scholarly journals Reduced Atherosclerotic Lesion Size inP-Selectin Deficient ApolipoproteinE-Knockout Mice Fed a Chow but Not a Fat Diet

2006 ◽  
Vol 2006 ◽  
pp. 1-8 ◽  
Author(s):  
Marie-Claude Bourdillon ◽  
Jacques Randon ◽  
Lydie Barek ◽  
Kazem Zibara ◽  
Chantal Covacho ◽  
...  
Keyword(s):  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Vascular Lesions ◽  
Chow Diet ◽  
Double Knockout ◽  
Beneficial Effects ◽  
Atherosclerotic Lesions ◽  
Cholesterol Levels ◽  
Human Arteries ◽  
Lower Ratio

Endothelial cells lining atherosclerotic, but not healthy sites, on human arteries expressP-selectin. We investigated the role ofP-selectin on the development of vascular lesions in an ApoE−/−male mice. Double-knockout (ApoE−/−,P-selectin-/-; DKO) were compared to single-knockout (ApoE−/−; SKO) mice. They were fed a chow or fat diet for 3, 6, 15, and 20 weeks, without any differences in cholesterol levels. DKO mice fed a chow diet exhibited a ratio of lesion area over media lower than SKO mice, for 3 (P<.03) , 6 (P<.001), and 15 (P<.02) weeks. DKO mice fed a fat diet showed a lower ratio only at 3 weeks.P-selectin deficiency in ApoE−/−mice has a protective effect in atherosclerotic lesions development. Reduction of lesion size depends on diet type and duration. A fat diet could neutralize the beneficial effects ofP-selectin deficiency, inducing atherosclerotic lesions via probably other adhesion molecules.

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 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.

ICAM-1 deficiency reduces atherosclerotic lesions in double knockout mice (apo-E−/−/ICAM-1−/−) fed a fat or a chow diet

1999 ◽  
Vol 144 ◽  
pp. 166-167
Author(s):  
M.C. Bourdillon ◽  
C. Covacho ◽  
R.N. Poston ◽  
E. Chignier ◽  
G. Canard ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Chow Diet ◽  
Double Knockout ◽  
Atherosclerotic Lesions ◽  
Apo E

Abstract 69: Anacetrapib Dose-dependently Decreases Atherosclerosis Development and Adds to the Beneficial Effects of Atorvastatin in APOE*3Leiden.CETP Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Susan Kühnast ◽  
Sam J van der Tuin ◽  
Louis M Havekes ◽  
Ko Willems van Dijk ◽  
Patrick C Rensen ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Plasma Lipids ◽  
Atherosclerotic Lesion ◽  
Hdl Cholesterol ◽  
Statin Treatment ◽  
Epidemiological Studies ◽  
Lesion Size ◽  
Beneficial Effects ◽  
Atherosclerosis Development ◽  
C 32

Introduction The residual risk of cardiovascular disease that remains after statin treatment has triggered the search for a secondary treatment target. Epidemiological studies propose HDL-cholesterol (HDL-C) as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. In human intervention trials, the CETP inhibitor anacetrapib decreases (V)LDL-C by 30-40% and increases HDL-C by 40-140%. Hypothesis Complete inhibition of CETP activity may result in adverse effects as compared to partial inhibition due to the appearance of a dysfunctional HDL. We, therefore, evaluated the effect of a broad treatment window of anacetrapib-induced CETP inhibition with partial to full inhibition, as well as the combination of atorvastatin and anacetrapib on atherosclerosis development in APOE*3Leiden.CETP mice. Methods Female mice were fed a Western-type diet containing 0.1% cholesterol without or with incremental dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/d), atorvastatin (2.4 mg/kg/d) or a combination of anacetrapib (0.3 mg/kg/d) and atorvastatin (2.4 mg/kg/d) for 20 weeks. Effects on plasma lipids, CETP activity and levels, as well as atherosclerotic lesion size and severity were assessed. Results Anacetrapib dose-dependently reduced CETP activity (-60% to -100%, P<0.001) and increased CETP levels (+13% to +31%, P<0.05), thereby decreasing nonHDL-C (-23% to -44%, P<0.001) and increasing HDL-C (+32% to +88%, P<0.001). Atorvastatin decreased CETP activity (-29%, P<0.001) and nonHDL-C (-36%, P<0.001). Anacetrapib dose-dependently decreased atherosclerotic lesion size (-36%, P<0.05 to -92%, P<0.001) and the percentage severe lesions. Anacetrapib added to the effects of atorvastatin by further reducing nonHDL-C (-36%, P<0.001), increasing HDL-C (+72%, P<0.001) and decreasing lesion size (-86%, P<0.001) and severity. Results on lesion composition are pending. Conclusions Anacetrapib dose-dependently decreases atherosclerosis development and adds to the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice. Total blockage of CETP activity does not reveal adverse effects as compared to partial blockage.

