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A murine model of obesity with accelerated atherosclerosis.

ABSTRACT: The epidemic of obesity sweeping developed nations is accompanied by an increase in atherosclerotic cardiovascular diseases. Dyslipidemia, diabetes, hypertension, and obesity are risk factors for cardiovascular disease. However, delineating the mechanism of obesity-accelerated atherosclerosis has been hampered by a paucity of animal models. Similar to humans, apolipoprotein E-deficient (apoE(-/-)) mice spontaneously develop atherosclerosis over their lifetime. To determine whether apoE(-/-) mice would develop obesity with accelerated atherosclerosis, we fed mice diets containing 10 (low fat (LF)) or 60 (high fat (HF)) kcal % from fat for 17 weeks. Mice fed the HF diet had a marked increase in body weight and atherosclerotic lesion formation compared to mice fed the LF diet. There were no significant differences between groups in serum total cholesterol, triglycerides, or leptin concentrations. Plasma concentrations of the acute-phase reactant serum amyloid A (SAA) are elevated in both obesity and cardiovascular disease. Accordingly, plasma SAA concentrations were increased fourfold (P < 0.01) in mice fed the HF diet. SAA was associated with both pro- and antiatherogenic lipoproteins in mice fed the HF diet compared to those fed the LF diet, in which SAA was primarily associated with the antiatherogenic lipoprotein high-density lipoprotein (HDL). Moreover, SAA was localized with apoB-containing lipoproteins and biglycan in the vascular wall. Taken together, these data suggest male apoE-deficient mice are a model of metabolic syndrome and that chronic low level inflammation associated with increased SAA concentrations may mediate atherosclerotic lesion formation.

SUBMITTER: King VL

PROVIDER: S-EPMC2811527 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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A murine model of obesity with accelerated atherosclerosis.

King Victoria L VL Hatch Nicholas W NW Chan Huei-Wei HW de Beer Marcielle C MC de Beer Frederick C FC Tannock Lisa R LR

Obesity (Silver Spring, Md.) 20090604 1

The epidemic of obesity sweeping developed nations is accompanied by an increase in atherosclerotic cardiovascular diseases. Dyslipidemia, diabetes, hypertension, and obesity are risk factors for cardiovascular disease. However, delineating the mechanism of obesity-accelerated atherosclerosis has been hampered by a paucity of animal models. Similar to humans, apolipoprotein E-deficient (apoE(-/-)) mice spontaneously develop atherosclerosis over their lifetime. To determine whether apoE(-/-) mice ...[more]

PMID: 19498343

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Project description:The purpose of this study was to evaluate the effects of L-4F, an apolipoprotein A-1 mimetic peptide, alone or with pravastatin, in apoE-/-Fas-/-C57BL/6 mice that spontaneously develop immunoglobulin G (IgG) autoantibodies, glomerulonephritis, osteopenia, and atherosclerotic lesions on a normal chow diet.Female mice, starting at eight to nine weeks of age, were treated for 27 weeks with 1) pravastatin, 2) L-4F, 3) L-4F plus pravastatin, or 4) vehicle control, followed by disease phenotype assessment.In preliminary studies, dysfunctional, proinflammatory high-density lipoproteins (piHDL) were decreased six hours after a single L-4F, but not scrambled L-4F, injection in eight- to nine-week old mice. After 35 weeks, L-4F-treated mice, in the absence/presence of pravastatin, had significantly smaller lymph nodes and glomerular tufts (PL, LP<0.05), lower serum levels of IgG antibodies to double stranded DNA (dsDNA) (PL<0.05) and oxidized phospholipids (oxPLs) (PL, LP<0.005), and elevated total and vertebral bone mineral density (PL, LP<0.01) compared to vehicle controls. Although all treatment groups presented larger aortic root lesions compared to vehicle controls, enlarged atheromas in combination treatment mice had significantly less infiltrated CD68+ macrophages (PLP<0.01), significantly increased mean alpha-actin stained area (PLP<0.05), and significantly lower levels of circulating markers for atherosclerosis progression, CCL19 (PL, LP<0.0005) and VCAM-1 (PL<0.0002).L-4F treatment, alone or with pravastatin, significantly reduced IgG anti-dsDNA and IgG anti-oxPLs, proteinuria, glomerulonephritis, and osteopenia in a murine lupus model of accelerated atherosclerosis. Despite enlarged aortic lesions, increased smooth muscle content, decreased macrophage infiltration, and decreased pro-atherogenic chemokines in L-4F plus pravastatin treated mice suggest protective mechanisms not only on lupus-like disease, but also on potential plaque remodeling in a murine model of systemic lupus erythematosus (SLE) and accelerated atherosclerosis.

