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Cardiovascular Research Jul 2023Cardiovascular disease (CVD) is a serious health challenge, causing more deaths worldwide than cancer. The vascular endothelium, which forms the inner lining of blood... (Review)
Review
Cardiovascular disease (CVD) is a serious health challenge, causing more deaths worldwide than cancer. The vascular endothelium, which forms the inner lining of blood vessels, plays a central role in maintaining vascular integrity and homeostasis and is in direct contact with the blood flow. Research over the past century has shown that mechanical perturbations of the vascular wall contribute to the formation and progression of atherosclerosis. While the straight part of the artery is exposed to sustained laminar flow and physiological high shear stress, flow near branch points or in curved vessels can exhibit 'disturbed' flow. Clinical studies as well as carefully controlled in vitro analyses have confirmed that these regions of disturbed flow, which can include low shear stress, recirculation, oscillation, or lateral flow, are preferential sites of atherosclerotic lesion formation. Because of their critical role in blood flow homeostasis, vascular endothelial cells (ECs) have mechanosensory mechanisms that allow them to react rapidly to changes in mechanical forces, and to execute context-specific adaptive responses to modulate EC functions. This review summarizes the current understanding of endothelial mechanobiology, which can guide the identification of new therapeutic targets to slow or reverse the progression of atherosclerosis.
Topics: Humans; Endothelial Cells; Atherosclerosis; Endothelium, Vascular; Hemodynamics; Cardiovascular Diseases; Stress, Mechanical; Mechanotransduction, Cellular
PubMed: 37163659
DOI: 10.1093/cvr/cvad076 -
Cell Death & Disease Oct 2023Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow... (Review)
Review
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow and lead to complications such as heart attack or stroke. The development of atherosclerosis is influenced by a variety of factors, including age, genetics, lifestyle, and underlying health conditions such as high blood pressure or diabetes. Atherosclerotic plaques in stable form are characterized by slow growth, which leads to luminal stenosis, with low embolic potential or in unstable form, which contributes to high risk for thrombotic and embolic complications with rapid clinical onset. In this complex scenario of atherosclerosis, macrophages participate in the whole process, including the initiation, growth and eventually rupture and wound healing stages of artery plaque formation. Macrophages in plaques exhibit high heterogeneity and plasticity, which affect the evolving plaque microenvironment, e.g., leading to excessive lipid accumulation, cytokine hyperactivation, hypoxia, apoptosis and necroptosis. The metabolic and functional transitions of plaque macrophages in response to plaque microenvironmental factors not only influence ongoing and imminent inflammatory responses within the lesions but also directly dictate atherosclerotic progression or regression. In this review, we discuss the origin of macrophages within plaques, their phenotypic diversity, metabolic shifts, and fate and the roles they play in the dynamic progression of atherosclerosis. It also describes how macrophages interact with other plaque cells, particularly T cells. Ultimately, targeting pathways involved in macrophage polarization may lead to innovative and promising approaches for precision medicine. Further insights into the landscape and biological features of macrophages within atherosclerotic plaques may offer valuable information for optimizing future clinical treatment for atherosclerosis by targeting macrophages.
Topics: Humans; Plaque, Atherosclerotic; Atherosclerosis; Macrophages; Apoptosis; Myocardial Infarction
PubMed: 37863894
DOI: 10.1038/s41419-023-06206-z -
European Heart Journal Aug 2023Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical...
AIMS
Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association.
METHODS AND RESULTS
Whole blood methylomics, transcriptomics, and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. In healthy individuals, the presence, extension, and progression of subclinical atherosclerosis were associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional cardiovascular risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased systemic inflammation and associated with a score of low-grade, chronic inflammation. Mediation analysis using transcriptomics and proteomics data revealed key pro-inflammatory pathways (IL6, Inflammasome, and IL10) and genes (IL1B, OSM, TLR5, and CD14) mediating the association between subclinical atherosclerosis and epigenetic age acceleration.
CONCLUSION
The presence, extension, and progression of subclinical atherosclerosis in middle-aged asymptomatic individuals are associated with an acceleration in the Grim epigenetic age. Mediation analysis using transcriptomics and proteomics data suggests a key role of systemic inflammation in this association, reinforcing the relevance of interventions on inflammation to prevent cardiovascular disease.
