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.

scholarly journals The interaction of estrogen and CSE/H2S pathway in the development of atherosclerosis

2017 ◽  
Vol 312 (3) ◽  
pp. H406-H414 ◽  
Author(s):  
Hongzhu Li ◽  
Sarathi Mani ◽  
Lingyun Wu ◽  
Ming Fu ◽  
Tian Shuang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Control Diet ◽  
Atherosclerotic Lesion ◽  
Plasma Lipid ◽  
Atherogenic Diet ◽  
Estrogen Signaling ◽  
Wild Type ◽  
Vascular Tissues ◽  
Female Mice ◽  
Antiatherosclerotic Effect

Both estrogen and hydrogen sulfide (H2S) have been shown to inhibit the development of atherosclerosis. We previously reported that cystathionine γ-lyase knockout (CSE-KO) male mice develop atherosclerosis earlier than male wild-type (WT) mice. The present study investigated the interaction of CSE/H2S pathway and estrogen on the development of atherosclerosis in female mice. Plasma estrogen levels were significantly lower in female CSE-KO mice than in female WT mice. NaHS treatment had no effect on plasma estrogen levels in both WT and CSE-KO female mice. After CSE-KO and WT female mice were fed with atherogenic diet for 12 wk, plasma lipid levels were significantly increased and triglyceride levels decreased compared with those of control diet-fed mice. Atherogenic diet induced more atherosclerotic lesion, oxidative stress, intracellular adhesion molecule-1 (ICAM-1), and NF-κB in CSE-KO mice than in WT mice. Estrogen treatment of atherogenic diet-fed WT mice attenuated hypercholesterolemia, oxidative stress, ICAM-1 expression, and NF-κB in WT mice but not in atherogenic diet-fed CSE-KO mice. Furthermore, H2S production in both the liver and vascular tissues was enhanced by estrogen in WT mice but not in CSE-KO mice. It is concluded that the antiatherosclerotic effect of estrogen is mediated by CSE-generated H2S. This study provides new insights into the interaction of H2S and estrogen signaling pathways on the regulation of cardiovascular functions. NEW & NOTEWORTHY Female cystathionine γ-lyase (CSE)-knockout mice have significantly lower plasma estrogen levels and more severe early atherosclerotic lesion than female wild-type mice. H2S production in liver and vascular tissues is enhanced by estrogen via its stimulatory effect on CSE activity. The antiatherosclerotic effect of estrogen is mediated by CSE-generated H2S.

Abstract 156: Macrophage Low-Density Receptor--Related Protein 1 Deficiency Facilitates Atherosclerosis Regression in Hyperlipidemic Mice

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Lin Zhu ◽  
Patricia G Yancey ◽  
Lei Ding ◽  
John L Blakemore ◽  
Youmin Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Chow Diet ◽  
Low Density ◽  
Related Protein ◽  
Wild Type ◽  
Lesion Area ◽  
Cholesterol Levels ◽  
Inflammatory Macrophages

Atherosclerosis regression is characterized by egress of macrophages out of the artery wall. We have previously shown that macrophages lacking low-density receptor related protein 1 (MFLRP1-/-) are pro-inflammatory and lead to increased lesion formation in apoE-/- mice. To study the role of macrophage inflammation during atherosclerosis regression, bone marrow from four different types of mice (wild-type, MFLRP1-/-, apoE-/- and apoE-/-/ MFLRP1-/-) was transplanted into apoE-/- recipient mice who had been fed a Western-type diet for 12 weeks. ApoE-/- recipient mice transplanted with apoE-/- bone marrow were sacrificed 2 weeks post-BMT for determination of baseline aortic atherosclerosis. After 8 weeks on chow diet, cholesterol levels were normalized in mice reconstituted with wild-type (WT) and MFLRP1-/- bone marrow (157± 36 mg/dl and 136 ± 33 mg/dl, respectively), and significantly lowered in mice with apoE-/- (302±33 mg/dl) or apoE-/-/ MFLRP1-/- (294±52 mg/dl) macrophages compared to baseline (387±34 mg/dl). Total atherosclerotic lesion area in the aortic root decreased by 15% in mice receiving WT macrophages, and decreased by an additional 10% in mice transplanted with LRP1 deficient macrophages (p<0.05 compared to WT). Similarly, mice reconstituted with apoE-/-/ MFLRP1-/- bone marrow had 15% (p < 0.01) smaller lesion size than mice receiving apoE-/- marrow. The lesion area positive for CD68 was significantly smaller in MFLRP1-/- mice compared to WT mice, and in apoE-/-/ MFLRP1-/- mice compared to apoE-/- mice. The ratio of necrotic to total lesion area was significantly lowered by WT and LRP1-/- macrophages, and was also reduced in recipients of apoE-/-/MFLRP1-/- compared to apoE-/- bone marrow. Here we demonstrate that absence of LRP1 in macrophages, which is known to cause pro-inflammatory changes, promotes atherosclerosis regression. Our study supports the novel idea that pro-inflammatory macrophages efficiently egress from the plaque in a regressive environment caused by switching from a high-fat to a chow diet. This observation sets the stage for a change in paradigm on how to target inflammation for prevention of atherosclerotic cardiovascular events.

