scholarly journals Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice

2018 ◽  
Vol 115 (1) ◽  
pp. 243-254 ◽  
Author(s):  
Anna-Kaisa Ruotsalainen ◽  
Jari P Lappalainen ◽  
Emmi Heiskanen ◽  
Mari Merentie ◽  
Virve Sihvola ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sudden Death ◽  
Plasma Cholesterol ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Chow Diet ◽  
Related Factor ◽  
Plaque Instability ◽  
Plaque Inflammation ◽  
Deficient Mice

Abstract Aims Oxidative stress and inflammation play an important role in the progression of atherosclerosis. Transcription factor NF-E2-related factor 2 (Nrf2) has antioxidant and anti-inflammatory effects in the vessel wall, but paradoxically, global loss of Nrf2 in apoE deficient mice alleviates atherosclerosis. In this study, we investigated the effect of global Nrf2 deficiency on early and advanced atherogenesis in alternative models of atherosclerosis, LDL receptor deficient mice (LDLR−/−), and LDLR−/− mice expressing apoB-100 only (LDLR−/− ApoB100/100) having a humanized lipoprotein profile. Methods and results LDLR−/− mice were fed a high-fat diet (HFD) for 6 or 12 weeks and LDLR−/−ApoB100/100 mice a regular chow diet for 6 or 12 months. Nrf2 deficiency significantly reduced early and more advanced atherosclerosis assessed by lesion size and coverage in the aorta in both models. Nrf2 deficiency in LDLR−/− mice reduced total plasma cholesterol after 6 weeks of HFD and triglycerides in LDLR−/−ApoB100/100 mice on a chow diet. Nrf2 deficiency aggravated aortic plaque maturation in aged LDLR−/−ApoB100/100 mice as it increased plaque calcification. Moreover, ∼36% of Nrf2−/−LDLR−/−ApoB100/100 females developed spontaneous myocardial infarction (MI) or sudden death at 5 to 12 months of age. Interestingly, Nrf2 deficiency increased plaque instability index, enhanced plaque inflammation and calcification, and reduced fibrous cap thickness in brachiocephalic arteries of LDLR−/−ApoB100/100 female mice at age of 12 months. Conclusions Absence of Nrf2 reduced atherosclerotic lesion size in both atherosclerosis models, likely via systemic effects on lipid metabolism. However, Nrf2 deficiency in aged LDLR−/−ApoB100/100 mice led to an enhanced atherosclerotic plaque instability likely via increased plaque inflammation and oxidative stress, which possibly predisposed to MI and sudden death.

Maternal high-fat feeding in pregnancy programs atherosclerotic lesion size in the ApoE*3 Leiden mouse

2016 ◽  
Vol 7 (3) ◽  
pp. 290-297 ◽  
Author(s):  
E. J. Tarling ◽  
K. J. P. Ryan ◽  
R. Austin ◽  
S. J. Kugler ◽  
A. M. Salter ◽  
...  
Keyword(s):  
Plasma Cholesterol ◽  
Maternal Diet ◽  
Atherosclerotic Lesion ◽  
Plasma Lipid ◽  
Lesion Size ◽  
Atherogenic Diet ◽  
Chow Diet ◽  
Wild Type ◽  
High Fat ◽  
Cell Proliferation And Differentiation

Periods of rapid growth seen during the early stages of fetal development, including cell proliferation and differentiation, are greatly influenced by the maternal environment. We demonstrate here that over-nutrition, specifically exposure to a high-fat dietin utero, programed the extent of atherosclerosis in the offspring of ApoE*3 Leiden transgenic mice. Pregnant ApoE*3 Leiden mice were fed either a control chow diet (2.8% fat,n=12) or a high-fat, moderate-cholesterol diet (MHF, 19.4% fat,n=12). Dams were fed the chow diet during the suckling period. At 28 days postnatal age wild type and ApoE*3 Leiden offspring from chow or MHF-fed mothers were fed either a control chow diet (n=37) or a diet rich in cocoa butter (15%) and cholesterol (0.25%), for 14 weeks to induce atherosclerosis (n=36). Offspring from MHF-fed mothers had 1.9-fold larger atherosclerotic lesions (P<0.001). There was no direct effect of prenatal diet on plasma triglycerides or cholesterol; however, transgenic ApoE*3 Leiden offspring displayed raised cholesterol when on an atherogenic diet compared with wild-type controls (P=0.031). Lesion size was correlated with plasma lipid parameters after adjustment for genotype, maternal diet and postnatal diet (R2=0.563,P<0.001). ApoE*3 Leiden mothers fed a MHF diet developed hypercholesterolemia (plasma cholesterol two-fold higher than in chow-fed mothers,P=0.011). The data strongly suggest that maternal hypercholesterolemia programs later susceptibility to atherosclerosis. This is consistent with previous observations in humans and animal models.

