Abstract 285: Granzymes: Major Players in Vascular Remodelling, Atherosclerosis and Longevity

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Rani P Cruz ◽  
Wendy A Boivin ◽  
Ciara M Chamberlain ◽  
Jonathan C Choy ◽  
Bruce M McManus ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Chronic Inflammation ◽  
Proteolytic Activity ◽  
Hair Loss ◽  
High Fat Diet ◽  
Target Cells ◽  
High Fat ◽  
Elastin Degradation ◽  
Apoe Ko Mice ◽  
Apoe Ko

Introduction: Granzymes A and B (GrA/GrB) are cytotoxic proteases that are released by immune cells to eliminate target cells. GrB is present in human vessels and its expression corresponds to increased disease severity. In addition to their cytotoxic roles, in conditions of chronic inflammation, GrA and GrB may contribute to the degradation of extracellular matrix (ECM) proteins leading to tissue degeneration. Hypothesis: GrA and GrB levels are elevated in atherosclerotic patients and play a key role in the degradation of ECM and atherosclerosis. Methods: ApoE −/− x GrB −/− double knockout (apoE/GrB-DKO) mice were generated. C57-wt, GrB-KO, apoE-KO or apoE/GrB-DKO mice were fed a high fat diet for 30 weeks, sacrificed, tissues processed and lesion morphology and morphometry assessed. GrA and GrB levels were also measured in human plasma from patients with or without clinically evident atherosclerosis by ELISA. GrA/GrB-mediated ECM proteolytic activity was also assessed. Results: GrB deficiency significantly reduced the development of xanthomatosis, hair loss and atherosclerosis in the apoE-KO mice. GrB deficiency resulted in a marked reduction of elastin degradation in both the skin and blood vessels. GrB was found to co-localize to elastin fibres in atherosclerotic plaques and was capable of binding to, and cleaving elastin in vitro. ECM cleavage assays demonstrated that GrA and GrB cleave other ECM such as fibronectin. Preliminary studies indicate that GrB deficiency increases the lifespan of the apoE-KO mice as the apoE/GrB-DKO mice can survive up to 60 weeks of age on a high fat diet with no external indication of disease, skin degeneration or hair loss. In humans, preliminary evidence indicates that GrA/GrB levels are elevated in atherosclerosis. Smoking also appears to elevate plasma granzyme levels. Conclusions: During chronic inflammation, granzymes accumulate extracellularly and exhibit proteolytic activity towards extracellular matrix proteins that results in vascular remodeling and atherosclerosis with age. Attenuation of GrB resulted not only in a significant reduction of atherosclerosis, but also prolonged the lifespan of apoE-KO mice.

Endotracheal Exposure Of LPS Enhances Plaque Rupture In ApoE-KO Mice Fed With A Short-Term High Fat Diet

2012 ◽  
Author(s):  
Jen-erh (David) Jaw ◽  
Masashi Tsuruta ◽  
Yuexin Li ◽  
Sheena Tam ◽  
Yeni Oh ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Plaque Rupture ◽  
High Fat ◽  
Short Term ◽  
Apoe Ko Mice ◽  
Apoe Ko

scholarly journals Imaging Fibrogenesis in a Diet-Induced Model of Nonalcoholic Steatohepatitis (NASH)

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
S. V. Hartimath ◽  
R. Boominathan ◽  
V. Soh ◽  
P. Cheng ◽  
X. Deng ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Liver Fibrosis ◽  
Early Detection ◽  
Pet Imaging ◽  
Nonalcoholic Steatohepatitis ◽  
High Fat Diet ◽  
Detection Sensitivity ◽  
Chow Diet ◽  
High Fat ◽  
Standard Chow Diet