Abstract 104: Apolipoprotein D: Implications for Multiple Roles in Lipid Metabolism

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Ujala Srivastava ◽  
Ehab M Abo-Ali ◽  
Susanna Nguy ◽  
Jean Lebegue ◽  
Kamilah Ali
Keyword(s):  
Lipid Metabolism ◽  
Plasma Cholesterol ◽  
Atherosclerotic Lesion ◽  
Minor Component ◽  
Chow Diet ◽  
Lcat Activity ◽  
Wild Type ◽  
Cholesterol Acyl Transferase ◽  
Cholesterol Levels ◽  
Significant Difference

Introduction- ApoD is a ubiquitously expressed protein that binds small hydrophobic ligands and is a minor component of lipoproteins. Polymorphisms of the human ApoD gene are associated with lipid abnormalities, specifically the reduction of HDL and ApoA1 levels. In fact, hepatic overexpression of ApoD has been shown to regulate the amount of plasma triglycerides. ApoD is also upregulated in human and mouse models of atherosclerosis, and is localized in cell types involved in atherosclerotic lesion formation. These data suggest that ApoD plays a role in lipid metabolism by modulating cellular processes in vascular cells during atherogenesis. In this study, our objective is to identify the role(s) of ApoD in lipid metabolism and to elucidate the mechanisms involved in this process. Methods and Results- To accomplish our objective, we used a two-pronged approach. We first studied the effect of ApoD on lipid metabolism on a chow diet. There was no significant difference between the levels of plasma cholesterol in ApoD -/- and wild-type mice on a chow diet; however, hepatic cholesterol levels had more than doubled. A 96-gene PCR array was used to assess differential expression of genes involved in fatty liver biogenesis. There was at least a 2-fold difference in expression in about 10 genes involved in insulin/glucose signaling, lipogenesis, and inflammation in the ApoD -/- mice. We then studied the effect of a Western diet in the ApoD -/- mice, which showed a significant reduction in plasma LDL-cholesterol and HDL-cholesterol when compared to wild-type mice. Analysis of the HDL fractions after subjecting plasma to a Fast Protein Liquid Chromatography column revealed increased levels of ApoA1 and Lecithin Cholesterol Acyl Transferase (LCAT) activity in ApoD -/- mice. Conclusion- A decrease in plasma cholesterol and an increase in ApoA1 and LCAT activity suggest that ApoD may play a role in the catabolism of HDL particles, resulting in lower plasma cholesterol levels in ApoD -/- mice. Our current data implies that ApoD plays a multifunctional role in lipid metabolism and the mechanism by which this occurs must be further examined.

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.

scholarly journals Olive Leaf Extract Attenuates Obesity in High-Fat Diet-Fed Mice by Modulating the Expression of Molecules Involved in Adipogenesis and Thermogenesis

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Ying Shen ◽  
Su Jin Song ◽  
Narae Keum ◽  
Taesun Park
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Leaf Extract ◽  
Body Weight Gain ◽  
Plasma Lipid ◽  
Epididymal Adipose Tissue ◽  
Chow Diet ◽  
Olive Leaf ◽  
High Fat ◽  
Olive Leaf Extract

