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Stroke and Vascular Neurology Apr 2024Atherosclerosis (AS) and tumours are the leading causes of death worldwide and share common risk factors, detection methods and molecular markers. Therefore, searching...
BACKGROUND
Atherosclerosis (AS) and tumours are the leading causes of death worldwide and share common risk factors, detection methods and molecular markers. Therefore, searching for serum markers shared by AS and tumours is beneficial to the early diagnosis of patients.
METHODS
The sera of 23 patients with AS-related transient ischaemic attack were screened by serological identification of antigens through recombinant cDNA expression cloning (SEREX), and cDNA clones were identified. Pathway function enrichment analysis was performed on cDNA clones to identify their biological pathways and determine whether they were related to AS or tumours. Subsequently, gene-gene and protein-protein interactions were performed and AS-associated markers would be discovered. The expression of AS biomarkers in human normal organs and pan-cancer tumour tissues were explored. Then, immune infiltration level and tumour mutation burden of various immune cells were evaluated. Survival curves analysis could show the expression of AS markers in pan-cancer.
RESULTS
AS-related sera were screened by SEREX, and 83 cDNA clones with high homology were obtained. Through functional enrichment analysis, it was found that their functions were closely related to AS and tumour functions. After multiple biological information interaction screening and the external cohort validating, poly(A) binding protein cytoplasmic 1 (PABPC1) was found to be a potential AS biomarker. To assess whether PABPC1 was related to pan-cancer, its expression in different tumour pathological stages and ages was screened. Since AS-associated proteins were closely related to cancer immune infiltration, we investigated and found that PABPC1 had the same role in pan-cancer. Finally, analysis of Kaplan-Meier survival curves revealed that high PABPC1 expression in pan-cancer was associated with high risk of death.
CONCLUSIONS
Through the findings of SEREX and bioinformatics pan-cancer analysis, we concluded that PABPC1 might serve as a potential biomarker for the prediction and diagnosis of AS and pan-cancer.
Topics: Humans; Neoplasms; Male; Predictive Value of Tests; Middle Aged; Female; Atherosclerosis; Poly(A)-Binding Protein I; Biomarkers, Tumor; Protein Interaction Maps; Aged; Prognosis; Risk Assessment; Gene Regulatory Networks
PubMed: 37311641
DOI: 10.1136/svn-2022-002246 -
Journal of Nanobiotechnology May 2023PCSK9, which is closely related to atherosclerosis, is significantly expressed in vascular smooth muscle cells (VSMCs). Moreover, Proprotein Convertase Subtilisin/Kexin...
PCSK9, which is closely related to atherosclerosis, is significantly expressed in vascular smooth muscle cells (VSMCs). Moreover, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) mediated phenotypic transformation, abnormal proliferation, and migration of VSMCs play key roles in accelerating atherosclerosis. In this study, by utilizing the significant advantages of nano-materials, a biomimetic nanoliposome loading with Evolocumab (Evol), a PCSK9 inhibitor, was designed to alleviate atherosclerosis. In vitro results showed that (Lipo + M)@E NPs up-regulated the levels of α-SMA and Vimentin, while inhibiting the expression of OPN, which finally result in the inhibition of the phenotypic transition, excessive proliferation, and migration of VSMCs. In addition, the long circulation, excellent targeting, and accumulation performance of (Lipo + M)@E NPs significantly decreased the expression of PCSK9 in serum and VSMCs within the plaque of ApoE mice.
Topics: Mice; Animals; Proprotein Convertase 9; Liposomes; Atherosclerosis
PubMed: 37208681
DOI: 10.1186/s12951-023-01904-4 -
Nutrients Aug 2020Atherosclerotic cardiovascular disease (ASCVD) is a major cause of morbidity and mortality worldwide [...].
Atherosclerotic cardiovascular disease (ASCVD) is a major cause of morbidity and mortality worldwide [...].