Purpose. Liver fibrosis is the hallmark of chronic nonalcoholic steatohepatitis (NASH) and is characterised by the excessive deposition of extracellular matrix proteins. Early detection and accurate staging of liver fibrosis is critically important for patient management. One of the earliest pathological markers in NASH is the activation of hepatic stellate cells (HSCs) which may be exploited as a marker of fibrogenesis. Activated HSCs secreting factors such as integrin αvβ3 propagate fibrosis. The purpose of the current study was to assess the utility of the integrin αvβ3 imaging agent [18F]FtRGD for the early detection of fibrosis in a diet-induced model of NASH longitudinally using PET imaging. Procedures. Mice were fed with either standard chow diet (SD), high-fat diet (HFD), or a choline-deficient, L-amino acid-defined high-fat fibrogenic diet (CDAHFD) to mimic the clinical pathology of liver disease and followed longitudinally for 10 weeks to assess the development of liver fibrosis using [18F]FtRGD positron emission tomography (PET) imaging. Standard blood biochemistry, histological measures, and qPCR were used to quantify integrin αvβ3, smooth muscle actin, and collagen types 1 and 6 to assess the extent of NASH pathology and accurately stage liver fibrosis. Results. The CDAHFD fibrogenic diet predictably developed hepatic inflammation and steatosis over the 10 weeks studied with little NASH pathology detected in high fat diet-treated animals. Stage 1 fibrosis was detected early by histology at day 21 and progressed to stage 2 by day 35 and stage 3 by day 56 in mice fed with CDAHFD diet only. Noninvasive imaging with [18F]FtRGD correlated well with integrin αvβ3 and was able to distinguish early mild stage 2 fibrosis in CDAHFD animals compared with standard chow diet-fed animals at day 35. When compared with high fat diet-fed animals, [18F]FtRGD was only able to distinguish later moderate stage 2 fibrosis in CDAHFD animals at day 49. Conclusions. The diet-induced progression of liver fibrosis was confirmed using histology and correlated well with the mRNA of integrin αvβ3 and extracellular matrix protein expression. [18F]FtRGD showed very good correlation between liver uptake and integrin αvβ3 expression and similar detection sensitivity to the current clinical gold standard modalities for staging of liver fibrosis.

scholarly journals Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet

2019 ◽  
Vol 7 (1) ◽  
pp. e000783 ◽  
Author(s):  
Liang Xu ◽  
Naoto Nagata ◽  
Guanliang Chen ◽  
Mayumi Nagashimada ◽  
Fen Zhuge ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Weight Gain ◽  
Energy Expenditure ◽  
Chronic Inflammation ◽  
Plasma Levels ◽  
High Fat Diet ◽  
Macrophage Activation ◽  
Low Grade ◽  
Obese Mice ◽  
High Fat

ObjectiveWe reported previously that empagliflozin—a sodium-glucose cotransporter (SGLT) 2 inhibitor—exhibited preventive effects against obesity. However, it was difficult to extrapolate these results to human subjects. Here, we performed a therapeutic study, which is more relevant to clinical situations in humans, to investigate antiobesity effects of empagliflozin and illustrate the mechanism underlying empagliflozin-mediated enhanced fat browning in obese mice.Research design and methodsAfter 8 weeks on a high-fat diet (HFD), C57BL/6J mice exhibited obesity, accompanied by insulin resistance and low-grade chronic inflammation. Cohorts of obese mice were continued on the HFD for an additional 8-week treatment period with or without empagliflozin.ResultsTreatment with empagliflozin for 8 weeks markedly increased glucose excretion in urine, and suppressed HFD-induced weight gain, insulin resistance and hepatic steatosis. Notably, empagliflozin enhanced oxygen consumption and carbon dioxide production, leading to increased energy expenditure. Consistently, the level of uncoupling protein 1 expression was increased in both brown and white (WAT) adipose tissues of empagliflozin-treated mice. Furthermore, empagliflozin decreased plasma levels of interleukin (IL)-6 and monocyte chemoattractant protein-1, but increased plasma levels of IL-33 and adiponectin in obese mice. Finally, we found that empagliflozin reduced M1-polarized macrophage accumulation, while inducing the anti-inflammatory M2 phenotype of macrophages in the WAT and liver, thereby attenuating obesity-related chronic inflammation.ConclusionsTreatment with empagliflozin attenuated weight gain by increasing energy expenditure and adipose tissue browning, and alleviated obesity-associated inflammation and insulin resistance by alternative macrophage activation in the WAT and liver of obese mice.