The present study aimed to investigate whether olive leaf extract (OLE) prevents high-fat diet (HFD)-induced obesity in mice and to explore the underlying mechanisms. Mice were randomly divided into groups that received a chow diet (CD), HFD, or 0.15% OLE-supplemented diet (OLD) for 8 weeks. OLD-fed mice showed significantly reduced body weight gain, visceral fat-pad weights, and plasma lipid levels as compared with HFD-fed mice. OLE significantly reversed the HFD-induced upregulation of WNT10b- and galanin-mediated signaling molecules and key adipogenic genes (PPARγ, C/EBPα, CD36, FAS, and leptin) in the epididymal adipose tissue of HFD-fed mice. Furthermore, the HFD-induced downregulation of thermogenic genes involved in uncoupled respiration (SIRT1, PGC1α, and UCP1) and mitochondrial biogenesis (TFAM, NRF-1, and COX2) was also significantly reversed by OLE. These results suggest that OLE exerts beneficial effects against obesity by regulating the expression of genes involved in adipogenesis and thermogenesis in the visceral adipose tissue of HFD-fed mice.

Abstract 463: TLT-1 Deficiency Affects Hypercholesterolemia and Progression of the Atherosclerotic Plaque in Apoe Null Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Marieli Gonzalez ◽  
Fiorella Reyes ◽  
Deborah Marrero ◽  
A V Washington
Keyword(s):  
Platelet Activation ◽  
Inflammatory Responses ◽  
Plaque Rupture ◽  
Atherosclerotic Lesion ◽  
Soluble Form ◽  
Chow Diet ◽  
Fatty Streak ◽  
Wild Type ◽  
Platelet Surface ◽  
Cholesterol Levels

Platelet activation at sites of inflammation triggers the secretion of molecules that induce the transition of atherosclerosis from fatty streak to an acute disease, featuring an increased vulnerability of the atherosclerotic lesion that results in plaque rupture and thrombosis. TLT-1 (Triggering Receptor Expressed in Myeloid cells (TREM)-like transcript-1) is a molecule exclusively found in the α-granules of megakarocytes and platelets and has a demonstrated effect in inflammatory responses. Upon platelet activation, TLT-1 is moved to the platelet surface, while its soluble form, s-TLT-1, is secreted and detected in serum. Studies using the C57Bl/6 treml1 - /- mouse demonstrated a predisposition to hemorrhage after an acute inflammatory challenge suggesting that TLT-1 may be a key regulatory molecule in the interface between hemostatic and inflammatory mechanisms. Because we have found that sTLT-1 levels are significantly elevated in apoE mice when compared to wild type, we hypothesized that TLT-1 may be playing an important role in the progression of atherosclerosis. To address this possibility, we generated apoE - /- / treml1 - /- double knockout mice [DN]. Assessment of lesions after 4 weeks high-fat diet (HFD) demonstrated that at early stages, TLT-1 deficiency accelerates fatty streak formation. After 20 weeks on HFD, lesions in both apoE - /- and [DN] mice progressed to an advance fibrous plaque stage. Although their lesion sizes were not substantially different, lesion compositions were. The mechanistic basis of these differences appears to be that the [DN] mice have significantly higher cholesterol levels when compared to apoE - /- mice. The increased cholesterol levels extend to the treml1 -/- mouse when compared to wild type mice at 4 weeks on HFD, this difference, however, gradually subsides as wild type mice cholesterol levels increase over 20 weeks. Interestingly, cholesterol levels in 50 week old mice on chow diet revealed minimal differences between test and control mice suggesting the higher cholesterol levels are related to increased dietary intake. Our work defines a surprising role for TLT-1 in the regulation of serum cholesterol levels during atherogenesis.

Abstract 67: Intervention With Citrus Flavonoids Reverses Existing Metabolic Disorders and Attenuates the Progression of Advanced Atherosclerosis in High Fat--Fed LDLr-/- Mice

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Amy C Burke ◽  
Brian G Sutherland ◽  
Cynthia G Sawyez ◽  
Dawn E Telford ◽  
Joseph Umoh ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Caloric Intake ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
High Fat ◽  
Rapid Weight Gain ◽  
Metabolic Dysregulation ◽  
The Metabolic Syndrome ◽  
Citrus Flavonoids