Topics: Atherosclerosis; Cholesterol; Diabetes Mellitus, Type 2; Diet, Mediterranean; Humans; Inflammation; Life Style; Nutritional Physiological Phenomena; Obesity
PubMed: 32823869
DOI: 10.3390/nu12082444 -
Circulation Sep 2021The necrotic core partly formed by ineffective efferocytosis increases the risk of an atherosclerotic plaque rupture. Microribonucleic acids contribute to necrotic core...
BACKGROUND
The necrotic core partly formed by ineffective efferocytosis increases the risk of an atherosclerotic plaque rupture. Microribonucleic acids contribute to necrotic core formation by regulating efferocytosis and macrophage apoptosis. Atherosclerotic plaque rupture occurs at increased frequency in the early morning, indicating diurnal changes in plaque vulnerability. Although circadian rhythms play a role in atherosclerosis, the molecular clock output pathways that control plaque composition and rupture susceptibility are unclear.
METHODS
Circadian gene expression, necrotic core size, apoptosis, and efferocytosis in aortic lesions were investigated at different times of the day in mice and mice after consumption of a high-fat diet for 12 weeks. Genome-wide gene expression and lesion formation were analyzed in bone marrow-transplanted mice. Diurnal changes in apoptosis and clock gene expression were determined in human atherosclerotic lesions.
RESULTS
The expression of molecular clock genes, lesional apoptosis, and necrotic core size were diurnally regulated in mice. Efferocytosis did not match the diurnal increase in apoptosis at the beginning of the active phase. However, in parallel with apoptosis, expression levels of oscillating strands decreased in the mouse atherosclerotic aorta. knockout abolished circadian regulation of apoptosis and reduced necrotic core size but did not affect core clock gene expression. Further, knockout upregulated expression of proapoptotic Xaf1 (XIAP-associated factor 1) in the atherosclerotic aorta, which abolished circadian expression of Xaf1. The antiapoptotic effect of was mediated by noncanonical targeting of through both strands. knockout in bone marrow cells also reduced atherosclerosis and necrotic core size. Circadian regulation of clock gene expression was confirmed in human atherosclerotic lesions. Apoptosis oscillated diurnally in phase with expression, demonstrating an early morning peak antiphase to that of the strands.
CONCLUSIONS
Our findings suggest that the molecular clock in atherosclerotic lesions induces a diurnal rhythm of apoptosis regulated by circadian expression in macrophages that is not matched by efferocytosis, thus increasing the size of the necrotic core.
Topics: Animals; Apoptosis; Atherosclerosis; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; MicroRNAs
PubMed: 34233454
DOI: 10.1161/CIRCULATIONAHA.120.051614 -
BMC Cardiovascular Disorders Oct 2021Atherosclerosis is the leading cause of cardiovascular disease with a high mortality worldwide. Understanding the atherosclerosis pathogenesis and identification of...
BACKGROUND
Atherosclerosis is the leading cause of cardiovascular disease with a high mortality worldwide. Understanding the atherosclerosis pathogenesis and identification of efficient diagnostic signatures remain major problems of modern medicine. This study aims to screen the potential diagnostic genes for atherosclerosis.
METHODS
We downloaded the gene chip data of 135 peripheral blood samples, including 57 samples with atherosclerosis and 78 healthy subjects from GEO database (Accession Number: GSE20129). The weighted gene co-expression network analysis was applied to identify atherosclerosis-related genes. Functional enrichment analysis was conducted by using the clusterProfiler R package. The interaction pairs of proteins encoded by atherosclerosis-related genes were screened using STRING database, and the interaction network was further optimized with the cytoHubba plug-in of Cytoscape software.
RESULTS
The logistic regression diagnostic model was constructed to predict normal and atherosclerosis samples. A gene module which included 532 genes related to the occurrence of atherosclerosis were screened. Functional enrichment analysis basing on the 532 genes identified 235 significantly enriched GO terms and 44 significantly enriched KEGG pathways. The top 50 hub genes of the protein-protein interaction network were identified. The final logistic regression diagnostic model was established by the optimal 10 key genes, which could distinguish atherosclerosis samples from normal samples.
