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Hamostaseologie Dec 2021Atherosclerotic vascular disease and its related complications are the major cause of mortality in Western societies. Atherosclerosis is a chronic inflammatory disease... (Review)
Review
Atherosclerotic vascular disease and its related complications are the major cause of mortality in Western societies. Atherosclerosis is a chronic inflammatory disease of the arterial wall triggered by traditional and nontraditional risk factors and mediated by inflammatory and immune responses. Recent clinical trials provided compelling evidence corroborating that atherosclerosis is an inflammatory disease and demonstrated efficacy of anti-inflammatory interventions in reducing cardiovascular events and mortality. Traditional risk factors drive vascular inflammation, further justifying the instrumental role of intensified risk factor management in attenuating and preventing atherosclerotic disease and complications. Promising therapeutic approaches specifically related to inhibition of inflammation span traditional anti-inflammatory drugs, specific immunomodulation, and development of vaccination against atherosclerotic disease. Here, we review the inflammatory component in atherogenesis, the available evidence from clinical trials evaluating efficacy of therapeutic anti-inflammatory interventions in patients with high cardiovascular risk, and discuss potential future targets for anti-inflammatory or immune modulatory treatment in atherosclerotic cardiovascular disease.
Topics: Anti-Inflammatory Agents; Arteries; Atherosclerosis; Humans; Immunomodulation; Inflammation
PubMed: 34942656
DOI: 10.1055/a-1661-0020 -
Frontiers in Immunology 2020It is no longer controversial that atherosclerosis is a vascular wall chronic inflammatory disease mediated by cells of innate and adaptive immunity. Galectin-9 (Gal-9)... (Review)
Review
It is no longer controversial that atherosclerosis is a vascular wall chronic inflammatory disease mediated by cells of innate and adaptive immunity. Galectin-9 (Gal-9) seems to be a crucial regulator of T-cell immunity by inducing apoptosis in specific T-cell subpopulations associated with autoimmunity and inflammatory disease. Accumulating evidence showed that galectin-9 signaling T-cell immunoglobulin mucin 3 (TIM-3) is concerned with different regulatory functions in autoimmunity, including direct depletion of pro-inflammatory T-cells, expanding the number of regulatory T cells, altering macrophages to an anti-inflammatory state and the induction of repressive myeloid-derived suppressor cells. In addition, anti-Tim-3-Ab administration increased atherosclerotic plaque formation by blocking Tim-3-galectin-9 interaction. Hence, we hypothesize that galectin-9 may be a novel therapy for atherosclerotic disease. Further researches are needed to investigate the precise effect of galectin-9 in the process of atherosclerosis.
Topics: Animals; Arteries; Atherosclerosis; Galectins; Hepatitis A Virus Cellular Receptor 2; Humans; Phenotype; Plaque, Atherosclerotic; Signal Transduction; T-Lymphocyte Subsets
PubMed: 33250901
DOI: 10.3389/fimmu.2020.604265 -
Bioscience Reports Jul 2022An estimated 97% of the human genome consists of non-protein-coding sequences. As our understanding of genome regulation improves, this has led to the characterization... (Review)
Review
An estimated 97% of the human genome consists of non-protein-coding sequences. As our understanding of genome regulation improves, this has led to the characterization of a diverse array of non-coding RNAs (ncRNA). Among these, micro-RNAs (miRNAs) belong to the short ncRNA class (22-25 nucleotides in length), with approximately 2500 miRNA genes encoded within the human genome. From a therapeutic perspective, there is interest in exploiting miRNA as biomarkers of disease progression and response to treatments, as well as miRNA mimics/repressors as novel medicines. miRNA have emerged as an important class of RNA master regulators with important roles identified in the pathogenesis of atherosclerotic cardiovascular disease. Atherosclerosis is characterized by a chronic inflammatory build-up, driven largely by low-density lipoprotein cholesterol accumulation within the artery wall and vascular injury, including endothelial dysfunction, leukocyte recruitment and vascular remodelling. Conventional therapy focuses on lifestyle interventions, blood pressure-lowering medications, high-intensity statin therapy and antiplatelet agents. However, a significant proportion of patients remain at increased risk of cardiovascular disease. This continued cardiovascular risk is referred to as residual risk. Hence, a new drug class targeting atherosclerosis could synergise with existing therapies to optimise outcomes. Here, we review our current understanding of the role of ncRNA, with a focus on miRNA, in the development and progression of atherosclerosis, highlighting novel biological mechanisms and therapeutic avenues.