Long term dietary vitamin E reduces atherosclerotic lesion size and increases plaque stability in heterozygous LDL-receptor deficient mice

2001 ◽  
Vol 2 (2) ◽  
pp. 109
Author(s):  
O.L. Volger ◽  
J. van der Boom ◽  
W. van Duyvenvoorde ◽  
E.H. Offerman ◽  
R. Leenen ◽  
...  
Keyword(s):  
Vitamin E ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Dietary Vitamin ◽  
Plaque Stability ◽  
Deficient Mice

scholarly journals Vitamin A-Deficient Diet Accelerated Atherogenesis in Apolipoprotein E−/−Mice and Dietaryβ-Carotene Prevents This Consequence

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Noa Zolberg Relevy ◽  
Dror Harats ◽  
Ayelet Harari ◽  
Ami Ben-Amotz ◽  
Rafael Bitzur ◽  
...  
Keyword(s):  
Vitamin A ◽  
Apolipoprotein E ◽  
Vitamin A Deficiency ◽  
Plasma Cholesterol ◽  
Atherosclerotic Lesion ◽  
Dietary Vitamin ◽  
Control Group ◽  
Chow Diet ◽  
Deficient Diet ◽  
Aortic Sinus

Vitamin A is involved in regulation of glucose concentrations, lipid metabolism, and inflammation, which are major risk factors for atherogenesis. However, the effect of vitamin A deficiency on atherogenesis has not been investigated. Therefore, the objective of the current study was to examine whether vitamin A deficiency accelerates atherogenesis in apolipoprotein E-deficient mice (apoE−/−). ApoE−/−mice were allocated into the following groups: control, fed vitamin A-containing chow diet; BC, fed chow diet fortified withDunaliellapowder containingβc isomers; VAD, fed vitamin A-deficient diet; and VAD-BC group, fed vitamin A-deficient diet fortified with aDunaliellapowder. Following 15 weeks of treatment, liver retinol concentration had decreased significantly in the VAD group to about 30% that of control group. Vitamin A-deficient diet significantly increased both plasma cholesterol concentrations and the atherosclerotic lesion area at the aortic sinus (+61%) compared to the control group. Dietaryβc fortification inhibited the elevation in plasma cholesterol and retarded atherogenesis in mice fed the vitamin A-deficient diet. The results imply that dietary vitamin A deficiency should be examined as a risk factor for atherosclerosis and that dietaryβc, as a sole source of retinoids, can compensate for vitamin A deficiency.

Deficiency in TDAG51 Decreases Atherosclerotic Lesion Development in ApoE-Deficient Mice.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3940-3940
Author(s):  
Gazi S. Hossain ◽  
Ji Zhou ◽  
Kenneth Maclean ◽  
Sarka Lhotak ◽  
Sudesh K. Sood ◽  
...  
Keyword(s):  
Cell Death ◽  
Hepatic Steatosis ◽  
Plasma Cholesterol ◽  
Control Diet ◽  
Atherosclerotic Lesion ◽  
Double Knockout ◽  
Lesion Development ◽  
Ppar Γ ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Development

