Animal models of atherosclerosis Emini Veseli, Besa; Perrotta, Paola; De Meyer, Gregory R.A. ...
European journal of pharmacology,
12/2017, Letnik:
816
Journal Article
Recenzirano
Odprti dostop
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 ApoE-/-Fbn1C1039G+/- mice, which can be used as a validated model in pre-clinical studies to evaluate novel plaque-stabilizing drugs.
Atherosclerosis develops preferentially at branches and curvatures of the arterial tree, where blood flow pattern is disturbed rather than being laminar, and wall shear stress has an irregular ...distribution without defined directions. The endothelium in the atherosusceptible regions, in comparison to that in atheroresistant regions, shows activation of proproliferative and proinflammatory gene expressions, reduced production of nitric oxide (NO), increased leukocyte adhesion, and permeability, as well as other atheroprone phenotypes. Differences in gene expressions and cell phenotypes have been detected in endothelia residing in native atherosusceptible and atheroresistant regions of the arteries, or in arteries from animal models with artificial creation of disturbed flow. Similar results have also been shown in in vitro systems that apply controlled shear stresses with or without clear directions to cultured endothelial cells in fluid-dynamically designed flow-loading devices. The available evidence indicates that the coordination of multiple signaling networks, rather than individual separate pathways, links the mechanical signals to specific genetic circuitries in orchestrating the mechanoresponsive networks to evoke comprehensive genetic and functional responses.
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.
RATIONALE:Several studies have suggested a role for the gut microbiota in inflammation and atherogenesis. A causal relation relationship between gut microbiota, inflammation, and atherosclerosis has ...not been explored previously.
OBJECTIVE:Here, we investigated whether a proinflammatory microbiota from Caspase1 (Casp1) mice accelerates atherogenesis in Ldlr mice.
METHOD AND RESULTS:We treated female Ldlr mice with antibiotics and subsequently transplanted them with fecal microbiota from Casp1 mice based on a cohousing approach. Autologous transplantation of fecal microbiota of Ldlr mice served as control. Mice were cohoused for 8 or 13 weeks and fed chow or high-fat cholesterol–rich diet. Fecal samples were collected, and factors related to inflammation, metabolism, intestinal health, and atherosclerotic phenotypes were measured. Unweighted Unifrac distances of 16S rDNA (ribosomal DNA) sequences confirmed the introduction of the Casp1 and Ldlr microbiota into Ldlr mice (referred to as Ldlr(Casp1) or Ldlr(Ldlr) mice). Analysis of atherosclerotic lesion size in the aortic root demonstrated a significant 29% increase in plaque size in 13-week high-fat cholesterol–fed Ldlr(Casp1) mice compared with Ldlr(Ldlr) mice. We found increased numbers of circulating monocytes and neutrophils and elevated proinflammatory cytokine levels in plasma in high-fat cholesterol–fed Ldlr(Casp1) compared with Ldlr(Ldlr) mice. Neutrophil accumulation in the aortic root of Ldlr(Casp1) mice was enhanced compared with Ldlr(Ldlr) mice. 16S-rDNA-encoding sequence analysis in feces identified a significant reduction in the short-chain fatty acid–producing taxonomies Akkermansia, Christensenellaceae, Clostridium, and Odoribacter in Ldlr(Casp1) mice. Consistent with these findings, cumulative concentrations of the anti-inflammatory short-chain fatty acids propionate, acetate and butyrate in the cecum were significantly reduced in 13-week high-fat cholesterol–fed Ldlr(Casp1) compared with Ldlr(Ldlr) mice.
CONCLUSIONS:Introduction of the proinflammatory Casp1 microbiota into Ldlr mice enhances systemic inflammation and accelerates atherogenesis.
Abstract
Current knowledge suggests that intimal smooth muscle cells (SMCs) in native atherosclerotic plaque derive mainly from the medial arterial layer. During this process, SMCs undergo complex ...structural and functional changes giving rise to a broad spectrum of phenotypes. Classically, intimal SMCs are described as dedifferentiated/synthetic SMCs, a phenotype characterized by reduced expression of contractile proteins. Intimal SMCs are considered to have a beneficial role by contributing to the fibrous cap and thereby stabilizing atherosclerotic plaque. However, intimal SMCs can lose their properties to such an extent that they become hard to identify, contribute significantly to the foam cell population, and acquire inflammatory-like cell features. This review highlights mechanisms of SMC plasticity in different stages of native atherosclerotic plaque formation, their potential for monoclonal or oligoclonal expansion, as well as recent findings demonstrating the underestimated deleterious role of SMCs in this disease.