Topics: Middle Aged; Humans; Multiomics; Atherosclerosis; Coronary Artery Disease; Inflammation; Epigenesis, Genetic; Risk Factors
PubMed: 37339167
DOI: 10.1093/eurheartj/ehad361 -
Cells Oct 2023Lipoprotein(a) (Lp(a)) molecule includes two protein components: apolipoprotein(a) and apoB100. The molecule is the main transporter of oxidized phospholipids (OxPL) in... (Review)
Review
Lipoprotein(a) (Lp(a)) molecule includes two protein components: apolipoprotein(a) and apoB100. The molecule is the main transporter of oxidized phospholipids (OxPL) in plasma. The concentration of this strongly atherogenic lipoprotein is predominantly regulated by the LPA gene expression. Lp(a) is regarded as a risk factor for several cardiovascular diseases. Numerous epidemiological, clinical and in vitro studies showed a strong association between increased Lp(a) and atherosclerotic cardiovascular disease (ASCVD), calcific aortic valve disease/aortic stenosis (CAVD/AS), stroke, heart failure or peripheral arterial disease (PAD). Although there are acknowledged contributions of Lp(a) to the mentioned diseases, clinicians struggle with many inconveniences such as a lack of well-established treatment lowering Lp(a), and common guidelines for diagnosing or assessing cardiovascular risk among both adult and pediatric patients. Lp(a) levels are different with regard to a particular race or ethnicity and might fluctuate during childhood. Furthermore, the lack of standardization of assays is an additional impediment. The review presents the recent knowledge on Lp(a) based on clinical and scientific research, but also highlights relevant aspects of future study directions that would approach more suitable and effective managing risk associated with increased Lp(a), as well as control the Lp(a) levels.
Topics: Humans; Aortic Valve; Aortic Valve Stenosis; Atherosclerosis; Lipoprotein(a); Risk Factors
PubMed: 37887316
DOI: 10.3390/cells12202472 -
International Journal of Molecular... Oct 2023Endothelial cells (ECs) form the inner linings of blood vessels, and are directly exposed to endogenous hazard signals and metabolites in the circulatory system. The... (Review)
Review
Endothelial cells (ECs) form the inner linings of blood vessels, and are directly exposed to endogenous hazard signals and metabolites in the circulatory system. The senescence and death of ECs are not only adverse outcomes, but also causal contributors to endothelial dysfunction, an early risk marker of atherosclerosis. The pathophysiological process of EC senescence involves both structural and functional changes and has been linked to various factors, including oxidative stress, dysregulated cell cycle, hyperuricemia, vascular inflammation, and aberrant metabolite sensing and signaling. Multiple forms of EC death have been documented in atherosclerosis, including autophagic cell death, apoptosis, pyroptosis, NETosis, necroptosis, and ferroptosis. Despite this, the molecular mechanisms underlying EC senescence or death in atherogenesis are not fully understood. To provide a comprehensive update on the subject, this review examines the historic and latest findings on the molecular mechanisms and functional alterations associated with EC senescence and death in different stages of atherosclerosis.
Topics: Humans; Endothelial Cells; Cellular Senescence; Atherosclerosis; Oxidative Stress; Signal Transduction
PubMed: 37894840
DOI: 10.3390/ijms242015160 -
European Heart Journal Dec 2023Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated... (Observational Study)
Observational Study
BACKGROUND AND AIMS
Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated with atherosclerosis in experimental studies. This study aimed to investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches.
METHODS
Observational studies were conducted in the Copenhagen General Population Study (n = 101 730). Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank (n = 365 913); secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium (n = 563 085). Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation.
RESULTS
Observational analyses showed associations between high neutrophil counts with high risks of all outcomes. In the UK Biobank, odds ratios (95% confidence intervals) per 1-SD higher genetically predicted neutrophil counts were 1.15 (1.08, 1.21) for ischaemic heart disease, 1.22 (1.12, 1.34) for myocardial infarction, and 1.19 (1.04, 1.36) for peripheral arterial disease; similar results were observed in men and women separately. In two-sample MR, corresponding estimates were 1.14 (1.05, 1.23) for ischaemic heart disease and 1.11 (1.02, 1.20) for myocardial infarction; multiple sensitivity analyses showed consistent results. No robust associations in two-sample MR analyses were found for other types of leucocytes.
CONCLUSIONS
Observational and genetically determined high neutrophil counts were associated with atherosclerotic cardiovascular disease, supporting that high blood neutrophil counts is a causal risk factor for atherosclerotic cardiovascular disease.
Topics: Male; Humans; Female; Cardiovascular Diseases; Neutrophils; Brain Ischemia; Stroke; Myocardial Infarction; Myocardial Ischemia; Atherosclerosis; Peripheral Arterial Disease; Coronary Artery Disease; Mendelian Randomization Analysis; Genome-Wide Association Study; Polymorphism, Single Nucleotide
PubMed: 37950632
DOI: 10.1093/eurheartj/ehad649 -
ELife Dec 2023A deep analysis of multiple genomic datasets reveals which genetic pathways associated with atherosclerosis and coronary artery disease are shared between mice and...
A deep analysis of multiple genomic datasets reveals which genetic pathways associated with atherosclerosis and coronary artery disease are shared between mice and humans.