Project description:BackgroundObesity and particularly the metabolic syndrome, which is often associated with obesity, combine a major risk for type 2 diabetes and cardiovascular disease. Emerging evidence indicate obesity-associated subclinical inflammation primarily originating from adipose tissue as a common cause for type 2 diabetes and cardiovascular disease. However, a suitable and well-characterized mouse model to simultaneously study obesity-associated metabolic disorders and atherosclerosis is not available yet. Here we established and characterized a murine model combining diet-induced obesity and associated adipose tissue inflammation and metabolic deteriorations as well as atherosclerosis, hence reflecting the human situation of cardio-metabolic disease.MethodsWe compared a common high-fat diet with 0.15% cholesterol (HFC), and a high-fat, high-sucrose diet with 0.15% cholesterol (HFSC) fed to LDL receptor-deficient (LDLR-/-) mice. Insulin resistance, glucose tolerance, atherosclerotic lesion formation, hepatic lipid accumulation, and inflammatory gene expression in adipose tissue and liver were assessed.ResultsAfter 12-16 weeks, LDLR-/- mice fed HFSC or HFC developed significant diet-induced obesity, adipose tissue inflammation, insulin resistance, and impaired glucose tolerance compared to lean controls. Notably, HFSC-fed mice developed significantly higher adipose tissue inflammation in parallel with significantly elevated atherosclerotic lesion area compared to those on HFC. Moreover, LDLR-/- mice on HFSC showed increased insulin resistance and impaired glucose tolerance relative to those on HFC. After prolonged feeding (20 weeks), however, no significant differences in inflammatory and metabolic parameters as well as atherosclerotic lesion formation were detectable any more between LDLR-/- mice fed HFSC or HFC.ConclusionThe use of high sucrose rather than more complex carbohydrates in high-fat diets significantly accelerates development of obesity-driven metabolic complications and atherosclerotic plaque formation parallel to obesity-induced adipose tissue inflammation in LDLR-/- mice. Hence LDLR-/- mice fed high-fat high-sucrose cholesterol-enriched diet appear to be a suitable and time-saving animal model for cardio-metabolic disease. Moreover our results support the suggested interrelation between adipose tissue inflammation and atherosclerotic plaque formation.

Project description:ObjectiveAtherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients. Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s).Methods and resultsWild-type mice were injected with gain-of-function PCSK9D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis, two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery) were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi) mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic plaques of HGHCi HFD animals were larger, showed a less stable phenotype (measured by the increased necrotic core area, reduced fibrous cap thickness, and less α-SMA-positive area) and had more inflammation (increased plasma IL-1β level, aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA) after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and extracellular matrix degradation (Adamts4 and Mmp14). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks. Hyperlipidemic and hyperglycemic mice fed a PD (HGHCi PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells) within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks.ConclusionWe established a nongenetically inducible mouse model allowing comparative analyses of atherosclerosis in HCi and HGHCi conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice.

Project description:IntroductionThe biggest risk factor for obesity and its associated comorbidities is a Western diet. This Western diet induces adipose tissue (AT) inflammation, which causes an AT dysfunction. Since AT is a vital endocrine organ, its dysfunction damages other organs, thus inducing a state of chronic inflammation and causing various comorbidities. Even though it is evident a Western diet, high in fat and carbohydrates, induces obesity and its complications, it is not known yet which macronutrient plays the most important role. Therefore, the aim of this study was to investigate the effect of macronutrient composition on obesity and to reverse the Western diet-induced metabolic risk via caloric restriction (CR) or a change of diet composition.Materials and methodsMale, C57BL/6JRj mice were fed with a diet high in fat, sucrose, fructose, sucrose and fructose, starch, a Western diet, or a control diet for 15 weeks. To assess reversibility of the metabolic risk, mice were first made obese via 15 weeks of WD and then put on either a CR or switched to a sucrose-rich diet.ResultsA sucrose-rich and high-starch diet induced less obesity and a better metabolic profile than a Western diet, evidenced by less hepatic steatosis, lower plasma cholesterol, and less insulin resistance. Furthermore, these diets induced less intra-abdominal AT inflammation than a Western diet, since mRNA levels of pro-inflammatory markers were lower and there was less macrophage infiltration. Expression of tight junction markers in colon tissue was higher in the sucrose-rich and high-starch group than the Western group, indicating a better intestinal integrity upon sucrose-rich and high-starch feeding. Additionally, CR induced weight loss and decreased both metabolic abnormalities and AT inflammation, regardless of macronutrient composition. However, effects were more pronounced upon CR with sucrose-rich or high-starch diet. Even without CR, switching obese mice to a sucrose-rich diet induced weight loss and decreased AT inflammation and metabolic aberrations.DiscussionA diet high in sucrose or starch induces less obesity and obesity-associated complications. Moreover, switching obese mice to a sucrose-rich diet elicits weight loss and decreases obesity-induced metabolic complications, highlighting the potential of carbohydrates to treat obesity.

