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Circulation Research May 2022Endothelial-to-mesenchymal transition (EndMT) has been identified as a critical driver of vascular inflammation and atherosclerosis, and TGF-β (transforming growth...
BACKGROUND
Endothelial-to-mesenchymal transition (EndMT) has been identified as a critical driver of vascular inflammation and atherosclerosis, and TGF-β (transforming growth factor β) is a key mediator of EndMT. Both EndMT and atherosclerosis are promoted by disturbed flow, whereas unidirectional laminar flow limits EndMT and is atheroprotective. How EndMT and endothelial TGF-β signaling are regulated by different flow patterns is, however, still poorly understood.
METHODS
Flow chamber experiments in vitro and endothelium-specific knockout mice were used to study the role of tenascin-X in the regulation of EndMT and atherosclerosis as well as the underlying mechanisms.
RESULTS
In human endothelial cells as well as in human and mouse aortae, unidirectional laminar flow but not disturbed flow strongly increased endothelial expression of the extracellular matrix protein TN-X (tenascin-X) in a KLF4 (Krüppel-like factor 4) dependent manner. Mice with endothelium-specific loss of TN-X (EC-Tnxb-KO) showed increased endothelial TGF-β signaling as well as increased endothelial expression of EndMT and inflammatory marker genes. When EC-Tnxb-KO mice were subjected to partial carotid artery ligation, we observed increased vascular remodeling. EC-Tnxb-KO mice crossed to low-density lipoprotein receptor-deficient mice showed advanced atherosclerotic lesions after being fed a high-fat diet. Treatment of EC-Tnxb-KO mice with an anti-TGF-beta antibody or additional endothelial loss of TGF-beta receptors 1 and 2 normalized endothelial TGF-beta signaling and prevented EndMT. In in vitro studies, we found that TN-X through its fibrinogen-like domain directly interacts with TGF-β and thereby interferes with its binding to the TGF-β receptor.
CONCLUSIONS
In summary, we show that TN-X is a central mediator of flow-induced inhibition of EndMT, endothelial inflammation and atherogenesis, which functions by binding to and by blocking the activity of TGF-β. Our data identify a novel mechanism of flow-dependent regulation of vascular TGF-β, which holds promise for generating new strategies to prevent vascular inflammation and atherosclerosis.
Topics: Animals; Atherosclerosis; Cells, Cultured; Endothelial Cells; Endothelium; Epithelial-Mesenchymal Transition; Inflammation; Mice; Signal Transduction; Tenascin; Transforming Growth Factor beta
PubMed: 35443807
DOI: 10.1161/CIRCRESAHA.121.320694 -
Circulation Aug 2021Lower extremity peripheral artery disease (PAD) affects >230 million adults worldwide and is associated with increased risk of various adverse clinical outcomes (other... (Review)
Review
Lower extremity peripheral artery disease (PAD) affects >230 million adults worldwide and is associated with increased risk of various adverse clinical outcomes (other cardiovascular diseases such as coronary heart disease and stroke and leg outcomes such as amputation). Despite its prevalence and clinical importance, PAD has been historically underappreciated by health care professionals and patients. This underappreciation seems multifactorial (eg, limited availability of the first-line diagnostic test, the ankle-brachial index, in clinics; incorrect perceptions that a leg vascular disease is not fatal and that the diagnosis of PAD would not necessarily change clinical practice). In the past several years, a body of evidence has indicated that these perceptions are incorrect. Several studies have consistently demonstrated that many patients with PAD are not receiving evidence-based therapies. Thus, this scientific statement provides an update for health care professionals regarding contemporary epidemiology (eg, prevalence, temporal trends, risk factors, and complications) of PAD, the present status of diagnosis (physiological tests and imaging modalities), and the major gaps in the management of PAD (eg, medications, exercise therapy, and revascularization). The statement also lists key gaps in research, clinical practice, and implementation related to PAD. Orchestrated efforts among different parties (eg, health care providers, researchers, expert organizations, and health care organizations) will be needed to increase the awareness and understanding of PAD and improve the diagnostic approaches, management, and prognosis of PAD.