Topics: Atherosclerosis; Biomarkers; Cardiovascular Diseases; Humans; MicroRNAs; RNA, Untranslated
PubMed: 35758143
DOI: 10.1042/BSR20212355 -
Current Atherosclerosis Reports Jun 2021Atherosclerosis, defined by inflammation and accumulation of cholesterol, extracellular matrix, and cell debris into the arteries is a common factor behind... (Review)
Review
PURPOSE OF REVIEW
Atherosclerosis, defined by inflammation and accumulation of cholesterol, extracellular matrix, and cell debris into the arteries is a common factor behind cardiovascular diseases (CVD), such as coronary artery disease, peripheral artery disease, and stroke. In this review, we discuss and describe novel RNA interference (RNAi)-based therapies in clinical trials and on the market.
RECENT FINDINGS
The first RNAi-based therapies have entered clinical use for the control of atherosclerosis risk factors, i.e., blood cholesterol levels. The most advanced treatment is silencing of proprotein convertase subtilisin/kexin type 9 (PCSK9) with a drug called inclisiran, which has been approved for the treatment of hypercholesterolemia in late 2020, and results in a robust decrease in plasma cholesterol levels. As the new RNAi therapies for atherosclerosis are now entering markets, the usefulness of these therapies will be further evaluated in larger patient cohorts. Thus, it remains to be seen how fast, effectively and eminently these new drugs consolidate their niche within the cardiovascular disease drug palette.
Topics: Atherosclerosis; Humans; Hypercholesterolemia; Proprotein Convertase 9; RNAi Therapeutics
PubMed: 34146172
DOI: 10.1007/s11883-021-00938-z -
Clinical Science (London, England :... May 2021Atherosclerosis is a disease of large and medium arteries that can lead to life-threatening cerebrovascular and cardiovascular consequences such as heart failure and... (Review)
Review
Atherosclerosis is a disease of large and medium arteries that can lead to life-threatening cerebrovascular and cardiovascular consequences such as heart failure and stroke and is a major contributor to cardiovascular-related mortality worldwide. Atherosclerosis development is a complex process that involves specific structural, functional and transcriptional changes in different vascular cell populations at different stages of the disease. The application of single-cell RNA sequencing (scRNA-seq) analysis has discovered not only disease-related cell-specific transcriptomic profiles but also novel subpopulations of cells once thought as homogenous cell populations. Vascular cells undergo specific transcriptional changes during the entire course of the disease. Epigenetics is the instruction-set-architecture in living cells that defines and maintains the cellular identity by regulating the cellular transcriptome. Although different cells contain the same genetic material, they have different epigenomic signatures. The epigenome is plastic, dynamic and highly responsive to environmental stimuli. Modifications to the epigenome are driven by an array of epigenetic enzymes generally referred to as writers, erasers and readers that define cellular fate and destiny. The reversibility of these modifications raises hope for finding novel therapeutic targets for modifiable pathological conditions including atherosclerosis where the involvement of epigenetics is increasingly appreciated. This article provides a critical review of the up-to-date research in the field of epigenetics mainly focusing on in vivo settings in the context of the cellular role of individual vascular cell types in the development of atherosclerosis.
Topics: Animals; Atherosclerosis; DNA Methylation; Endothelial Cells; Epigenesis, Genetic; Fibroblasts; Histone Code; Humans; Lymphocytes; Macrophages; Molecular Targeted Therapy; Myocytes, Smooth Muscle; Plaque, Atherosclerotic; Single-Cell Analysis
PubMed: 33988232
DOI: 10.1042/CS20201066 -
EMBO Molecular Medicine Apr 2022Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation...
Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis.
Topics: Animals; Atherosclerosis; Endoplasmic Reticulum Stress; Endoribonucleases; Fragile X Mental Retardation Protein; Membrane Proteins; Mice; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 35191199
DOI: 10.15252/emmm.202115344 -
International Journal of Molecular... Mar 2022Atherosclerosis is a chronic and progressive inflammatory disease of the arteries initiated by the functional and structural alteration of the endothelial layer...
Atherosclerosis is a chronic and progressive inflammatory disease of the arteries initiated by the functional and structural alteration of the endothelial layer responsible for promoting the subendothelial retention of modified low-density lipoproteins (LDL), which in turn generate an active proinflammatory state in which environmental factors, such as oxidizing agents, growth factors, cytokines, monocyte-macrophages and smooth muscle cells (SMCs), work in cooperation to promote the formation of plaque [...].
