Abstract 15768: Mitochondria-Targeted DNA Repair Glycosylase Ogg1 Suppresses Early Stage of Atherogenesis in Ogg1 Deficient Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Mykhaylo V Ruchko ◽  
Sergiy Sukhanov ◽  
Olena M Gorodnya ◽  
Lyudmila I Rachek ◽  
Svitlana D Danchuk ◽  
...  
Keyword(s):  
Aortic Valve ◽  
High Fat Diet ◽  
Excision Repair ◽  
Early Stage ◽  
Inflammatory Cells ◽  
Apoptotic Cells ◽  
High Fat ◽  
Knock Out ◽  
Mtdna Damage ◽  
Mtdna Repair

Introduction: Reactive oxygen species (ROS) play a key role in the development of atherosclerosis. Mitochondria are a main source of endogenous ROS in the cell. Mitochondrial DNA (mtDNA) is sensitive to oxidation and our previous results from cultured cell and intact animal models suggest that increasing mtDNA repair prevents both oxidative mtDNA damage and associated cytotoxicity and cellular dysfunction. Involvement of oxidative mtDNA damage in disorders characterized by chronic oxidative stress has been less thoroughly studied. Hypothesis: In the present study we tested the hypothesis that transgenic modulation of Ogg1, a DNA glycosylase mediating the first step in the base excision repair of oxidative mtDNA damage, coordinately regulates atherogenesis in mice fed a high fat diet. Methods: Wild type (WT) mice, Ogg1 knock-out (KO) mice and KO mice transgenically overexpressing mitochondria-targeted Ogg1 (KO-Tg) were fed pro-atherogenic Western type diet for 14 weeks and analyzed for mtDNA damage and signs of atherogenesis. Results: KO mice fed a high fat diet had increased oxidative mtDNA damage in cardiac tissue, whereas KO-Tg animals did not differ from WT mice (WT: 0.18 ± 0.04; KO: 0.35 ± 0.04; KO-Tg: 0.15 ± 0.01 lesions per 10 4 bp; n=3, P<0.05; quantitative Southern blot analysis). We did not observe significant atherosclerotic plaque formation in the aortic valve of animals from any group; however appearance of fatty streaks, indicative of early plaque development, was more evident in KO mice (WT: 179 ± 20; KO: 384 ± 59 pixels, n=4, P<0.05; immunohistochemistry for Fc receptor - general marker of inflammatory cells). This effect was completely blocked in KO-Tg mice. We found increased number of apoptotic cells in the aortic valve of KO, but not KO-Tg mice (WT: 2.00 ± 0.50; KO: 4.25 ± 0.48; KO-Tg: 2.14 ± 0.85 apoptotic cells, n=4, P<0.05; TUNEL assay). Conclusion: Our data demonstrate that Ogg1 deficiency in mice fed a high fat diet leads to increased oxidative mtDNA damage, appearance of fatty streaks and cell apoptosis. In contrast, enhancement of mtDNA repair with mitochondria-targeted Ogg1 reduces fatty streaks formation and apoptosis induced by a high fat diet. These results suggest mtDNA damage and repair could be important targets for atheroprotection.

The flavan-3-ol fraction of cocoa powder suppressed changes associated with early-stage metabolic syndrome in high-fat diet-fed rats

Life Sciences ◽  
2014 ◽  
Vol 114 (1) ◽  
pp. 51-56 ◽  
Author(s):  
Naomi Osakabe ◽  
Junpei Hoshi ◽  
Naoto Kudo ◽  
Masahiro Shibata
Keyword(s):  
Metabolic Syndrome ◽  
High Fat Diet ◽  
Early Stage ◽  
High Fat ◽  
Cocoa Powder

scholarly journals Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

2017 ◽  
Vol 114 (7) ◽  
pp. 1631-1636 ◽  
Author(s):  
Qingchun Zeng ◽  
Rui Song ◽  
David A. Fullerton ◽  
Lihua Ao ◽  
Yufeng Zhai ◽  
...  
Keyword(s):  
Aortic Valve ◽  
High Fat Diet ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
High Fat ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Valve Lesions ◽  
Osteogenic Factors

Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.

scholarly journals High Fat Diet Induces Adhesion of Platelets to Endothelium in Two Models of Dyslipidemia