Topics: American Heart Association; Atherosclerosis; Combined Modality Therapy; Diagnostic Tests, Routine; Disease Management; Disease Susceptibility; Female; Humans; Lower Extremity; Male; Mass Screening; Peripheral Arterial Disease; Prevalence; Prognosis; Public Health Surveillance; Risk Assessment; Risk Factors; Socioeconomic Factors; Treatment Outcome; United States
PubMed: 34315230
DOI: 10.1161/CIR.0000000000001005 -
Arteriosclerosis, Thrombosis, and... Jun 2022Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition that is believed to affect >25% of adults worldwide. Unless specific testing is done to... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition that is believed to affect >25% of adults worldwide. Unless specific testing is done to identify NAFLD, the condition is typically silent until advanced and potentially irreversible liver impairment occurs. For this reason, the majority of patients with NAFLD are unaware of having this serious condition. Hepatic complications from NAFLD include nonalcoholic steatohepatitis, hepatic cirrhosis, and hepatocellular carcinoma. In addition to these serious complications, NAFLD is a risk factor for atherosclerotic cardiovascular disease, which is the principal cause of death in patients with NAFLD. Accordingly, the purpose of this scientific statement is to review the underlying risk factors and pathophysiology of NAFLD, the associations with atherosclerotic cardiovascular disease, diagnostic and screening strategies, and potential interventions.
Topics: Adult; American Heart Association; Atherosclerosis; Cardiovascular Diseases; Heart Disease Risk Factors; Humans; Liver; Non-alcoholic Fatty Liver Disease; Risk Factors
PubMed: 35418240
DOI: 10.1161/ATV.0000000000000153 -
Biomedicine & Pharmacotherapy =... Sep 2020The ease of breeding, low cost of maintenance, and relatively short period for developing atherosclerosis make rodents ideal for atherosclerosis research. However, none... (Review)
Review
The ease of breeding, low cost of maintenance, and relatively short period for developing atherosclerosis make rodents ideal for atherosclerosis research. However, none of the current models accurately model human lipoprotein profile or atherosclerosis progression since each has its advantages and disadvantages. The advent of transgenic technologies much supports animal models' establishment. Notably, two classic transgenic mouse models, apoE-/- and Ldlr-/-, constitute the primary platforms for studying underlying mechanisms and development of pharmaceutical approaches. However, there exist crucial differences between mice and humans, such as the unhumanized lipoprotein profile, and the different plaque progression and characteristics. Among rodents, hamsters and guinea pigs might be the more realistic models in atherosclerosis research based on the similarities in lipoprotein metabolism to humans. Studies involving rat models, a rodent with natural resistance to atherosclerosis, have revealed evidence of atherosclerotic plaques under dietary induction and genetic manipulation by novel technologies, notably CRISPR-Cas9. Ldlr-/- hamster models were established in recent years with severe hyperlipidemia and atherosclerotic lesion formation, which could offer an alternative to classic transgenic mouse models. In this review, we provide an overview of classic and innovative small rodent models in atherosclerosis researches, including mice, rats, hamsters, and guinea pigs, focusing on their lipoprotein metabolism and histopathological changes.
Topics: Animals; Atherosclerosis; Cricetinae; Diet, High-Fat; Disease Models, Animal; Disease Progression; Genetic Predisposition to Disease; Guinea Pigs; Hypercholesterolemia; Lipoproteins; Mice, Knockout, ApoE; Phenotype; Plaque, Atherosclerotic; Rats, Transgenic; Receptors, LDL; Species Specificity
PubMed: 32574973
DOI: 10.1016/j.biopha.2020.110426 -
European Heart Journal Sep 2022Lipid risk factors for cardiovascular disease depend in part on lifestyle, but optimum control of lipids often demands additional measures. Low-density lipoprotein (LDL)... (Review)
Review
Lipid risk factors for cardiovascular disease depend in part on lifestyle, but optimum control of lipids often demands additional measures. Low-density lipoprotein (LDL) doubtless contributes causally to atherosclerosis. Recent human genetic findings have substantiated a number of novel targets for lipid-lowering therapy including apolipoprotein C-III, angiopoietin-like protein 3 and 4, apolipoprotein V, and ATP citrate lyase. These discoveries coupled with advances in biotechnology development afford new avenues for management of LDL and other aspects of lipid risk. Beyond LDL, new treatments targeting triglyceride-rich lipoproteins and lipoprotein(a) have become available and have entered clinical development. Biological and RNA-directed agents have joined traditional small-molecule approaches, which themselves have undergone considerable refinement. Innovative targeting strategies have increased efficacy of some of these novel interventions and markedly improved their tolerability. Gene-editing approaches have appeared on the horizon of lipid management. This article reviews this progress offering insight into novel biological and therapeutic discoveries, and places them into a practical patient care perspective.