Influence of the integrin alpha-1 subunit and its relationship with high-fat diet upon extracellular matrix synthesis in skeletal muscle and tendon

2020 ◽  
Vol 381 (1) ◽  
pp. 177-187
Author(s):  
Monika L. Bayer ◽  
Rene B. Svensson ◽  
Peter Schjerling ◽  
Ashley S. Williams ◽  
David H. Wasserman ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
High Fat Diet ◽  
High Fat ◽  
Matrix Synthesis

scholarly journals Hepatic Metabolomic Analysis in Mice Fed a High Fat Diet with Watermelon and Watermelon Byproducts Shows Improved Lipid Metabolism and Reduction of Chronic Inflammation (P06-023-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Alexandra Becraft ◽  
Marlena Sturm ◽  
Gavin Pierce ◽  
Rufa Mendez ◽  
Neil Shay
Keyword(s):  
Chronic Inflammation ◽  
High Fat Diet ◽  
Liver Tissue ◽  
Value Added ◽  
Principal Component ◽  
Metabolomic Analysis ◽  
High Fat ◽  
Tissue Samples ◽  
Metabolic Conditions ◽  
Ultrahigh Performance Liquid Chromatography

Abstract Objectives Watermelon is a nutrient-dense fruit shown previously to produce health benefits, particularly regarding blood pressure regulation. We tested the hypothesis that intake of whole watermelon flesh and value-added watermelon components would improve metabolic conditions in C57BL/6 J male mice fed a high-fat, high-sucrose diet modeling an obesogenic Western diet (HF). We further hypothesize that metabolomic profiling will show changes in relative levels of compounds related to lipid and glucose metabolism, and chronic inflammation. Methods In a prior study (Becraft et al., 2018), groups of mice (n = 8) were provided either low-fat diet (LF, 10% kcal fat), high-fat diet (HF, 45% kcal fat), HF plus Watermelon Skin (HF + WS), HF plus Watermelon Rind (HF + WR), or HF plus Watermelon Flesh (HF + WF) for 10 weeks. Watermelon flesh was provided at 10% of total energy and skin and rind were added at ∼ 0.2% (w/w) of diet. After ten weeks, animals were euthanized, and liver tissue saved for metabolomic analysis. Liver tissue samples were homogenized, and an identical mass equivalent of liver was subjected to methanol extraction and split into aliquots for analysis by ultrahigh performance liquid chromatography/mass spectrometry in the positive, negative or polar ion mode. There were 709 biochemicals identified and analyzed between groups. Welch's 2-sample t-test was performed with ArrayStudio (Omicsoft) or R software on log transformed data to compare data between experimental groups. Estimate of the false discovery rate (Q value) was calculated and Q ;< 0.05 used as an indication of high confidence in a result. Results Principal component analysis showed segregation of groups along three different components, representing 24.8%, 19.4%, and 9.0% of the variation. Profound differences were found in LF vs. HF liver tissue. Compared to HF-fed mice, mice fed WF showed reduced levels of bile acids and pro-inflammatory compounds 12-HETE, 15, HETE, and PGF2 (all P < 0.05) in the liver. Conclusions In mice consuming a high-fat western style diet, regular intake of watermelon flesh, and fiber-rich products made from rind and skin all improved metabolism as evidenced by metabolomic analysis of liver tissue. Most notably were reductions in pro-inflammatory compounds including HETEs and Prostaglandin F2. Funding Sources National Watermelon Promotion Board.

scholarly journals Chronic inflammation aggravates metabolic disorders of hepatic fatty acids in high-fat diet-induced obese mice

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Lei Zhao ◽  
Shan Zhong ◽  
Haiyang Qu ◽  
Yunxia Xie ◽  
Zhennan Cao ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Chronic Inflammation ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Obese Mice ◽  
High Fat

Tu2040 High Fat Diet Promotes Chronic Inflammation in DSS Murine Model of IBD

2012 ◽  
Vol 142 (5) ◽  
pp. S-908-S-909
Author(s):  
Violeta Arsenescu ◽  
Francesc Marti ◽  
Razvan Arsenescu
Keyword(s):  
Chronic Inflammation ◽  
Murine Model ◽  
High Fat Diet ◽  
High Fat
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