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Jaime Gonzalez ◽  
Wendy Donoso ◽  
Natalia Díaz ◽  
María Eliana Albornoz ◽  
Ricardo Huilcaman ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Early Stage ◽  
Endothelial Activation ◽  
Mice Model ◽  
High Fat ◽  
Early Stages ◽  
Endothelial Surface ◽  
Two Stages ◽  
Adhesion Of Platelets

Cardiovascular diseases (CVD) represent about 30% of all global deaths. It is currently accepted that, in the atherogenic process, platelets play an important role, contributing to endothelial activation and modulation of the inflammatory phenomenon, promoting the beginning and formation of lesions and their subsequent thrombotic complications. The objective of the present work was to study using immunohistochemistry, the presence of platelets, monocytes/macrophages, and cell adhesion molecules (CD61, CD163, and CD54), in two stages of the atheromatous process. CF-1 mice fed a fat diet were used to obtain early stages of atheromatous process, denominated early stage of atherosclerosis, and ApoE−/−mice fed a fat diet were used to observe advanced stages of atherosclerosis. The CF-1 mice model presented immunostaining on endothelial surface for all three markers studied; the advanced atherosclerosis model in ApoE−/−mice also presented granular immunostaining on lesion thickness, for the same markers. These results suggest that platelets participate in atheromatous process from early stages to advance d stages. High fat diet induces adhesion of platelets to endothelial cellsin vivo. These findings support studying the participation of platelets in the formation of atheromatous plate.

scholarly journals Influence of gender on OVA-induced airway inflammation in C57/B6J mice on a high-fat diet

2018 ◽  
Vol 16 ◽  
pp. 205873921876094 ◽  
Author(s):  
Gang Yu ◽  
Lili Zhu ◽  
Haiyan Li ◽  
Youyou Shao ◽  
Lei Chong ◽  
...  
Keyword(s):  
Body Weight ◽  
High Fat Diet ◽  
Inflammatory Cells ◽  
Normal Weight ◽  
Male Mice ◽  
High Fat ◽  
Low Fat ◽  
Control Male ◽  
Low Fat Diet ◽  
Asthma Group

Overweight/obesity has been suggested as a risk factor for asthma development, and prospective studies have confirmed that high body weight precedes asthma symptoms. However, the nature of the association between overweight/obese status and asthma remains unclear. Animal models of obesity-related asthma are very useful for understanding disease pathophysiology. Although C57/B6J mice are the most widely used animal model for researching obesity-related asthma, gender differences are not always taken into consideration. Therefore, to explore the effect of gender on the development of obesity-related asthma, both female and male C57/B6J mice were used in this study. The mice were fed with a high-fat diet or a low-fat diet as control. Body weight, body length, liver weight, and Lee’s Index were used to evaluate obesity status, and lung histology, lung inflammatory cells infiltration, and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were examined for asthma evaluation. We found that the mean body weight of male mice on a high-fat diet gradually increased and was significantly higher than control male mice on a low-fat diet ( P < 0.01), while no significant differences were found between female mice at the end of 12 weeks of feeding. Furthermore, the obese asthma group female and male mice exhibited significantly high inflammatory cells infiltration than normal weight or obese female and male mice ( P < 0.01). However, the obese asthma group presented higher Neu infiltration, Th1 cytokine, and interferon gamma (IFNγ) concentrations in BALF than the asthma group in both the genders ( P < 0.01). In conclusion, both female and male mice are suitable for the obesity-related asthma model, although male mice might be more stable. Besides, obesity-related asthma is not Th2 type asthma.

scholarly journals Tpcn2 Knock‐Out Mice Have Improved Insulin Sensitivity and Are Protected Against High‐Fat Diet Induced Weight Gain.

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Leah Solberg Woods ◽  
Katie Holl ◽  
Hong He ◽  
Sarah DeBehnke ◽  
Chay Teng Yeo ◽  
...  
Keyword(s):  
Weight Gain ◽  
Insulin Sensitivity ◽  
High Fat Diet ◽  
High Fat ◽  
Knock Out ◽  
Knock Out Mice

scholarly journals Insulin resistance and adipose tissue inflammation induced by a high-fat diet are attenuated in the absence of hepcidin

