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Signal Transduction and Targeted Therapy Apr 2022Atherosclerosis is a chronic inflammatory vascular disease driven by traditional and nontraditional risk factors. Genome-wide association combined with clonal lineage... (Review)
Review
Atherosclerosis is a chronic inflammatory vascular disease driven by traditional and nontraditional risk factors. Genome-wide association combined with clonal lineage tracing and clinical trials have demonstrated that innate and adaptive immune responses can promote or quell atherosclerosis. Several signaling pathways, that are associated with the inflammatory response, have been implicated within atherosclerosis such as NLRP3 inflammasome, toll-like receptors, proprotein convertase subtilisin/kexin type 9, Notch and Wnt signaling pathways, which are of importance for atherosclerosis development and regression. Targeting inflammatory pathways, especially the NLRP3 inflammasome pathway and its regulated inflammatory cytokine interleukin-1β, could represent an attractive new route for the treatment of atherosclerotic diseases. Herein, we summarize the knowledge on cellular participants and key inflammatory signaling pathways in atherosclerosis, and discuss the preclinical studies targeting these key pathways for atherosclerosis, the clinical trials that are going to target some of these processes, and the effects of quelling inflammation and atherosclerosis in the clinic.
Topics: Atherosclerosis; Genome-Wide Association Study; Humans; Inflammasomes; Inflammation; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction
PubMed: 35459215
DOI: 10.1038/s41392-022-00955-7 -
Circulation Research Jan 2019There is now overwhelming experimental and clinical evidence that atherosclerosis is a chronic inflammatory disease. Lessons from genome-wide association studies,... (Review)
Review
There is now overwhelming experimental and clinical evidence that atherosclerosis is a chronic inflammatory disease. Lessons from genome-wide association studies, advanced in vivo imaging techniques, transgenic lineage tracing mice, and clinical interventional studies have shown that both innate and adaptive immune mechanisms can accelerate or curb atherosclerosis. Here, we summarize and discuss the pathogenesis of atherosclerosis with a focus on adaptive immunity. We discuss some limitations of animal models and the need for models that are tailored to better translate to human atherosclerosis and ultimately progress in prevention and treatment.
Topics: Adaptive Immunity; Animals; Atherosclerosis; Disease Models, Animal; Humans; Inflammation; Inflammation Mediators; Mice; Plaque, Atherosclerotic; Signal Transduction; Species Specificity
PubMed: 30653442
DOI: 10.1161/CIRCRESAHA.118.313591 -
Biomolecules Aug 2018Atherosclerosis is a chronic inflammatory disease; unstable atherosclerotic plaque rupture, vascular stenosis, or occlusion caused by platelet aggregation and thrombosis... (Review)
Review
Atherosclerosis is a chronic inflammatory disease; unstable atherosclerotic plaque rupture, vascular stenosis, or occlusion caused by platelet aggregation and thrombosis lead to acute cardiovascular disease. Atherosclerosis-related inflammation is mediated by proinflammatory cytokines, inflammatory signaling pathways, bioactive lipids, and adhesion molecules. This review discusses the effects of inflammation and the systemic inflammatory signaling pathway on atherosclerosis, the role of related signaling pathways in inflammation, the formation of atherosclerosis plaques, and the prospects of treating atherosclerosis by inhibiting inflammation.
Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Biomarkers; Humans; Inflammation; Signal Transduction
PubMed: 30142970
DOI: 10.3390/biom8030080 -
International Journal of Molecular... Mar 2020Diabetes mellitus comprises a group of carbohydrate metabolism disorders that share a common main feature of chronic hyperglycemia that results from defects of insulin... (Review)
Review
Diabetes mellitus comprises a group of carbohydrate metabolism disorders that share a common main feature of chronic hyperglycemia that results from defects of insulin secretion, insulin action, or both. Insulin is an important anabolic hormone, and its deficiency leads to various metabolic abnormalities in proteins, lipids, and carbohydrates. Atherosclerosis develops as a result of a multistep process ultimately leading to cardiovascular disease associated with high morbidity and mortality. Alteration of lipid metabolism is a risk factor and characteristic feature of atherosclerosis. Possible links between the two chronic disorders depending on altered metabolic pathways have been investigated in numerous studies. It was shown that both types of diabetes mellitus can actually induce atherosclerosis development or further accelerate its progression. Elevated glucose level, dyslipidemia, and other metabolic alterations that accompany the disease development are tightly involved in the pathogenesis of atherosclerosis at almost every step of the atherogenic process. Chronic inflammation is currently considered as one of the key factors in atherosclerosis development and is present starting from the earliest stages of the pathology initiation. It may also be regarded as one of the possible links between atherosclerosis and diabetes mellitus. However, the data available so far do not allow for developing effective anti-inflammatory therapeutic strategies that would stop atherosclerotic lesion progression or induce lesion reduction. In this review, we summarize the main aspects of diabetes mellitus that possibly affect the atherogenic process and its relationship with chronic inflammation. We also discuss the established pathophysiological features that link atherosclerosis and diabetes mellitus, such as oxidative stress, altered protein kinase signaling, and the role of certain miRNA and epigenetic modifications.
Topics: Animals; Atherosclerosis; Diabetes Mellitus; Glucose; Humans; Inflammation; Insulin Resistance; Lipids; Oxidative Stress
PubMed: 32155866
DOI: 10.3390/ijms21051835 -
Circulation Research Feb 2016Dysfunction of the endothelial lining of lesion-prone areas of the arterial vasculature is an important contributor to the pathobiology of atherosclerotic cardiovascular... (Review)
Review
Dysfunction of the endothelial lining of lesion-prone areas of the arterial vasculature is an important contributor to the pathobiology of atherosclerotic cardiovascular disease. Endothelial cell dysfunction, in its broadest sense, encompasses a constellation of various nonadaptive alterations in functional phenotype, which have important implications for the regulation of hemostasis and thrombosis, local vascular tone and redox balance, and the orchestration of acute and chronic inflammatory reactions within the arterial wall. In this review, we trace the evolution of the concept of endothelial cell dysfunction, focusing on recent insights into the cellular and molecular mechanisms that underlie its pivotal roles in atherosclerotic lesion initiation and progression; explore its relationship to classic, as well as more recently defined, clinical risk factors for atherosclerotic cardiovascular disease; consider current approaches to the clinical assessment of endothelial cell dysfunction; and outline some promising new directions for its early detection and treatment.
Topics: Animals; Atherosclerosis; Endothelial Cells; Endothelium, Vascular; Hemodynamics; Humans; Inflammation Mediators; Nitric Oxide; Phenotype; Prognosis; Risk Assessment; Risk Factors; Signal Transduction
PubMed: 26892962
DOI: 10.1161/CIRCRESAHA.115.306301 -
European Journal of Pharmacology Dec 2017An ideal animal model of atherosclerosis resembles human anatomy and pathophysiology and has the potential to be used in medical and pharmaceutical research to obtain... (Review)
Review
An ideal animal model of atherosclerosis resembles human anatomy and pathophysiology and has the potential to be used in medical and pharmaceutical research to obtain results that can be extrapolated to human medicine. Moreover, it must be easy to acquire, can be maintained at a reasonable cost, is easy to handle and shares the topography of the lesions with humans. In general, animal models of atherosclerosis are based on accelerated plaque formation due to a cholesterol-rich/Western-type diet, manipulation of genes involved in the cholesterol metabolism, and the introduction of additional risk factors for atherosclerosis. Mouse and rabbit models have been mostly used, followed by pigs and non-human primates. Each of these models has its advantages and limitations. The mouse has become the predominant species to study experimental atherosclerosis because of its rapid reproduction, ease of genetic manipulation and its ability to monitor atherogenesis in a reasonable time frame. Both Apolipoprotein E deficient (ApoE) and LDL-receptor (LDLr) knockout mice have been frequently used, but also ApoE/LDLr double-knockout, ApoE3-Leiden and PCSK9-AAV mice are valuable tools in atherosclerosis research. However, a great challenge was the development of a model in which intra-plaque microvessels, haemorrhages, spontaneous atherosclerotic plaque ruptures, myocardial infarction and sudden death occur consistently. These features are present in ApoEFbn1 mice, which can be used as a validated model in pre-clinical studies to evaluate novel plaque-stabilizing drugs.