Previous studies demonstrated that addition of the citrus flavonoids naringenin or nobiletin to a high-fat diet prevented the development of many disorders linked to the metabolic syndrome. In the present study, we assessed the ability of intervention with nobiletin or naringenin to reverse pre-established obesity, insulin resistance, hepatic steatosis, dyslipidemia and attenuate atherogenesis. Ldlr-/- mice were fed chow or a high-fat, cholesterol-containing (HFHC) diet for 12 weeks. For an additional 12 weeks, the HFHC-fed mice: (1) continued on the HFHC diet or were transferred to (2) chow, (3) HFHC + 3% naringenin, or (4) HFHC + 0.3% nobiletin. Following rapid weight gain during HFHC-induction, intervention with naringenin or nobiletin stimulated weight loss, while maintaining caloric intake. Micro-CT imaging revealed flavonoid intervention reversed adipose tissue accumulation by 40-60% in both subcutaneous and visceral depots. At 12 weeks, the HFHC-fed mice were hyperinsulinemic (6-fold), which was accompanied by increased fasting plasma glucose. Intervention with either flavonoid normalized plasma insulin and glucose and corrected impaired insulin and glucose tolerance. The HFHC diet increased cholesterol within VLDL (10-fold) and LDL (6-fold), which was reduced (~50%) by either naringenin or nobiletin intervention. HFHC-induction significantly increased hepatic steatosis. Flavonoid intervention reduced hepatic cholesterol (>50%) and triglyceride (~20%) via increased expression of Pgc1a and Cpt1a and reduced expression of Srebp1c. HFHC-induction increased atherosclerotic lesion area (13-fold), which was increased a further 2.5-fold at 24 weeks. Flavonoid intervention modestly retarded lesion size progression (16-20%). As well, intervention with naringenin or nobiletin slowed the accumulation of aortic cholesterol (~30-45%) and reduced lesional necrotic area (~25%), suggesting improved lesion morphology. These studies demonstrate in mice with pre-existing metabolic dysregulation and atherosclerosis that intervention with naringenin or nobiletin reverses obesity, dyslipidemia, hepatic steatosis and insulin resistance, and modestly attenuates the progression of advanced atherosclerosis.

scholarly journals Androgen Receptor-Dependent and Independent Atheroprotection by Testosterone in Male Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5428-5437 ◽  
Author(s):  
Johan Bourghardt ◽  
Anna S. K. Wilhelmson ◽  
Camilla Alexanderson ◽  
Karel De Gendt ◽  
Guido Verhoeven ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Apolipoprotein E ◽  
High Fat Diet ◽  
Atherosclerotic Lesion ◽  
Male Mice ◽  
Wild Type ◽  
High Fat ◽  
Lesion Area ◽  
Major Pathway

The atheroprotective effect of testosterone is thought to require aromatization of testosterone to estradiol, but no study has adequately addressed the role of the androgen receptor (AR), the major pathway for the physiological effects of testosterone. We used AR knockout (ARKO) mice on apolipoprotein E-deficient background to study the role of the AR in testosterone atheroprotection in male mice. Because ARKO mice are testosterone deficient, we sham operated or orchiectomized (Orx) the mice before puberty, and Orx mice were supplemented with placebo or a physiological testosterone dose. From 8 to 16 wk of age, the mice consumed a high-fat diet. In the aortic root, ARKO mice showed increased atherosclerotic lesion area (+80%, P &lt; 0.05). Compared with placebo, testosterone reduced lesion area both in Orx wild-type (WT) mice (by 50%, P &lt; 0.001) and ARKO mice (by 24%, P &lt; 0.05). However, lesion area was larger in testosterone-supplemented ARKO compared with testosterone-supplemented WT mice (+57%, P &lt; 0.05). In WT mice, testosterone reduced the presence of a necrotic core in the plaque (80% among placebo-treated vs. 12% among testosterone-treated mice; P &lt; 0.05), whereas there was no significant effect in ARKO mice (P = 0.20). In conclusion, ARKO mice on apolipoprotein E-deficient background display accelerated atherosclerosis. Testosterone treatment reduced atherosclerosis in both WT and ARKO mice. However, the effect on lesion area and complexity was more pronounced in WT than in ARKO mice, and lesion area was larger in ARKO mice even after testosterone supplementation. These results are consistent with an AR-dependent as well as an AR-independent component of testosterone atheroprotection in male mice.

Abstract 686: Intervention with Naringenin Enhances Weight Loss, Potentiates Improvements in Metabolic Dysregulation and Halts Progression of Atherosclerosis Induced by a High-Fat Diet in LDLr-/- Mice.