scholarly journals Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice

2019 ◽  
Vol 61 (3) ◽  
pp. 365-375 ◽  
Author(s):  
Marianne G. Pouwer ◽  
Elsbet J. Pieterman ◽  
Nicole Worms ◽  
Nanda Keijzer ◽  
J. Wouter Jukema ◽  
...  
Keyword(s):  
Triple Therapy ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Lipid Lowering ◽  
Atherosclerosis Progression ◽  
Cholesterol Levels ◽  
Baseline Group ◽  
Current Therapies ◽  
Triple Treatment ◽  
Lesion Severity

Atherosclerosis-related CVD causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocumab or evinacumab, monoclonal antibodies against cholesterol-regulating proprotein convertase subtilisin/kexin type 9 and angiopoietin-like protein 3, may provide more benefit. We investigated the effect of such lipid-lowering interventions on atherosclerosis in APOE*3-Leiden.CETP mice, a well-established model for hyperlipidemia. Mice were fed a Western-type diet for 13 weeks and thereafter matched into a baseline group (euthanized at 13 weeks) and five groups that received diet alone (control) or with treatment [atorvastatin; atorvastatin and alirocumab; atorvastatin and evinacumab; or atorvastatin, alirocumab, and evinacumab (triple therapy)] for 25 weeks. We measured effects on cholesterol levels, plaque composition and morphology, monocyte adherence, and macrophage proliferation. All interventions reduced plasma total cholesterol (37% with atorvastatin to 80% with triple treatment; all P < 0.001). Triple treatment decreased non-HDL-C to 1.0 mmol/l (91% difference from control; P < 0.001). Atorvastatin reduced atherosclerosis progression by 28% versus control (P < 0.001); double treatment completely blocked progression and diminished lesion severity. Triple treatment regressed lesion size versus baseline in the thoracic aorta by 50% and the aortic root by 36% (both P < 0.05 vs. baseline), decreased macrophage accumulation through reduced proliferation, and abated lesion severity. Thus, high-intensive cholesterol-lowering triple treatment targeting all apoB-containing lipoproteins regresses atherosclerotic lesion area and improves lesion composition in mice, making it a promising potential approach for treating atherosclerosis.

ICAM-1 deficiency reduces atherosclerotic lesions in double knockout mice (Apo-E−/−/ICAM-I−/−) fed a fat or a chow diet

1999 ◽  
Vol 144 ◽  
pp. 94 ◽  
Author(s):  
M.C. Bourdillon ◽  
C. Covacho ◽  
R.N. Poston ◽  
E. Chignier ◽  
G. Canard ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Chow Diet ◽  
Double Knockout ◽  
Atherosclerotic Lesions ◽  
Apo E

scholarly journals ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE − /− /ICAM-1 − /− ) Fed a Fat or a Chow Diet

2000 ◽  
Vol 20 (12) ◽  
pp. 2630-2635 ◽  
Author(s):  
Marie-Claude Bourdillon ◽  
Robin N. Poston ◽  
Chantal Covacho ◽  
Elza Chignier ◽  
Giampiero Bricca ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Chow Diet ◽  
Double Knockout ◽  
Atherosclerotic Lesions

scholarly journals A Timing Effect of 17-β Estradiol on Atherosclerotic Lesion Development in Female ApoE−/− Mice