Topics: Atherosclerosis; Cardiovascular Diseases; Dyslipidemias; Humans; Hypolipidemic Agents; Lipoprotein(a); Triglycerides
PubMed: 35051271
DOI: 10.1093/eurheartj/ehab841 -
Nature Reviews. Cardiology Jan 2021The number of old people is rising worldwide, and advancing age is a major risk factor for atherosclerotic cardiovascular disease. However, the mechanisms underlying... (Review)
Review
The number of old people is rising worldwide, and advancing age is a major risk factor for atherosclerotic cardiovascular disease. However, the mechanisms underlying this phenomenon remain unclear. In this Review, we discuss vascular intrinsic and extrinsic mechanisms of how ageing influences the pathology of atherosclerosis. First, we focus on factors that are extrinsic to the vasculature. We discuss how ageing affects the development of myeloid cells leading to the expansion of certain myeloid cell clones and induces changes in myeloid cell functions that promote atherosclerosis via inflammation, including a potential role for IL-6. Next, we describe vascular intrinsic factors by which ageing promotes atherogenesis - in particular, the effects on mitochondrial function. Studies in mice and humans have shown that ageing leads to a decline in vascular mitochondrial function and impaired mitophagy. In mice, ageing is associated with an elevation in the levels of the inflammatory cytokine IL-6 in the aorta, which participates in a positive feedback loop with the impaired vascular mitochondrial function to accelerate atherogenesis. We speculate that vascular and myeloid cell ageing synergize, via IL-6 signalling, to accelerate atherosclerosis. Finally, we propose future avenues of clinical investigation and potential therapeutic approaches to reduce the burden of atherosclerosis in old people.
Topics: Aging; Atherosclerosis; Humans; Interleukin-6
PubMed: 32918047
DOI: 10.1038/s41569-020-0431-7 -
Circulation Research Apr 2020Atherosclerosis is a chronic inflammatory vascular disease and the predominant cause of heart attack and ischemic stroke. Despite the well-known sexual dimorphism in the... (Review)
Review
Atherosclerosis is a chronic inflammatory vascular disease and the predominant cause of heart attack and ischemic stroke. Despite the well-known sexual dimorphism in the incidence and complications of atherosclerosis, there are relatively limited data in the clinical and preclinical literature to rigorously address mechanisms underlying sex as a biological variable in atherosclerosis. In multiple histological and imaging studies, overall plaque burden and markers of inflammation appear to be greater in men than women and are predictive of cardiovascular events. However, while younger women are relatively protected from cardiovascular disease, by the seventh decade, the incidence of myocardial infarction in women ultimately surpasses that of men, suggesting an interaction between sex and age. Most preclinical studies in animal atherosclerosis models do not examine both sexes, and even in those that do, well-powered direct statistical comparisons for sex as an independent variable remain rare. This article reviews the available data. Overall, male animals appear to have more inflamed yet smaller plaques compared to female animals. Plaque inflammation is often used as a surrogate end point for plaque vulnerability in animals. The available data support the notion that rather than plaque size, plaque inflammation may be more relevant in assessing sex-specific mechanisms since the findings correlate with the sex difference in ischemic events and mortality and thus may be more reflective of the human condition. Overall, the number of preclinical studies directly comparing plaque inflammation between the sexes is extremely limited relative to the vast literature exploring atherosclerosis mechanisms. Failure to include both sexes and to address age in mechanistic atherosclerosis studies are missed opportunities to uncover underlying sex-specific mechanisms. Understanding the mechanisms driving sex as a biological variable in atherosclerotic disease is critical to future precision medicine strategies to mitigate what is still the leading cause of death of men and women worldwide.
Topics: Adult; Age Factors; Aged; Animals; Arteries; Atherosclerosis; Biological Variation, Population; Disease Models, Animal; Female; Health Status Disparities; Heart Disease Risk Factors; Humans; Inflammation; Male; Middle Aged; Plaque, Atherosclerotic; Risk Assessment; Sex Characteristics; Sex Factors
PubMed: 32324497
DOI: 10.1161/CIRCRESAHA.120.315930 -
Frontiers in Immunology 2021Although more and more evidence has supported psoriasis is prone to atherosclerosis, the common mechanism of its occurrence is still not fully elucidated. The purpose of...
BACKGROUND
Although more and more evidence has supported psoriasis is prone to atherosclerosis, the common mechanism of its occurrence is still not fully elucidated. The purpose of this study is to further explore the molecular mechanism of the occurrence of this complication.
METHODS
The gene expression profiles of psoriasis (GSE30999) and atherosclerosis (GSE28829) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the common differentially expressed genes (DEGs) of psoriasis and atherosclerosis, three kinds of analyses were performed, namely functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis.