Abstract T-cell death associated gene 51 (TDAG51) is a pro-apoptotic gene that can be induced by endoplasmic reticulum (ER) stress agents, including homocysteine, tunicamycin, thapsigargin or dithiothreitol. Our previous studies have demonstrated that transient overexpression of TDAG51 elicited significant changes in cell morphology, decreased cell adhesion and promoted detachment-induced programmed cell death (PCD). In support of these in vitro findings, we have further shown that TDAG51 expression was increased and correlated with PCD in the atherosclerotic lesions from apolipoprotein E (apoE)-deficient mice fed hyperhomocysteinemic diets, compared to mice fed control diet. We designed the current study to investigate the effect of TDAG51 deficiency in the development and progression of atherosclerosis. To assess in vivo significance of TDAG51 on atherosclerosis, we have crossed TDAG51-deficient mice with apoE-deficient mice to obtain double knockout mice. Our findings have demonstrated that TDAG51/apoE-deficient mice have a significant decrease in atherosclerotic lesion area, compared to age- and sex-matched apoE-deficient mice. Total plasma cholesterol and triglycerides as well as lipoprotein profiles were similar in both groups. However, TDAG51/apoE-deficient mice presented with increased hepatic steatosis. Further, a significant upregulation of peroxisome proliferator-activated receptor γ (PPAR-γ), a transcription factor required for adipose tissue formation, was demonstrated in TDAG51-deficient mouse embryonic fibroblasts (MEFs), compared to control wildtype MEFs. Interestingly, earlier studies in mice have reported that overexpression of PPAR-γ decreases atherosclerotic lesion development and increases hepatic steatosis - a phenotype similar to that observed in the mouse deficient in both apoE and TDAG51. Collectively, these findings provide evidence that TDAG51 mediates atherosclerotic lesion development and hepatic steatosis through a mechanism involving PPAR-γ.

Disodium ascorbyl phytostanyl phosphate reduces plasma cholesterol concentrations and atherosclerotic lesion formation in apolipoprotein E-deficient mice

Metabolism ◽  
2003 ◽  
Vol 52 (4) ◽  
pp. 425-431 ◽  
Author(s):  
Tatjana Lukic ◽  
Kishor M. Wasan ◽  
Daniela Zamfir ◽  
Mohammed H. Moghadasian ◽  
P.Haydn Pritchard
Keyword(s):  
Apolipoprotein E ◽  
Plasma Cholesterol ◽  
Atherosclerotic Lesion ◽  
Lesion Formation ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Formation

Abstract 435: Vascular Gene Therapy with Apolipoprotein A-I in a Rabbit Model of Atherosclerosis Regression

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Bradley K Wacker ◽  
Jingwan Zhang ◽  
Nagadhara Dronadula ◽  
David A Dichek
Keyword(s):  
Gene Therapy ◽  
Lipid Content ◽  
Subgroup Analysis ◽  
Plasma Cholesterol ◽  
Rabbit Model ◽  
Atherosclerotic Lesion ◽  
Chow Diet ◽  
Lesion Volume ◽  
Atherosclerotic Lesions ◽  
Bilateral Carotid

Background: Gene therapy, delivered directly to the vascular wall, could potentially protect against atherosclerotic lesion growth or regress existing lesions. Previously, we demonstrated that use of a helper-dependent adenoviral vector (HDAd) to express apolipoprotein (apo) A-I in carotid endothelium of fat-fed rabbits reduced carotid atherosclerosis measured 4 wk after vector infusion. Here we tested whether the same HDAd could promote atherosclerosis regression when delivered to existing lesions. Methods: To generate atherosclerotic lesions, rabbits were fed a high-fat diet for 4 wk, then underwent bilateral carotid artery surgery with brief intraluminal infusion of DMEM. This protocol yields large lipid- and macrophage-rich lesions within 6 mo. Postoperatively, diets were adjusted to maintain plasma cholesterol of 200 - 800 mg/dl. 6 mo later, rabbits underwent bilateral carotid gene transfer (HDAdApoAI on one side; HDAdNull on the other, with sides randomized) and were changed to chow diet. Carotids were harvested after 3 d (for RNA analysis) and after 7 wk (for analyses of RNA, DNA, and histology). Histologic sections were stained with H&E, oil red O, or antibodies that detect macrophages, smooth muscle actin, ICAM1, and VCAM1. Results: ApoA-I mRNA was detected only in arteries transduced with HDAdApoAI and was present in all HDAdApoAI-infused arteries both at 3 d and 7 wk after infusion. When compared to HDAdNull-infused arteries (n = 26), HDAdApoAI-infused arteries (n = 26) had 30 - 40% less median intimal lesion volume, lipid content, and macrophage content but these differences were not statistically significant (P = 0.3 - 0.9). Post-hoc subgroup analysis of small-to-moderate-sized lesions (n = 20 per group; excluding lesions with volume >1 SD above the mean of all lesions) showed that HDAdApoAI-infused lesions had 50 - 70% less median intimal volume (P = 0.04), lipid content (P = 0.02), and macrophage content (P = 0.03). Conclusions: 7 wk of vascular gene therapy with HDAdApoAI did not consistently cause lesion regression. However, subgroup analysis showed that HDAdApoAI significantly accelerated regression of small-to-moderate-sized atherosclerotic lesions. Prospective testing is required to evaluate the reproducibility of this finding.