2021 ◽  
Author(s):  
Jithu Varghese James ◽  
Joe Varghese ◽  
Nikhitha Mariya John ◽  
Jean Christophe Deschemin ◽  
Sophie Vaulont ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Iron Homeostasis ◽  
Wild Type ◽  
High Fat ◽  
Knock Out ◽  
Body Iron ◽  
Iron Stores ◽  
Underlying Basis

Increased body iron stores and inflammation in adipose tissue have been implicated in the pathogenesis of insulin resistance (IR) and type 2 diabetes mellitus. However, the underlying basis of these associations are unclear. In order to assess this, we studied how IR and associated inflammation in adipose tissue developed in the presence of increased body iron stores. Male hepcidin knock-out (Hamp1-/-) mice, which have increased body iron stores, and wild-type (WT) mice were fed a high-fat diet (HFD) for 12 and 24 weeks. Development of IR and metabolic parameters linked to this, insulin signaling in tissue, and inflammation and iron-related parameters in visceral adipose tissue were studied in these animals. HFD-feeding resulted in impaired glucose tolerance in both genotypes of mice. In response to the HFD for 24 weeks, Hamp1-/- mice gained less body weight and developed less IR than corresponding WT mice. This was associated with less lipid accumulation in the liver and decreased inflammation and lipolysis in the adipose tissue in the knock-out mice, than in the WT animals. Fewer macrophages infiltrated the adipose tissue in the knockout mice than in wild-type mice, with these macrophages exhibiting a predominantly anti-inflammatory (M2-like) phenotype. These observations suggest a novel role of hepcidin (central regulator of systemic iron homeostasis) in the development of inflammation in adipose tissue and insulin resistance, in response to a high-fat diet.

Abstract 14729: Weight Loss Reduces Atrial Fibrillation Inducibility and Burden in Severe Obesity Induced by Either High-Fat Diet or Genetic Hyperphagia in Mice

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Eleonora Savio-Galimberti ◽  
Prince Kannankeril ◽  
David Wasserman ◽  
Dawood Darbar
Keyword(s):  
Atrial Fibrillation ◽  
Morbid Obesity ◽  
Weight Loss ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Loss Of Function ◽  
High Fat ◽  
Knock Out ◽  
Mc4r Gene ◽  
Melanocortin 4 Receptor

Introduction: Atrial fibrillation (AF), the most common sustained arrhythmia worldwide, is associated with increased morbidity and mortality. Obesity is increasingly recognized as an important risk factor to develop AF and heart disease with a diet rich in fats leading to morbid obesity. Melanocortin-4 receptor (MC4R) gene is a critical regulator of energy homeostasis, and homozygous loss-of-function mutations cause hyperphagia and morbid obesity. Hypothesis: We hypothesized that obesity and its comorbidities can create a profibrillatory substrate for AF in high fat diet-induced obese (DIO) and MC4R knock-out (MC4R-KO) mice, and that this substrate can be reversed by weight loss. Methods: Transesophageal rapid pacing was performed using atrial burst pacing (cycle length: 50-15 ms, for 15 s) to determine AF inducibility (% of mice that develop AF) and AF burden (number of AF episodes and total AF duration/mouse) in lightly anesthesized normotensive mice (C57bl6 mice [LEAN], DIO, and MC4R-KO), with continuous ECG monitoring. Transthoracic echocardiography was performed to assess right (R) and left (L) atrial appendage (AA) sizes. Results: Atrial burst pacing induced AF in 91% of DIO and 100% of MC4R-KO vs. 50% of LEAN (P<0.01, N=8 mice/group). Compared to LEAN, both DIO and MC4R-KO exhibited greater number of inducible AF episodes (0.7±0.2 vs. 1.8±0.2 vs. 1.8±0.1, P<0.01, N=15 mice/group) with longer duration (17.9±3 vs. 196±22 vs. 244±34 s, P<0.0001, N=15 mice/group; Figure). Both DIO and MC4R-KO had greater LAA volumes as compared with LEAN (5.2±0.2 vs. 6.7±0.4 vs. 4.1±0.1 μl, P<0.01, N=8 mice/group). RAA volume was similar across groups. After 20% weight loss, both AF burden and LAA volumes were significantly reduced to those seen in LEAN (22±5 s, 4.5±0.1 μl, P<0.001, N=8 mice/group). Conclusions: High-fat diet or genetic hyperphagia-induced obesity increases LAA volume and creates a profibrillatory substrate for AF that can be reversed with weight loss.

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