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.

Platelet P-selectin facilitates atherosclerotic lesion development

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2661-2666 ◽  
Author(s):  
Peter C. Burger ◽  
Denisa D. Wagner
Keyword(s):  
Atherosclerotic Lesion ◽  
Soluble Form ◽  
Wild Type ◽  
Lesion Development ◽  
Atherosclerotic Lesions ◽  
Lesion Growth ◽  
Microparticle Formation ◽  
Apoe Deficient Mouse ◽  
Atherosclerotic Lesion Development

P-selectin is an adhesion molecule expressed on activated platelets and endothelium. It is known to play an important role in atherosclerosis. P-selectin also circulates in plasma in a soluble form (sP-selectin), which induces procoagulant microparticle formation. We investigated the role of platelet versus endothelial P-selectin in generating sP-selectin and in the formation of atherosclerotic lesions in the apolipoprotein E (apoE)–deficient mouse model. For this we transplanted apoE−/−P-selectin−/− and apoE−/−P-selectin+/+ lethally irradiated mice with bone marrow of either genotype. Seven months after transplantation, we determined from the chimeric animals that the majority of circulating sP-selectin was of endothelial origin. Thus, in atherosclerosis, the procoagulant sP-selectin reflects endothelial rather than platelet activation. We found that endothelial P-selectin was crucial for the promotion of atherosclerotic lesion growth because in its absence only relatively small lesions developed. However, platelet P-selectin also contributed to the lesion development because lesions in wild-type recipients receiving transplants with wild-type platelets were 30% larger than those receiving P-selectin-deficient platelets (P < .008) and were more frequently calcified (80% versus 44%). In comparison with P-selectin wild-type animals, absence of either endothelial or platelet P-selectin inhibited migration of smooth muscle cells into the lesion. Thus, in addition to endothelium, platelets and their P-selectin also actively promote advanced atherosclerotic lesion development.

Abstract 3693: Early Growth Response Gene-1 Deficiency In Bone-marrow-derived Cells Reduces Macrophage Accumulation And Atherosclerotic Lesion Formation In A Hyperlipidemic Mouse Model

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Michael R Preusch ◽  
Claudia Albrecht ◽  
Gotz Hofmann ◽  
Erwin Blessing ◽  
Hugo A Katus ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Atherosclerotic Lesion ◽  
Lesion Development ◽  
Early Growth Response ◽  
Atherosclerotic Lesions ◽  
Early Growth Response Gene ◽  
Bone Marrow Derived Cells ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Development ◽  
Macrophage Accumulation

Early growth response gene-1 (Egr-1), a prototype of a family of zinc-finger transcription factors, is a master regulator of many genes which play important roles in cardiovascular diseases. Within atherosclerotic lesions Egr-1 is expressed in several cell types, such as smooth muscle cells, endothelial cells and monocytes/macrophages. Since macrophages play a pivotal role in atherosclerotic lesion development, this study investigated the effects of Egr-1-deficiency within bone-marrow derived cells on the development of atherosclerosis in a hyperlipidemic mouse model. Therefore we transplanted bone-marrow from Egr-1 deficient mice and wild type controls into lethally irradiated low-density lipoprotein receptor deficient mice. After 20 weeks on a western diet atherosclerotic lesions within the aortic sinus and gene expression of inflammatory genes in the aortas of the recipients were evaluated. Mice receiving Egr-1 deficient bone-marrow had less atherosclerotic lesion development compared with mice receiving wild type bone-marrow (318 736 ± 98 910μm 2 vs. 404 539 ± 92 408μm 2 , p<0.05). The size of the necrotic core within the lesions was also reduced. Immunohistochemistry revealed that mice receiving Egr-1 deficient bone-marrow had less macrophages in comparison to controls. Gene expression analysis in the aortas of the mice demonstrated reduced expression of Vascular Cell Adhesion Molecule (VCAM-1), an important adhesion molecule during the development of atherosclerosis. These results were validated with in vitro studies where Egr-1-deficient peritoneal macrophages revealed less VCAM-1 mRNA expression after stimulation with lipopolysaccharide in comparison to wildtype macrophages. This study demonstrates that bone-marrow derived Egr-1 promotes macrophage accumulation and atherosclerotic lesion development possible over an increased expression of VCAM-1.

scholarly journals Splenic autonomic denervation increases inflammatory status but does not aggravate atherosclerotic lesion development

2015 ◽  
Vol 309 (4) ◽  
pp. H646-H654 ◽  
Author(s):  
Sander Kooijman ◽  
Illiana Meurs ◽  
Lianne van Beek ◽  
P. Padmini S. J. Khedoe ◽  
Annabel Giezekamp ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Lesion Development ◽  
Inflammatory Status ◽  
Sham Surgery ◽  
Peritoneal Leukocytes ◽  
Leukocyte Counts ◽  
The Brain ◽  
Atherosclerotic Lesion Development