Topics: Atherosclerosis; Humans; Lipoproteins, LDL; Molecular Biology; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Plaque, Atherosclerotic
PubMed: 35408804
DOI: 10.3390/ijms23073444 -
International Journal of Molecular... Apr 2021Lifestyle changes, such as overeating and underexercising, can increase the risk of prediabetes. Diabetes is one of the leading causes of atherosclerosis, and recently... (Review)
Review
Lifestyle changes, such as overeating and underexercising, can increase the risk of prediabetes. Diabetes is one of the leading causes of atherosclerosis, and recently it became clear that the pathophysiology of atherosclerosis progresses even before the onset of diabetic symptoms. In addition to changes in platelets and leukocytes in the hyperglycemic state and damage to vascular endothelial cells, extracellular vesicles and microRNAs were found to be involved in the progression of prediabetes atherosclerosis. This review discusses the cellular and molecular mechanisms of these processes, with an intention to enable a comprehensive understanding of the pathophysiology of prediabetes and atherosclerosis.
Topics: Animals; Atherosclerosis; Endothelium, Vascular; Extracellular Vesicles; Humans; Inflammation Mediators; Obesity; Prediabetic State
PubMed: 33921168
DOI: 10.3390/ijms22084108 -
Current Opinion in Lipidology Dec 2021Elevated LDL-C and triglycerides are important risk factors for the development of atherosclerotic cardiovascular disease. Although effective therapies for lipid... (Review)
Review
PURPOSE OF REVIEW
Elevated LDL-C and triglycerides are important risk factors for the development of atherosclerotic cardiovascular disease. Although effective therapies for lipid lowering exist, many people do not reach their treatment targets. In the last two decades, ANGPTL3 has emerged as a novel therapeutic target for lowering plasma LDL-C and triglycerides. Here, an overview of the recent literature on ANGPTL3 is provided, focusing on the therapeutic benefits of inactivation of ANGPTL3 via monoclonal antibodies, antisense oligonucleotides, and other more nascent approaches. In addition, the potential mechanisms by which ANGPTL3 inactivation lowers plasma LDL-C are discussed.
RECENT FINDINGS
ANGPTL3 is a factor secreted by the liver that inhibits lipoprotein lipase and other lipases via the formation of a complex with the related protein ANGPTL8. Large-scale genetic studies in humans have shown that carriers of loss-of-function variants in ANGPTL3 have lower plasma LDL-C and triglyceride levels, and are at reduced risk of atherosclerotic cardiovascular disease. Clinical studies in patients with different forms of dyslipidemia have demonstrated that inactivation of ANGPTL3 using monoclonal antibodies or antisense oligonucleotides markedly lowers plasma LDL-C and triglyceride levels.
SUMMARY
Anti-ANGPTL3 therapies hold considerable promise for reducing plasma LDL-C and triglycerides in selected patient groups.
Topics: Angiopoietin-Like Protein 3; Angiopoietin-Like Protein 8; Angiopoietin-like Proteins; Atherosclerosis; Dyslipidemias; Humans; Peptide Hormones; Triglycerides
PubMed: 34581310
DOI: 10.1097/MOL.0000000000000789 -
Cell Communication and Signaling : CCS Nov 2023Atherosclerosis, which is a vascular pathology characterized by inflammation and plaque build-up within arterial vessel walls, acts as the important cause of most... (Review)
Review
Atherosclerosis, which is a vascular pathology characterized by inflammation and plaque build-up within arterial vessel walls, acts as the important cause of most cardiovascular diseases. Except for a lipid-depository and chronic inflammatory, increasing evidences propose that epigenetic modifications are increasingly associated with atherosclerosis and are of interest from both therapeutic and biomarker perspectives. The chronic progressive nature of atherosclerosis has highlighted atherosclerosis heterogeneity and the fact that specific cell types in the complex milieu of the plaque are, by far, not the only initiators and drivers of atherosclerosis. Instead, the ubiquitous effects of cell type are tightly controlled and directed by the epigenetic signature, which, in turn, is affected by many proatherogenic stimuli, including low-density lipoprotein, proinflammatory, and physical forces of blood circulation. In this review, we summarize the role of DNA methylation and histone post-translational modifications in atherosclerosis. The future research directions and potential therapy for the management of atherosclerosis are also discussed. Video Abstract.
Topics: Humans; DNA Methylation; Histones; Atherosclerosis; Plaque, Atherosclerotic; Epigenesis, Genetic; Protein Processing, Post-Translational; Inflammation
PubMed: 38031118
DOI: 10.1186/s12964-023-01298-8