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.

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 83: Bone Marrow Derived Cells Do Not Mediate Reductions in Cholesterol, Atherosclerosis and Adiposity in Microsomal Prostaglindin E Synthase 1 Deficient Mice Fed High Fat Diets Enriched in Cholesterol

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Sarah Srodulski ◽  
Victoria L King
Keyword(s):  
Bone Marrow ◽  
Weight Gain ◽  
Marrow Cell ◽  
Atherosclerotic Lesion ◽  
Chimeric Mice ◽  
High Fat ◽  
Lesion Formation ◽  
Bone Marrow Derived Cells ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Formation

Microsomal prostaglandin E 2 synthase-1 (mPGES-1) catalyzes the conversion of COX-2 generated PGH 2 to PGE 2 and is the predominate source of PGE 2 during and inflammatory response. We and others have demonstrated that mPGES-1 deficiency attenuates atherosclerosis in mice on a mixed background. The present study investigated the effect of mPGES-1 deficiency on atherosclerosis in C57BL/6 low density lipoprotein receptor deficient (LDLr-/-) mice. mPGES-1 deficiency attenuated atherosclerosis in LDLr-/- mice fed either a low fat (LF) (P = 0.02) or high fat (HF) (P = 0.0026) diet enriched with cholesterol, or a western diet (P = 0.02) for 17 weeks. mPGES-1 deficiency attenuated weight gain and cholesterol concentrations in mice fed a western (P = 0.004 and P < 0.05; respectively) or HF diet (P = 0.01 and P = 0.012, respectively). However, body weight and cholesterol concentrations were not different in mice fed the LF diet. These data suggest that different mechanisms mediate the reduction in atherosclerosis in mPGES-1 deficient mice fed LF and HF diets. To determine if mPGES-1 deficiency in macrophages contributed to the reduction in atherosclerosis in mice fed HF diets, 4 groups of chimeric mice were generated. Four weeks post bone marrow cell transplant (BMT) mice were fed a western diet. BMT attenuated weight gain in all groups of chimeric mice; however, weight gain was not different between any of the groups. BMT decreased atherosclerotic lesion formation 10 fold in all groups of mice. Neither bone marrow cell specific deficiency of mPGES-1 (KO>WT) or mPGES-1 specific expression in bone marrow derived cells (WT>KO) had an effect on lesion formation compared to WT>WT or KO>KO mice. Cholesterol concentrations were decreased in KO>KO and WT>KO mice compared to WT>WT (P < 0.01) and KO>WT (P< 0.05) mice. These data suggest that mPGES-1 expression in bone marrow derived cells does not contribute to the development of atherosclerosis. Moreover, these data suggest that prostanoids may play a role in hepatic cholesterol homeostasis in mice fed HF diets enriched in cholesterol thereby contributing to atherosclerotic lesion formation. Moreover, these data provide further evidence that prostanoids play a role in regulating the accumulation of diet-induced adiposity.

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.

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