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Amy C Burke ◽  
Brian G Sutherland ◽  
Julia M Assini ◽  
Murray W Huff
Keyword(s):  
Insulin Resistance ◽  
Weight Loss ◽  
Plasma Glucose ◽  
High Fat Diet ◽  
Lesion Size ◽  
Chow Diet ◽  
High Fat ◽  
Metabolic Dysregulation ◽  
The Metabolic Syndrome ◽  
Progression Of Atherosclerosis

Previous studies demonstrate that the addition of naringenin, a grapefruit flavonoid, to a high-fat diet prevents the development of many disorders of the metabolic syndrome and atherosclerosis in Ldlr-/- mice. Furthermore, in intervention studies, the addition of naringenin to a high-fat, high cholesterol (HFHC) diet reversed pre-established obesity, hyperlipidemia, hepatic steatosis, insulin resistance and improved atherosclerotic lesion pathology, but not lesion size. In the present intervention study, we tested the hypothesis that addition of naringenin to a chow diet would further improve pre-established metabolic dysregulation and attenuate lesion development, compared to chow alone. Ldlr-/- mice were fed a HFHC diet for 12 weeks to induce metabolic dysregulation. Subsequently, mice received one of 3 diets for another 12 weeks: 1) continuation of the HFHC diet, 2) an isoflavone-free chow diet or 3) isoflavone-free chow with 3% naringenin. At 12 weeks, the HFHC diet induced significant weight gain and increased adiposity. Intervention with chow alone reduced the weight gained during induction by 22%, whereas the addition of naringenin to chow induced a weight loss of 71%. Specifically, the reduction in adiposity was 2.75-times greater in naringenin-treated mice, compared to chow alone. The HFHC diet increased VLDL cholesterol 20-fold and LDL cholesterol 5-fold, which were reduced by intervention with both chow (>60%) and chow supplemented with naringenin (>80%). The HFHC diet induced insulin resistance and glucose intolerance. Naringenin improved insulin tolerance (plasma glucose AUC -38%) and glucose tolerance (plasma glucose AUC -58%), which was accompanied by normalization of plasma insulin and glucose. HFHC-induction promoted the development of intermediate atherosclerotic lesions. Continuation of the HFHC diet doubled lesion size. Intervention with chow alone attenuated lesion size progression by 65%. The addition of naringenin to chow slowed lesion progression by 90%, resulting in smaller lesions compared to chow intervention alone (P=0.042). We conclude that intervention with naringenin-supplemented chow enhances weight loss, improves metabolic dysregulation and halts the progression of atherosclerosis.

scholarly journals Mild hyperlipidemia in mice aggravates platelet responsiveness in thrombus formation and exploration of platelet proteome and lipidome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Johanna P. van Geffen ◽  
Frauke Swieringa ◽  
Kim van Kuijk ◽  
Bibian M. E. Tullemans ◽  
Fiorella A. Solari ◽  
...  
Keyword(s):  
Plasma Lipids ◽  
Thrombus Formation ◽  
Plasma Cholesterol ◽  
Chow Diet ◽  
Wild Type ◽  
Fibrin Formation ◽  
Established Risk Factor ◽  
Arterial Thrombus ◽  
Normal Chow ◽  
Platelet Proteome

AbstractHyperlipidemia is a well-established risk factor for cardiovascular diseases. Millions of people worldwide display mildly elevated levels of plasma lipids and cholesterol linked to diet and life-style. While the prothrombotic risk of severe hyperlipidemia has been established, the effects of moderate hyperlipidemia are less clear. Here, we studied platelet activation and arterial thrombus formation in Apoe−/− and Ldlr−/− mice fed a normal chow diet, resulting in mildly increased plasma cholesterol. In blood from both knockout mice, collagen-dependent thrombus and fibrin formation under flow were enhanced. These effects did not increase in severe hyperlipidemic blood from aged mice and upon feeding a high-fat diet (Apoe−/− mice). Bone marrow from wild-type or Ldlr−/− mice was transplanted into irradiated Ldlr−/− recipients. Markedly, thrombus formation was enhanced in blood from chimeric mice, suggesting that the hyperlipidemic environment altered the wild-type platelets, rather than the genetic modification. The platelet proteome revealed high similarity between the three genotypes, without clear indication for a common protein-based gain-of-function. The platelet lipidome revealed an altered lipid profile in mildly hyperlipidemic mice. In conclusion, in Apoe−/− and Ldlr−/− mice, modest elevation in plasma and platelet cholesterol increased platelet responsiveness in thrombus formation and ensuing fibrin formation, resulting in a prothrombotic phenotype.

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