2020 ◽  
Vol 21 (13) ◽  
pp. 4710
Author(s):  
Obialunanma V. Ebenebe ◽  
Zoe Ashley ◽  
Jeffrey R. Erickson ◽  
Alison K. Heather
Keyword(s):  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Vehicle Control ◽  
Intimal Thickening ◽  
Lesion Development ◽  
Atherosclerotic Lesions ◽  
Timing Effect ◽  
Increased Risk ◽  
17Β Estradiol ◽  
Atherosclerotic Lesion Development

Differences in size or composition of existing plaques at the initiation of estrogen (E2) therapy may underpin evidence of increased risk of atherosclerosis-associated clinical sequelae. We investigated whether E2 had divergent effects on actively-growing versus established-advanced atherosclerotic lesions. Eight weeks of subcutaneous bi-weekly injections of 3 µg/g 17β-estradiol (n = 18) or vehicle control (n = 22) were administered to female Apolipoprotein null-mice aged 25- or 45 weeks old. Histological assessment of lesion size within the brachiocephalic artery was conducted. Lesion composition was also assessed with acellular, calcification and fibrosis areas measured and other cellular features (intimal thickening, foam cells, lipid pools and cholesterol) scored (0–3) for severity. The comparison showed increased lesion size and calcified area with advancing age but no effect of E2. However, subtle changes in composition were observed following E2. Within the younger group, E2 increased intima thickening and acceleration of calcification. In the older group, E2 increased the thickness of the lesion cap. Therefore, this study shows different effects of E2 depending on the underlying stage of lesion development at the time of initiation of treatment. These divergent changes help explain the controversy of the adverse effects of E2 treatment in cardiovascular disease.

Abstract 3968: Bone Marrow Derived Growth Differentiation Factor-15 (GDF-15) Protects from Macrophage Accumulation and Effects Atherosclerotic Lesion Stabilisation in Low-Density Lipoprotein Receptor-Null Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Michael R Preusch ◽  
Jens Strelau ◽  
Matthias Baeuerle ◽  
Erwin Blessing ◽  
Marc Bischof ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Peritoneal Macrophages ◽  
Lesion Size ◽  
Fibrous Cap ◽  
Atherosclerotic Lesions ◽  
Density Lipoprotein Receptor ◽  
Macrophage Accumulation

Atherosclerosis is considered to be a chronic inflammatory disease. Macrophages are the prime sources of a variety of inflammatory cytokines and growth factors, which contribute to the initiation and progression of atherosclerotic lesions. The cytokine growth differentiation factor-15 (GDF-15) is a newly discovered member of the transforming growth factor-beta cytokine. GDF-15 participates in vascular inflammation and is mostly expressed by macrophages within the lesions. In this study the impact of GDF-15 deficiency in bone marrow-derived cells on atherogenesis in a mouse model was examined. Bone marrow from GDF15 −/−or GDF-15 +/+ mice was transplanted into lethally irradiated low-density lipoprotein receptor (LDLR−/−) mice (n=38). Twentyfour weeks after administration of a high-fat/high-cholesterol Western type diet atherosclerotic lesion size within the aortic root as well as macrophage content was quantified and compared. In addition features of lesion destabilisation like size of the necrotic core, thinning of the fibrous cap, intra-plaque hemorrhage and calcification were evaluated. In an in-vitro experiment peritoneal macrophages from transplanted mice were harvested and stimulated with tumor necrosis factor alpha (TNFα). Transplantation of GDF-15 −/− bone marrow cells resulted in an enhanced macrophage accumulation within the atherosclerotic lesions (ratio mac/lesion 0.51 versus 0.31; p<0.05) and a significant thinning of the fibrous cap (30.5 versus 48.5 μm; p<0.05). Cell culture experiments demonstrated that macrophages from GDF-15 −/− mice had a much higher induction of ICAM-1 and MCP-1 after stimulation with TNFα in comparison to wildtype peritoneal macrophages. However no difference in lesion size could be reported. Furthermore, there was no difference in plasma lipid levels and body weight. Our data indicates that bone marrow derived GDF-15 protects from macrophage accumulation within atherosclerotic lesions and promotes lesion stabilisation possibly due to inhibition of adhesion molecules and MCP-1.

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.

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