Topics: Humans; Mice; Animals; Gene Regulatory Networks; Coronary Artery Disease; Atherosclerosis; Genomics; Genome-Wide Association Study
PubMed: 38060304
DOI: 10.7554/eLife.94382 -
Nature Reviews. Cardiology Jul 2023Lipophagy is a type of selective autophagy that targets lipid droplets for degradation. Since the discovery of lipophagy in 2009, research has uncovered a central role...
Lipophagy is a type of selective autophagy that targets lipid droplets for degradation. Since the discovery of lipophagy in 2009, research has uncovered a central role for this process in cellular lipid metabolism, including in atherogenic foam cells. Therefore, increasing lipophagy might be a therapeutic target to reverse lipid build-up in atherosclerosis.
Topics: Humans; Atherosclerosis; Autophagy; Lipid Metabolism
PubMed: 37161064
DOI: 10.1038/s41569-023-00885-z -
Signal Transduction and Targeted Therapy Aug 2023Previous studies suggested a beneficial effect of natriuretic peptides in animal models of cardiovascular disease, but the role of natriuretic peptide receptor C (NPRC)...
Previous studies suggested a beneficial effect of natriuretic peptides in animal models of cardiovascular disease, but the role of natriuretic peptide receptor C (NPRC) in the pathogenesis of atherosclerosis (AS) remains unknown. This study was designed to test the hypothesis that NPRC may promote AS lesion formation and instability by enhancing oxidative stress, inflammation, and apoptosis via protein kinase A (PKA) signaling. ApoE mice were fed chow or Western diet for 12 weeks and NPRC expression was significantly increased in the aortic tissues of Western diet-fed mice. Systemic NPRC knockout mice were crossed with ApoE mice to generate ApoENPRC mice, and NPRC deletion resulted in a significant decrease in the size and instability of aortic atherosclerotic lesions in ApoENPRC versus ApoE mice. In addition, endothelial cell-specific NPRC knockout attenuated atherosclerotic lesions in mice. In contrast, endothelial cell overexpression of NPRC aggravated the size and instability of atherosclerotic aortic lesions in mice. Experiments in vitro showed that NPRC knockdown in human aortic endothelial cells (HAECs) inhibited ROS production, pro-inflammatory cytokine expression and endothelial cell apoptosis, and increased eNOS expression. Furthermore, NPRC knockdown in HAECs suppressed macrophage migration, cytokine expression, and phagocytosis via its effects on endothelial cells. On the contrary, NPRC overexpression in endothelial cells resulted in opposite effects. Mechanistically, the anti-inflammation and anti-atherosclerosis effects of NPRC deletion involved activation of cAMP/PKA pathway, leading to downstream upregulated AKT1 pathway and downregulated NF-κB pathway. In conclusion, NPRC deletion reduced the size and instability of atherosclerotic lesions in ApoE mice via attenuating inflammation and endothelial cell apoptosis and increasing eNOS expression by modulating cAMP/PKA-AKT1 and NF-κB pathways. Thus, targeting NPRC may provide a promising approach to the prevention and treatment of atherosclerosis.
Topics: Animals; Humans; Mice; Apoptosis; Atherosclerosis; Cytokines; Endothelial Cells; Inflammation; Mice, Knockout; Mice, Knockout, ApoE; NF-kappa B; Oxidative Stress; Receptors, Atrial Natriuretic Factor
PubMed: 37553374
DOI: 10.1038/s41392-023-01560-y -
International Journal of Molecular... Oct 2023Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population and whose... (Review)
Review
Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population and whose prevalence is increasing worldwide due to the pandemic of obesity. Obesity, impaired glucose metabolism, high blood pressure and atherogenic dyslipidemia are risk factors for MASLD. Therefore, insulin resistance may be closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids released from adipose tissue, increase in fatty acid synthesis and reduced fatty acid oxidation in the liver and hepatic overproduction of triglyceride-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease. Considering that the development of cardiovascular diseases determines the prognosis of MASLD patients, the therapeutic interventions for MASLD should reduce body weight and improve coronary risk factors, in addition to an improving in liver function. Lifestyle modifications, such as improved diet and increased exercise, and surgical interventions, such as bariatric surgery and intragastric balloons, have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to improve coronary risk factors and to suppress the occurrence of cardiovascular diseases. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator pemafibrate improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs and whether such drugs and the combination therapy of such drugs could be the treatments for MASLD.
Topics: Humans; Cardiovascular Diseases; Insulin Resistance; PPAR alpha; Sodium-Glucose Transporter 2 Inhibitors; Fatty Liver; Obesity; Fatty Acids; Atherosclerosis
PubMed: 37895151
DOI: 10.3390/ijms242015473