scholarly journals A Phenotype-Sensitizing Apoe-Deficient Genetic Background Reveals Novel Atherosclerosis Predisposition Loci in the Mouse

Genetics ◽  
2002 ◽  
Vol 160 (4) ◽  
pp. 1599-1608
Author(s):  
Hayes M Dansky ◽  
Pei Shu ◽  
M Donavan ◽  
Jill Montagno ◽  
Deborah L Nagle ◽  
...  
Keyword(s):  
Atherosclerotic Lesion ◽  
Inbred Strains ◽  
Lesion Size ◽  
Susceptibility Loci ◽  
Cholesterol Levels ◽  
Significant Locus ◽  
Trait Locus ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Formation ◽  
Do So

Abstract Therapeutic intervention for atherosclerosis has predominantly concentrated on regulating cholesterol levels; however, these therapeutics are not efficacious for all patients, suggesting that other factors are involved. This study was initiated to identify mechanisms that regulate atherosclerosis predisposition in mice other than cholesterol level regulation. To do so we performed quantitative trait locus analysis using two inbred strains that each carry the atherosclerosis phenotype-sensitizing Apoe deficiency and that have been shown to have widely disparate predilection to atherosclerotic lesion formation. One highly significant locus on chromosome 10 (LOD = 7.8) accounted for 19% of the variance in lesion area independent of cholesterol. Two additional suggestive loci were identified on chromosomes 14 (LOD = 3.2) and 19 (LOD = 3.2), each accounting for 7–8% of the lesion variance. In all, five statistically significant and suggestive loci affecting lesion size but not lipoprotein levels were identified. Many of these were recapitulated in an independent confirmatory cross. In summary, two independently performed crosses between C57BL/6 and FVB/N Apoe-deficient mice have revealed several previously unreported atherosclerosis susceptibility loci that are distinct from loci linked to lipoprotein levels.

Abstract 240: T Cell Specific CD40L Promotes to Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Christina Bürger ◽  
Holger Winkels ◽  
Charlotte Spitz ◽  
Svenja Meiler ◽  
Sigrid Reim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Inflammatory Diseases ◽  
Atherosclerotic Lesion ◽  
Analysis Data ◽  
Lesion Size ◽  
Ascending Aorta ◽  
Chow Diet ◽  
Draining Lymph Nodes