The brain plays a prominent role in the regulation of inflammation. Immune cells are under control of the so-called cholinergic anti-inflammatory reflex, mainly acting via autonomic innervation of the spleen. Activation of this reflex inhibits the secretion of proinflammatory cytokines and may reduce the development of atherosclerosis. Therefore, the aim of this study was to evaluate the effects of selective parasympathetic (Px) and sympathetic (Sx) denervation of the spleen on inflammatory status and atherosclerotic lesion development. Female APOE*3-Leiden.CETP mice, a well-established model for human-like lipid metabolism and atherosclerosis, were fed a cholesterol-containing Western-type diet for 4 wk after which they were subdivided into three groups receiving either splenic Px, splenic Sx, or sham surgery. The mice were subsequently challenged with the same diet for an additional 15 wk. Selective Px increased leukocyte counts (i.e., dendritic cells, B cells, and T cells) in the spleen and increased gene expression of proinflammatory cytokines in the liver and peritoneal leukocytes compared with Sx and sham surgery. Both Px and Sx increased circulating proinflammatory cytokines IL-1β and IL-6. However, the increased proinflammatory status in denervated mice did not affect atherosclerotic lesion size or lesion composition. Conclusion: Predominantly selective Px of the spleen enhances the inflammatory status, which, however, does not aggravate diet-induced atherosclerotic lesion development.

scholarly journals Chlamydia pneumoniae and Hyperlipidemia Are Co-Risk Factors for Atherosclerosis: Infection Prior to Induction of Hyperlipidemia Does Not Accelerate Development of Atherosclerotic Lesions in C57BL/6J Mice

2002 ◽  
Vol 70 (9) ◽  
pp. 5332-5334 ◽  
Author(s):  
Erwin Blessing ◽  
Lee Ann Campbell ◽  
Michael E. Rosenfeld ◽  
Cho-chou Kuo
Keyword(s):  
Chlamydia Pneumoniae ◽  
Atherosclerotic Lesion ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat ◽  
Lesion Development ◽  
Atherosclerotic Lesions ◽  
Accelerate Development ◽  
Atherosclerotic Lesion Development

ABSTRACT Chlamydia pneumoniae has been shown to accelerate atherosclerotic lesion development in hyperlipidemic animals. This study showed that C. pneumoniae did not accelerate lesion development in mice if a high-fat/high-cholesterol diet was started after infection, indicating that C. pneumoniae is a co-risk factor with hyperlipidemia for cardiovascular disease.

ClC-3 deficiency prevents atherosclerotic lesion development in ApoE−/− mice

2015 ◽  
Vol 87 ◽  
pp. 237-247 ◽  
Author(s):  
Jing Tao ◽  
Can-Zhao Liu ◽  
Jing Yang ◽  
Zhi-Zhong Xie ◽  
Ming-Ming Ma ◽  
...  
Keyword(s):  
Atherosclerotic Lesion ◽  
Lesion Development ◽  
Atherosclerotic Lesion Development

Chlamydia pneumoniae infection accelerates hyperlipidemia induced atherosclerotic lesion development in C57BL/6J mice

2001 ◽  
Vol 158 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Erwin Blessing ◽  
Lee Ann Campbell ◽  
Michael E. Rosenfeld ◽  
Natacha Chough ◽  
Cho-Chou Kuo
Keyword(s):  
Chlamydia Pneumoniae ◽  
Atherosclerotic Lesion ◽  
Lesion Development ◽  
Atherosclerotic Lesion Development

Abstract 1721: Deletion of Both Macrophage ABCG1 and ApoE Independently Promotes Atherosclerotic Lesion Development in LDL Receptor Knockout Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ruud Out ◽  
Bart Lammers ◽  
Reeni B. Hildebrand ◽  
Carmel M. Quinn ◽  
David Williamson ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Independent Effect ◽  
High Cholesterol Diet ◽  
Moderate Increase ◽  
Lesion Development ◽  
Macrophage Cholesterol Efflux ◽  
Atherosclerotic Lesion Development

Objective ATP-binding cassette transporter G1 (ABCG1) and apolipoprotein E (apoE) play a role in macrophage cholesterol efflux and consequently the development of atherosclerosis. Although a possible interaction between ABCG1 and apoE in cholesterol efflux was postulated, the combined action of these proteins in atherosclerosis is still unclear. Methods and Results LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCG1/apoE double KO (dKO) mice, their respective single knockouts, and wild-type (WT) controls. After feeding a high-fat/high-cholesterol diet for 6 weeks, no differences were found in serum lipid levels. However, the mean atherosclerotic lesion area in dKO transplanted animals (187 ± 18 × 10 3 μ m 2 ) was 1.4-fold (p < 0.01) increased compared to single knockouts (ABCG1 KO: 138 ± 5 × 10 3 μm 2 ; apoE KO: 131 ± 7 × 10 3 μm 2 ) and 1.9-fold (p< 0.001) as compared to WT controls (97 ± 15 × 10 3 μm 2 ). In vitro cholesterol efflux experiments confirmed that combined deletion of ABCG1 and apoE resulted in a larger attenuation of macrophage cholesterol efflux to HDL as compared to single knockouts. Conclusions Deletion of macrophage ABCG1 or apoE does lead to a moderate increase in atherosclerotic lesion development while combined deletion of ABCG1 and apoE induces a more dramatic increase in atherosclerosis. These results indicate an added, independent effect for both macrophage ABCG1 and apoE in atherosclerosis.

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