CONCLUSIONS
A predictive model based on 10 potential atherosclerosis-related genes was obtained, which should shed light on the diagnostic research of atherosclerosis.
Topics: Atherosclerosis; Biomarkers; Case-Control Studies; Gene Expression Profiling; Gene Regulatory Networks; Humans; Logistic Models; Oligonucleotide Array Sequence Analysis; Protein Interaction Maps
PubMed: 34688276
DOI: 10.1186/s12872-021-02323-9 -
Arteriosclerosis, Thrombosis, and... Nov 2023Inflammation contributes to the pathogenesis of atherosclerosis. But little is known about the potential benefits of inflammatory cells to atherosclerosis. The aim of...
BACKGROUND
Inflammation contributes to the pathogenesis of atherosclerosis. But little is known about the potential benefits of inflammatory cells to atherosclerosis. The aim of this study was to investigate the function of inflammatory cells/endothelium axis and determine whether and how inflammatory cell-derived MYDGF (myeloid-derived growth factor) inhibited endothelial LDL (low-density lipoprotein) transcytosis.
METHODS
In in vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of inflammatory cell-derived MYDGF on LDL transcytosis. We generated monocyte/macrophage-targeted MYDGF-null mice on an Ldlr (LDL receptor) background in the loss-of-function strategy and restored the inflammatory cell-derived MYDGF by bone marrow transplantation and inflammatory cell-specific overexpression of MYDGF mice model in the gain-of-function strategy. In in vitro experiments, coculture experiments between primary mouse aortic endothelial cells and macrophages and mouse aortic endothelial cells supplemented with or without recombinant MYDGF were conducted.
RESULTS
Inflammatory cell-derived MYDGF deficiency aggravated endothelial LDL transcytosis, drove LDL uptake by artery wall, and thus exacerbated atherosclerosis in vivo. Inflammatory cell-derived MYDGF restoration by bone marrow transplantation and inflammatory cell MYDGF overexpression alleviated LDL transport across the endothelium, prevented LDL accumulation in the subendothelial space, and subsequently ameliorated atherosclerosis in vivo. Furthermore, in the in vitro study, macrophages isolated from MYDGF mice and recombinant MYDGF attenuated LDL transcytosis and uptake in mouse aortic endothelial cells. Mechanistically, MYDGF inhibited MAP4K4 (mitogen-activated protein kinase kinase kinase kinase isoform 4) phosphorylation, enhanced activation of Akt (protein kinase B)-1, and diminished the FoxO (forkhead box O) 3a signaling cascade to exert protective effects of MYDGF on LDL transcytosis and atherosclerosis.
CONCLUSIONS
The findings support a role for inflammatory cell-derived MYDGF served as a cross talk factor between inflammatory cells and endothelial cells that inhibits LDL transcytosis across endothelium. MYDGF may become a novel therapeutic drug for atherosclerosis, and the beneficial effects of inflammatory cell in atherosclerosis deserve further attention.
Topics: Mice; Animals; Endothelial Cells; Atherosclerosis; Lipoproteins, LDL; Receptors, LDL; Mice, Knockout; Transcytosis; Endothelium
PubMed: 37767706
DOI: 10.1161/ATVBAHA.123.319905 -
Trends in Molecular Medicine Dec 2023Multiomics studies offer accurate preventive and therapeutic strategies for atherosclerotic cardiovascular disease (ASCVD) beyond traditional risk factors. By using... (Review)
Review
Multiomics studies offer accurate preventive and therapeutic strategies for atherosclerotic cardiovascular disease (ASCVD) beyond traditional risk factors. By using artificial intelligence (AI) and machine learning (ML) approaches, it is possible to integrate multiple 'omics and clinical data sets into tools that can be utilized for the development of personalized diagnostic and therapeutic approaches. However, currently multiple challenges in data quality, integration, and privacy still need to be addressed. In this opinion, we emphasize that joined efforts, exemplified by the AtheroNET COST Action, have a pivotal role in overcoming the challenges to advance multiomics approaches in ASCVD research, with the aim to foster more precise and effective patient care.
