; Atherosclerosis; Plaque, Atherosclerotic; Ischemic Stroke; Apolipoproteins E; RNA
PubMed: 38179058
DOI: 10.3389/fimmu.2023.1289223 -
Atherosclerosis Jul 2023We investigated the causal relevance of alcohol intake with measures of carotid artery thickness and atherosclerosis in Chinese adults.
BACKGROUND AND AIMS
We investigated the causal relevance of alcohol intake with measures of carotid artery thickness and atherosclerosis in Chinese adults.
METHODS
The study included 22,384 adults from the China Kadoorie Biobank, with self-reported alcohol use at baseline and resurvey, carotid artery ultrasound measurements, and genotyping data for ALDH2-rs671 and ADH1B-rs1229984. Associations of carotid intima media thickness (cIMT), any carotid plaque, and total plaque burden (derived from plaque number and size) with self-reported (conventional analyses) and genotype-predicted mean alcohol intake (Mendelian randomization) were assessed using linear and logistic regression models.
RESULTS
Overall 34.2% men and 2.1% women drank alcohol regularly at baseline. Mean cIMT was 0.70 mm in men and 0.64 mm in women, with 39.1% and 26.5% having carotid plaque, respectively. Among men, cIMT was not associated with self-reported or genotype-predicted mean alcohol intake. The risk of plaque increased significantly with self-reported intake among current drinkers (odds ratio 1.42 [95% CI 1.14-1.76] per 280 g/week), with directionally consistent findings with genotype-predicted mean intake (1.21 [0.99-1.49]). Higher alcohol intake was significantly associated with higher carotid plaque burden in both conventional (0.19 [0.10-0.28] mm higher per 280 g/week) and genetic analyses (0.09 [0.02-0.17]). Genetic findings in women suggested the association of genotype-predicted alcohol with carotid plaque burden in men was likely to due to alcohol itself, rather than pleiotropic genotypic effects.
CONCLUSIONS
Higher alcohol intake was associated with a higher carotid plaque burden, but not with cIMT, providing support for a potential causal association of alcohol intake with carotid atherosclerosis.
Topics: Adult; Female; Humans; Male; Alcohol Drinking; Aldehyde Dehydrogenase, Mitochondrial; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; East Asian People; Plaque, Atherosclerotic; Risk Factors
PubMed: 37392542
DOI: 10.1016/j.atherosclerosis.2023.06.012 -
Journal of Ethnopharmacology Oct 2023QiShenYiQi pill (QSYQ), a Chinese compound medicine, originate from BuYangHuanWu decoction in the Qing dynasty, and has been used to treat ischemic cardiovascular...
ETHNOPHARMACOLOGICAL RELEVANCE
QiShenYiQi pill (QSYQ), a Chinese compound medicine, originate from BuYangHuanWu decoction in the Qing dynasty, and has been used to treat ischemic cardiovascular diseases for more than two hundred years in China. Multi-central randomized double-blind controlled studies have proved that QSYQ has similar efficacy as enteric coated aspirin in the secondary prevention of myocardial infarction.
AIM OF STUDY
The aim of study was to explore the effect of QSYQ on reverse cholesterol transport (RCT) pathway during atherosclerosis.
MATERIALS AND METHODS
Eight-week-old male apoE mice (on the gene background of C57BL/6J) were fed with a high-fat western diet and treated with low dose and high dose of QSYQ, as well as the positive control agent, liver X receptor-α (LXR-α) agonist GW3965. Eight weeks later, mice were sacrificed and the aorta was collected for atherosclerotic analysis. The aortic root was stained with Oil red O to evaluate the area of atherosclerotic lesion, and stained with immunohistochemistry to analyze the intra-plaque component and RCT protein in atherosclerotic plaque. The thoracic aorta was used to detect differentially expressed genes by comparative transcriptome RNA-seq and the protein expression of RCT pathway by western blotting.