RESULTS
A total of 94 common DEGs (24 downregulated genes and 70 upregulated genes) was selected for subsequent analyses. Functional analysis emphasizes the important role of chemokines and cytokines in these two diseases. In addition, lipopolysaccharide-mediated signaling pathway is closely related to both. Finally, 16 important hub genes were identified using cytoHubba, including LYN, CSF2RB, IL1RN, RAC2, CCL5, IRF8, C1QB, MMP9, PLEK, PTPRC, FYB, BCL2A1, LCP2, CD53, NCF2 and TLR2.
CONCLUSIONS
Our study reveals the common pathogenesis of psoriasis and atherosclerosis. These common pathways and hub genes may provide new ideas for further mechanism research.
Topics: Atherosclerosis; Databases, Genetic; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Oligonucleotide Array Sequence Analysis; Protein Interaction Maps; Psoriasis; Signal Transduction; Transcriptome
PubMed: 34122426
DOI: 10.3389/fimmu.2021.667690 -
Circulation Research Jan 2021Atherosclerotic cardiovascular disease (ASCVD) proceeds through a series of stages: initiation, progression (or regression), and complications. By integrating known... (Review)
Review
Atherosclerotic cardiovascular disease (ASCVD) proceeds through a series of stages: initiation, progression (or regression), and complications. By integrating known biology regarding molecular signatures of each stage with recent advances in high-dimensional molecular data acquisition platforms (to assay the genome, epigenome, transcriptome, proteome, metabolome, and gut microbiome), snapshots of each phase of atherosclerotic cardiovascular disease development can be captured. In this review, we will summarize emerging approaches for assessment of atherosclerotic cardiovascular disease risk in humans using peripheral blood molecular signatures and molecular imaging approaches. We will then discuss the potential (and challenges) for these snapshots to be integrated into a personalized movie providing dynamic readouts of an individual's atherosclerotic cardiovascular disease risk status throughout the life course.
Topics: Animals; Atherosclerosis; Bacteria; Biomarkers; Disease Progression; Gastrointestinal Microbiome; Gene Expression Profiling; Heart Disease Risk Factors; Humans; Metabolome; Metabolomics; Molecular Imaging; Plaque, Atherosclerotic; Predictive Value of Tests; Proteome; Proteomics; Risk Assessment; Transcriptome
PubMed: 33476202
DOI: 10.1161/CIRCRESAHA.120.315890 -
Journal of the American College of... Nov 2023Atherosclerosis is a systemic disease that frequently begins early in life. However, knowledge about the temporal disease dynamics (ie, progression or regression) of...
BACKGROUND
Atherosclerosis is a systemic disease that frequently begins early in life. However, knowledge about the temporal disease dynamics (ie, progression or regression) of human subclinical atherosclerosis and their determinants is scarce.
OBJECTIVES
This study sought to investigate early subclinical atherosclerosis disease dynamics within a cohort of middle-aged, asymptomatic individuals by using multiterritorial 3-dimensional vascular ultrasound (3DVUS) imaging.
METHODS
A total of 3,471 participants from the PESA (Progression of Early Subclinical Atherosclerosis) cohort study (baseline age 40-55 years; 36% female) underwent 3 serial 3DVUS imaging assessments of peripheral arteries at 3-year intervals. Subclinical atherosclerosis was quantified as global plaque volume (mm) (bilateral carotid and femoral plaque burden). Multivariable logistic regression models for progression and regression were developed using stepwise forward variable selection.
RESULTS
Baseline to 6-year subclinical atherosclerosis progression occurred in 32.7% of the cohort (17.5% presenting with incident disease and 15.2% progressing from prevalent disease at enrollment). Regression was observed in 8.0% of those patients with baseline disease. The effects of higher low-density lipoprotein cholesterol (LDL-C) and elevated systolic blood pressure (SBP) on 6-year subclinical atherosclerosis progression risk were more pronounced among participants in the youngest age stratum (P = 0.04 and 0.02, respectively).
CONCLUSIONS
Over 6 years, subclinical atherosclerosis progressed in one-third of middle-age asymptomatic subjects. Atherosclerosis regression is possible in early stages of the disease. The impact of LDL-C and SBP on subclinical atherosclerosis progression was more pronounced in younger participants, a finding suggesting that the prevention of atherosclerosis and its progression could be enhanced by tighter risk factor control at younger ages, with a likely long-term impact on reducing the risk of clinical events. (Progression of Early Subclinical Atherosclerosis [PESA; also PESA-CNIC-Santander]; NCT01410318).
Topics: Middle Aged; Humans; Female; Adult; Male; Cohort Studies; Cholesterol, LDL; Disease Progression; Atherosclerosis; Plaque, Atherosclerotic; Carotid Arteries; Risk Factors
PubMed: 37993199
DOI: 10.1016/j.jacc.2023.09.814