Topics: Humans; Artificial Intelligence; Cardiovascular Diseases; Multiomics; Atherosclerosis; Machine Learning
PubMed: 37806854
DOI: 10.1016/j.molmed.2023.09.004 -
Atherosclerosis Jun 2023Atherosclerotic cardiovascular disease (ASCVD) remains the major cause of premature death and disability worldwide, even when patients with an established manifestation... (Review)
Review
Atherosclerotic cardiovascular disease (ASCVD) remains the major cause of premature death and disability worldwide, even when patients with an established manifestation of atherosclerotic heart disease are optimally treated according to the clinical guidelines. Apart from the epigenetic control of transcription of the genetic information to messenger RNAs (mRNAs), gene expression is tightly controlled at the post-transcriptional level before the initiation of translation. Although mRNAs are traditionally perceived as the messenger molecules that bring genetic information from the nuclear DNA to the cytoplasmic ribosomes for protein synthesis, emerging evidence suggests that processes controlling RNA metabolism, driven by RNA-binding proteins (RBPs), affect cellular function in health and disease. Over the recent years, vascular endothelial cell, smooth muscle cell and immune cell RBPs have emerged as key co- or post-transcriptional regulators of several genes related to vascular inflammation and atherosclerosis. In this review, we provide an overview of cell-specific function of RNA-binding proteins involved in all stages of ASCVD and how this knowledge may be used for the development of novel precision medicine therapeutics.
Topics: Humans; Atherosclerosis; RNA-Binding Proteins; Inflammation
PubMed: 36759270
DOI: 10.1016/j.atherosclerosis.2023.01.008 -
Redox Biology Apr 2024Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more...
Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more protective phenotype and reducing the occurrence of clinical events is thought to be a promising method of treating atherosclerotic patients. In the current study, we investigate the immunomodulatory properties of itaconate, an immunometabolite derived from the TCA cycle intermediate cis-aconitate and synthesised by the enzyme Aconitate Decarboxylase 1 (ACOD1, also known as IRG1), in the context of atherosclerosis. Ldlr atherogenic mice transplanted with Acod1 bone marrow displayed a more stable plaque phenotype with smaller necrotic cores and showed increased recruitment of monocytes to the vessel intima. Macrophages from Acod1 mice contained more lipids whilst also displaying reduced induction of apoptosis. Using multi-omics approaches, we identify a metabolic shift towards purine metabolism, in addition to an altered glycolytic flux towards production of glycerol for triglyceride synthesis. Overall, our data highlight the potential of therapeutically blocking ACOD1 with the aim of stabilizing atherosclerotic plaques.
Topics: Humans; Animals; Mice; Plaque, Atherosclerotic; Atherosclerosis; Succinates; Macrophages
PubMed: 38309122
DOI: 10.1016/j.redox.2024.103054 -
Current Cardiology Reviews 2020The article provides an overview of current views on the role of biomechanical forces in the pathogenesis of atherosclerosis. The importance of biomechanical forces in... (Review)
Review
The article provides an overview of current views on the role of biomechanical forces in the pathogenesis of atherosclerosis. The importance of biomechanical forces in maintaining vascular homeostasis is considered. We provide descriptions of mechanosensing and mechanotransduction. The roles of wall shear stress and circumferential wall stress in the initiation, progression and destabilization of atherosclerotic plaque are described. The data on the possibilities of assessing biomechanical factors in clinical practice and the clinical significance of this approach are presented. The article concludes with a discussion on current therapeutic approaches based on the modulation of biomechanical forces.
Topics: Atherosclerosis; Biomechanical Phenomena; Disease Progression; Humans; Mechanotransduction, Cellular; Stress, Mechanical
PubMed: 31362692
DOI: 10.2174/1573403X15666190730095153