RESULTS
After eight weeks of treatment, we found that both of QSYQ and LXR-α agonist reduced atherosclerotic plaque area significantly, and decreased the intra-plaque component, including the lipid, the smooth muscle cell and the macrophage. Compared with the control group, there were 49 differentially expressed genes in low-dose QSYQ group, including 21 up-regulated genes and 28 down-regulated genes. The results of GO and KEGG analysis showed that the differentially expressed genes mainly concentrated in the negative regulation of lipid biosynthesis, positive regulation of lipid metabolism, cell response to lipids, negative regulation of lipid storage, fatty acid degradation, and glycerol ester metabolism. Both of QSYQ and LXR-α agonist reduced the protein expression of CD36 and increased the protein expression of PPARγ-LXRα/β-ABCA1 in atherosclerotic plaque.
CONCLUSION
The anti-atherosclerotic mechanism of QSYQ was involved in inhibiting lipid phagocytosis and promoting reverse cholesterol transport, therefore reducing lipid deposition and inflammatory cells in plaque.
Topics: Animals; Male; Mice; Atherosclerosis; ATP Binding Cassette Transporter 1; Cholesterol; Lipids; Mice, Inbred C57BL; Plaque, Atherosclerotic; PPAR gamma; Mice, Knockout, ApoE
PubMed: 37230281
DOI: 10.1016/j.jep.2023.116684 -
Cells Jul 2023Current clinical data show that, despite constant efforts to develop novel therapies and clinical approaches, atherosclerotic cardiovascular diseases (ASCVD) are still... (Review)
Review
Current clinical data show that, despite constant efforts to develop novel therapies and clinical approaches, atherosclerotic cardiovascular diseases (ASCVD) are still one of the leading causes of death worldwide. Advanced and unstable atherosclerotic plaques most often trigger acute coronary events that can lead to fatal outcomes. However, despite the fact that different plaque phenotypes may require different treatments, current approaches to prognosis, diagnosis, and classification of acute coronary syndrome do not consider the diversity of plaque phenotypes. Long non-coding RNAs (lncRNAs) represent an important class of molecules that are implicated in epigenetic control of numerous cellular processes. Here we review the latest knowledge about lncRNAs' influence on plaque development and stability through regulation of immune response, lipid metabolism, extracellular matrix remodelling, endothelial cell function, and vascular smooth muscle function, with special emphasis on pro-atherogenic and anti-atherogenic lncRNA functions. In addition, we present current challenges in the research of lncRNAs' role in atherosclerosis and translation of the findings from animal models to humans. Finally, we present the directions for future lncRNA-oriented research, which may ultimately result in patient-oriented therapeutic strategies for ASCVD.
Topics: Animals; Humans; Plaque, Atherosclerotic; RNA, Long Noncoding; Atherosclerosis; Endothelial Cells
PubMed: 37508497
DOI: 10.3390/cells12141832 -
European Heart Journal. Cardiovascular... Aug 2023The totality of atherosclerotic plaque derived from coronary computed tomography angiography (CCTA) emerges as a comprehensive measure to assess the intensity of medical...
AIMS
The totality of atherosclerotic plaque derived from coronary computed tomography angiography (CCTA) emerges as a comprehensive measure to assess the intensity of medical treatment that patients need. This study examines the differences in age onset and prognostic significance of atherosclerotic plaque burden between sexes.
METHODS AND RESULTS
From a large multi-center CCTA registry the Leiden CCTA score was calculated in 24 950 individuals. A total of 11 678 women (58.5 ± 12.4 years) and 13 272 men (55.6 ± 12.5 years) were followed for 3.7 years for major adverse cardiovascular events (MACE) (death or myocardial infarction). The age where the median risk score was above zero was 12 years higher in women vs. men (64-68 years vs. 52-56 years, respectively, P < 0.001). The Leiden CCTA risk score was independently associated with MACE: score 6-20: HR 2.29 (1.69-3.10); score > 20: HR 6.71 (4.36-10.32) in women, and score 6-20: HR 1.64 (1.29-2.08); score > 20: HR 2.38 (1.73-3.29) in men. The risk was significantly higher for women within the highest score group (adjusted P-interaction = 0.003). In pre-menopausal women, the risk score was equally predictive and comparable with men. In post-menopausal women, the prognostic value was higher for women [score 6-20: HR 2.21 (1.57-3.11); score > 20: HR 6.11 (3.84-9.70) in women; score 6-20: HR 1.57 (1.19-2.09); score > 20: HR 2.25 (1.58-3.22) in men], with a significant interaction for the highest risk group (adjusted P-interaction = 0.004).