Background: Adaptive immunity and co-stimulatory signals are pivotal to all stages of atherosclerosis. CD40-CD40L (CD154) co-stimulatory molecules are central mediators of disease progression. However, it remains undetermined whether platelet- or T cell-specific CD40L contributes to its pro-atherogenic function. Method: We generated mice carrying a mutated allele of the CD40L gene flanked by loxp-sites sensitive to cre-mediated inactivation. We crossed these to Apoe -/- -deficient mice which also expressed Cre specifically in T cells ( Cd4Cre tg ) or platelets (Pf4Cre tg ) to generate Apoe -/- Cd40lg fl/fl -Cd4Cre tg , -Cd4Cre wt , -Pf4Cre tg , or -Pf4Cre wt mice. After consuming chow diet for 28 weeks the immune status and atherosclerosis was assessed by flow cytometry, RNA expression analysis and histology of the ascending aorta, blood, draining lymph nodes, and spleen. Results: Specific deletion of CD40L on T cells leads to decreased atherosclerotic lesion size in the ascending aorta while plaque size in Apoe -/- Cd40lg fl/fl -Pf4Cre tg or -Pf4Cre wt mice did not differ. Furthermore, platelet-specific ablation of CD40L did not results in changes of immune cells distribution. In contrast, cytokine and RNA analysis data pointed to a less inflammatory phenotype in Apoe -/- Cd40lg fl/fl Cd4Cre tg mice compared to Apoe -/- Cd40lg fl/fl Cd4Cre wt controls. Interestingly, T cell-specific inactivation of CD40L also caused a systemic decrease of Tregs in draining lymph nodes, spleen, blood, and thymus. Conclusion: Taken together our data confirm that CD40L expressed on T cells but not on platelets contributes to the disease-aggravating role of the CD40/CD40L dyad in atherosclerosis. Thus, T cell-expressed CD40L may provide a promising candidate for further investigation in atherosclerosis and other inflammatory diseases.

Abstract 068: Endothelin-1 Exaggerates Type-1 Diabetes-accelerated Atherosclerosis Through NADPH Oxidases 1 and 4

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sofiane Ouerd ◽  
Noureddine Idris-Khodja ◽  
Michelle Trindade ◽  
Suellen C Coelho ◽  
Mario F Neves ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Plasma Cholesterol ◽  
Vascular Complications ◽  
Atherosclerotic Lesion ◽  
Fold Increase ◽  
Mesenteric Arteries ◽  
Aortic Sinus ◽  
Accelerated Atherosclerosis ◽  
Plaque Area ◽  
Atherosclerotic Lesions

Objective: NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout ( Apoe -/- ) mice exaggerated high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We hypothesized that ET-1 overexpression in the endothelium would exaggerate diabetes-accelerated atherosclerosis through a mechanism involving NOX1 but not NOX4. Methods: Six-week-old male Apoe -/- mice, eET-1/ Apoe -/- and eET-1/ Apoe -/- mice deficient in Nox1 (eET-1/ Apoe -/- / Nox1 y/- ) or Nox4 (eET-1/ Apoe -/- / Nox4 -/- ) were rendered diabetic with 55 mg/kg/day streptozotocin (STZ) IP injections for 5 days and studied 14 weeks later. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) using pressurized myography. Aortic atherosclerotic lesions were quantified using Oil Red O staining. Plasma cholesterol, HDL and triglycerides were measured. Results: Diabetic Apoe -/- mice presented an impaired endothelium-dependent vasodilatory response to acetylcholine, which was not observed in diabetic eET-1/ Apoe -/- , eET-1/ Apoe -/- / Nox1 y/- or eET-1/ Apoe -/- / Nox4 -/- mice (E max : 20±6 vs 99±1, 98±1 and 100±0%). ET-1 overexpression caused a 1.8-fold increase in MA media/lumen of diabetic Apoe -/- mice (5.3±0.3 vs 2.9±0.2%), which was further increased 1.2-fold by Nox4 (6.4±0.3%) but not Nox1 knockout (5.5±0.3%). ET-1 overexpression exaggerated >2-fold the atherosclerotic lesion area in the aortic sinus in diabetic Apoe -/- mice (plaque area [x10 5 μm 2 ]: 5.3±0.5 vs 2.9±0.6), which was reduced ~40% by Nox1 and Nox4 knockout (plaque area [x10 5 μm 2 ]: 3.3±0.6 and 3.6±0.6). Plasma triglycerides were unaffected by ET-1 overexpression but reduced by Nox1 (2.2±0.4 vs 3.4±0.3 mmol/L) and Nox4 knockout (1.8±0.4 mmol/L). Plasma HDL and cholesterol were similar between groups. Conclusions: Increased levels of ET-1 exaggerate diabetes-accelerated atherosclerosis through NOX1 and NOX4, despite paradoxically improving endothelium-dependent relaxation in small arteries.

Sign in / Sign up

Export Citation Format

Share Document