Atherosclerosis is a chronic inflammatory arterial disease driven by both innate and adaptive immune responses to modified lipoproteins and components of the injured vascular wall. Specific T ...lymphocyte responses driven by T helper-1 or T regulatory cells play distinct and opposing roles in atherosclerosis. More recently, T helper-17 cells, which produce the prototype cytokine interleukin-17, have been characterized and shown to be critical in mucosal host defense against microbial and fungal pathogens. Sustained production of interleukin-17 in an inflammatory context has been linked to the pathology of several autoimmune and inflammatory diseases. However, regulatory and protective roles have also been reported in selective disease settings. Studies in atherosclerosis led to conflicting results on the roles of interleukin-17 and T helper-17 cells in disease development and plaque stability. The present review provides a summary of the available evidence and putative mechanisms linking this pathway to atherosclerosis, as well as a perspective on the risks and benefits of interleukin-17–targeted cytokine therapy in patients at high cardiovascular risk.
ATP citrate lyase (ACLY) is an important enzyme linking carbohydrate to lipid metabolism by generating acetyl-CoA from citrate for fatty acid and cholesterol biosynthesis. Mendelian randomization of ...large human cohorts has validated ACLY as a promising target for low-density-lipoprotein-cholesterol (LDL-C) lowering and cardiovascular protection. Among current ACLY inhibitors, Bempedoic acid (ETC-1002) is a first-in-class, prodrug-based direct competitive inhibitor of ACLY which regulates lipid metabolism by upregulating hepatic LDL receptor (LDLr) expression and activity. ACLY deficiency in hepatocytes protects from hepatic steatosis and dyslipidemia. In addition, pharmacological inhibition of ACLY by bempedoic acid, prevents dyslipidemia and attenuates atherosclerosis in hypercholesterolemic ApoE−/− mice, LDLr−/− mice, and LDLr−/− miniature pigs. Convincing data from clinical trials have revealed that bempedoic acid significantly lowers LDL-C as monotherapy, combination therapy, and add-on with statin therapy in statin-intolerant patients. More recently, a phase 3 CLEAR Harmony clinical trial (“Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol”) has shown that bempedoic acid reduces the level of LDL-C in hypercholesterolemic patients receiving guideline-recommended statin therapy with a good safety profile. Hereby, we provide a updated review of the expression, regulation, genetics, functions of ACLY in lipid metabolism and atherosclerosis, and highlight the therapeutic potential of ACLY inhibitors (such as bempedoic acid, SB-204990, and other naturally-occuring inhibitors) to treat atherosclerotic cardiovascular diseases. It must be pointed out that long-term large-scale clinical trials in high-risk patients, are warranted to validate whether ACLY represent a promising therapeutic target for pharmaceutic intervention of dyslipidemia and atherosclerosis; and assess the safety and efficacy profile of ACLY inhibitors in improving cardiovascular outcome of patients.
Atherosclerosis is a chronic disease of the arterial wall, and a leading cause of death and loss of productive life years worldwide. Research into the disease has led to many compelling hypotheses ...about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke. Yet, despite these advances, we still lack definitive evidence to show that processes such as lipoprotein oxidation, inflammation and immunity have a crucial involvement in human atherosclerosis. Experimental atherosclerosis in animals furnishes an important research tool, but extrapolation to humans requires care. Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
30.
The role of B cells in atherosclerosis Sage, Andrew P; Tsiantoulas, Dimitrios; Binder, Christoph J ...
Nature reviews cardiology,
03/2019, Letnik:
16, Številka:
3
Journal Article
Recenzirano
The cardiovascular system is subject to hyperlipidaemic, inflammatory, and pro-oxidant stressors. Over time, these factors drive prevalent chronic diseases, of which atherosclerosis is most prominent ...and accounts for the majority of deaths globally. Antibody-producing B cells perform a unique role in responses to stress, injury, and infection. The power, inducibility, and adaptability of the antibody repertoire require an equally complex range of control measures. Defects and chronic perturbations in these checkpoints lead to inappropriate antibody responses, which might have important roles in shaping the development and outcome of atherosclerotic disease. A unique aspect related to atherosclerosis is the prominent role of natural antibodies, specifically those binding to the oxidized epitopes that are abundant on modified lipoproteins and cellular debris. B cells control cellular immune responses through cell-cell contact, antigen presentation, and cytokine production, and thereby participate in systemic and local immune responses in atherosclerotic arteries. To date, both proatherogenic and antiatherogenic properties have been assigned to B cells, depending on subsets and how they are functionally targeted. For these reasons, a deeper understanding of how B cells influence atherosclerotic plaque development is being pursued with the hope of providing novel B cell-targeted interventions to prevent inflammation-driven cardiovascular events.
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