CONCLUSION
Women developed coronary atherosclerosis approximately 12 years later than men. Post-menopausal women within the highest atherosclerotic burden group were at significantly higher risk for MACE than their male counterparts, which may have implications for the medical treatment intensity.
Topics: Humans; Male; Female; Child; Plaque, Atherosclerotic; Coronary Stenosis; Coronary Angiography; Coronary Artery Disease; Tomography, X-Ray Computed; Prognosis; Computed Tomography Angiography; Age Factors; Predictive Value of Tests
PubMed: 37165981
DOI: 10.1093/ehjci/jead094 -
Journal of the American College of... Jun 2024Total coronary atherosclerotic plaque activity across the entire coronary arterial tree is associated with patient-level clinical outcomes.
BACKGROUND
Total coronary atherosclerotic plaque activity across the entire coronary arterial tree is associated with patient-level clinical outcomes.
OBJECTIVES
We aimed to investigate whether vessel-level coronary atherosclerotic plaque activity is associated with vessel-level myocardial infarction.
METHODS
In this secondary analysis of an international multicenter study of patients with recent myocardial infarction and multivessel coronary artery disease, we assessed vessel-level coronary atherosclerotic plaque activity using coronary F-sodium fluoride positron emission tomography to identify vessel-level myocardial infarction.
RESULTS
Increased F-sodium fluoride uptake was found in 679 of 2,094 coronary arteries and 414 of 691 patients. Myocardial infarction occurred in 24 (4%) vessels with increased coronary atherosclerotic plaque activity and in 25 (2%) vessels without increased coronary atherosclerotic plaque activity (HR: 2.08; 95% CI: 1.16-3.72; P = 0.013). This association was not demonstrable in those treated with coronary revascularization (HR: 1.02; 95% CI: 0.47-2.25) but was notable in untreated vessels (HR: 3.86; 95% CI: 1.63-9.10; P = 0.024). Increased coronary atherosclerotic plaque activity in multiple coronary arteries was associated with heightened patient-level risk of cardiac death or myocardial infarction (HR: 2.43; 95% CI: 1.37-4.30; P = 0.002) as well as first (HR: 2.19; 95% CI: 1.18-4.06; P = 0.013) and total (HR: 2.50; 95% CI: 1.42-4.39; P = 0.002) myocardial infarctions.
CONCLUSIONS
In patients with recent myocardial infarction and multivessel coronary artery disease, coronary atherosclerotic plaque activity prognosticates individual coronary arteries and patients at risk for myocardial infarction.
Topics: Humans; Plaque, Atherosclerotic; Myocardial Infarction; Male; Female; Middle Aged; Coronary Artery Disease; Aged; Positron-Emission Tomography; Coronary Vessels; Risk Factors
PubMed: 38811091
DOI: 10.1016/j.jacc.2024.03.419 -
Current Cardiology Reports Nov 2023Coronary computed tomography angiography (CCTA) is the diagnostic modality of choice for patients with stable chest pain. In this review, we scrutinize the evidence on... (Review)
Review
PURPOSE OF REVIEW
Coronary computed tomography angiography (CCTA) is the diagnostic modality of choice for patients with stable chest pain. In this review, we scrutinize the evidence on the use of CCTA for the screening of asymptomatic patients.
RECENT FINDINGS
Clinical evidence suggests that CCTA imaging enhances cardiovascular risk stratification and prompts the timely initiation of preventive treatment leading to reduced risk of major adverse coronary events. Visualization of coronary plaques by CCTA also helps patients to comply with preventive medications. The presence of non-obstructive plaques and total plaque burden are prognostic for cardiovascular events. High-risk plaque features and pericoronary fat attenuation index, enrich the prognostic output of CCTA on top of anatomical information by capturing information on plaque vulnerability and coronary inflammatory burden. Timely detection of atherosclerotic disease or coronary inflammation by CCTA can assist in the deployment of targeted preventive strategies and novel therapeutics to prevent cardiovascular disease.
Topics: Humans; Coronary Artery Disease; Computed Tomography Angiography; Coronary Angiography; Heart; Tomography, X-Ray Computed; Plaque, Atherosclerotic; Predictive Value of Tests; Coronary Vessels
PubMed: 37897677
DOI: 10.1007/s11886-023-01982-8