Project description:The effect of psychological stress on the gastrointestinal microbiota is widely recognized. Chronic psychological stress may be associated with increased disease activity in inflammatory bowel disease, but the relationships among psychological stress, the gastrointestinal microbiota, and the severity of colitis is not yet fully understood. Here, we examined the impact of 12-week repeated water-avoidance stress on the microbiota of two inbred strains of T cell receptor alpha chain gene knockout mouse (background, BALB/c and C57BL/6) by means of next-generation sequencing of bacterial 16S rRNA genes. In both mouse strains, knockout of the T cell receptor alpha chain gene caused a loss of gastrointestinal microbial diversity and stability. Chronic exposure to repeated water-avoidance stress markedly altered the composition of the colonic microbiota of C57BL/6 mice, but not of BALB/c mice. In C57BL/6 mice, the relative abundance of genus Clostridium, some members of which produce the toxin phospholipase C, was increased, which was weakly positively associated with colitis severity, suggesting that expansion of specific populations of indigenous pathogens may be involved in the exacerbation of colitis. However, we also found that colitis was not exacerbated in mice with a relatively diverse microbiota even if their colonic microbiota contained an expanded phospholipase C-producing Clostridium population. Exposure to chronic stress also altered the concentration of free immunoglobulin A in colonic contents, which may be related to both the loss of bacterial diversity in the colonic microbiota and the severity of the colitis exacerbation. Together, these results suggest that long-term exposure to psychological stress induces dysbiosis in the immunodeficient mouse in a strain-specific manner and also that alteration of microbial diversity, which may be related to an altered pattern of immunoglobulin secretion in the gastrointestinal tract, might play a crucial role in the development of chronic stress-induced colitis.

Project description:Background: Rheumatoid arthritis (RA) is a highly prevalent, chronic inflammatory condition of the synovial joints that affects approximately 1% of the global population. The pathogenesis of RA is predominantly inflammatory in nature, thereby accelerating the co-occurrence of other immunoinflammatory conditions such as atherosclerosis. Apart from traditional cardiovascular risk factors, RA patients possess a multitude of other factors that predispose them to early atherosclerotic disease. The aim of this systematic review is to assess the prevalence of premature atherosclerosis in RA patients and elucidate the role that proinflammatory cytokines, RA-related autoantibodies, and endothelial dysfunction play in the pathophysiology of RA-mediated atherosclerosis. We also discussed novel biomarkers that can be used to predict early atherosclerosis in RA and current guidelines used to treat RA. Methods: This review followed the PRISMA guidelines to select and analyze relevant articles. A literature search for articles was performed on February 25, 2022, through three research databases including PubMed, ProQuest, and ScienceDirect. The query used to identify relevant publications was "Rheumatoid arthritis and atherosclerosis" and the search duration was set from 2012-2022. Relevant articles were selected based on the inclusion and exclusion criteria. Results: Our initial search generated 21,235 articles. We narrowed our search according to the inclusion and exclusion criteria. After assessing eligibility based on the full content of the articles, 73 articles were ultimately chosen for this review. Conclusion: There is an increased prevalence of accelerated atherosclerosis among RA patients. We found evidence to explain the role of proinflammatory cytokines, RA-related autoantibodies, and endothelial dysfunction in the pathophysiology RA-mediated atherosclerosis. Therapies targeting either the inflammatory load or traditional CV risk-factors seem to improve vascular outcomes in RA patients. Novel markers of atherosclerosis in RA may be useful in predicting premature atherosclerosis and serve as new targets for therapeutic intervention.

Dataset Information

A murine model of obesity with accelerated atherosclerosis.

Publications

A murine model of obesity with accelerated atherosclerosis.

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