Topics: Animals; Atherosclerosis; Disease Models, Animal; Plaque, Atherosclerotic
PubMed: 28483459
DOI: 10.1016/j.ejphar.2017.05.010 -
Circulation Research Feb 2016
Topics: Animals; Atherosclerosis; Biomarkers; Humans; Lipids; Prognosis; Risk Factors
PubMed: 26892955
DOI: 10.1161/CIRCRESAHA.116.308334 -
European Journal of Preventive... Mar 2020Despite major efforts to reduce atherosclerotic cardiovascular disease (ASCVD) burden with conventional risk factor control, significant residual risk remains. Recent... (Review)
Review
Despite major efforts to reduce atherosclerotic cardiovascular disease (ASCVD) burden with conventional risk factor control, significant residual risk remains. Recent evidence on non-traditional determinants of cardiometabolic health has advanced our understanding of lifestyle-disease interactions. Chronic exposure to environmental stressors like poor diet quality, sedentarism, ambient air pollution and noise, sleep deprivation and psychosocial stress affect numerous traditional and non-traditional intermediary pathways related to ASCVD. These include body composition, cardiorespiratory fitness, muscle strength and functionality and the intestinal microbiome, which are increasingly recognized as major determinants of cardiovascular health. Evidence points to partially overlapping mechanisms, including effects on inflammatory and nutrient sensing pathways, endocrine signalling, autonomic function and autophagy. Of particular relevance is the potential of low-risk lifestyle factors to impact on plaque vulnerability through altered adipose tissue and skeletal muscle phenotype and secretome. Collectively, low-risk lifestyle factors cause a set of phenotypic adaptations shifting tissue cross-talk from a proinflammatory milieu conducive for high-risk atherosclerosis to an anti-atherogenic milieu. The ketone body ß-hydroxybutyrate, through inhibition of the NLRP-3 inflammasome, is likely to be an intermediary for many of these observed benefits. Adhering to low-risk lifestyle factors adds to the prognostic value of optimal risk factor management, and benefit occurs even when the impact on conventional risk markers is discouragingly minimal or not present. The aims of this review are (a) to discuss novel lifestyle risk factors and their underlying biochemical principles and (b) to provide new perspectives on potentially more feasible recommendations to improve long-term adherence to low-risk lifestyle factors.
Topics: Atherosclerosis; Healthy Lifestyle; Heart Disease Risk Factors; Humans; Life Style; Protective Factors; Risk Assessment; Risk Reduction Behavior
PubMed: 31408370
DOI: 10.1177/2047487319869400 -
Circulation Research Oct 2018
Review
Topics: Animals; Atherosclerosis; Autoimmunity; CD4-Positive T-Lymphocytes; Humans; Vaccination
PubMed: 30359201
DOI: 10.1161/CIRCRESAHA.118.313816 -
Advances in Experimental Medicine and... 2017In this chapter, we discuss the manner through which the immune system regulates the cardiovascular system in health and disease. We define the cardiovascular system and... (Review)
Review
In this chapter, we discuss the manner through which the immune system regulates the cardiovascular system in health and disease. We define the cardiovascular system and elements of atherosclerotic disease, the main focus in this chapter. Herein we elaborate on the disease process that can result in myocardial infarction (heart attack), ischaemic stroke and peripheral arterial disease. We have discussed broadly the homeostatic mechanisms in place that help autoregulate the cardiovascular system including the vital role of cholesterol and lipid clearance as well as the role lipid homeostasis plays in cardiovascular disease in the context of atherosclerosis. We then elaborate on the role played by the immune system in this setting, namely, major players from the innate and adaptive immune system, as well as discussing in greater detail specifically the role played by monocytes and macrophages.This chapter should represent an overview of the role played by the immune system in cardiovascular homeostasis; however further reading of the references cited can expand the reader's knowledge of the detail, and we point readers to many excellent reviews which summarise individual immune systems and their role in cardiovascular disease.
Topics: Animals; Arteries; Atherosclerosis; Cell Communication; Humans; Immune System; Immunity, Innate; Lipid Metabolism; Plaque, Atherosclerotic; Risk Factors; Signal Transduction
PubMed: 28667557
DOI: 10.1007/978-3-319-57613-8_7