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.

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 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 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.

scholarly journals Chronic NaHS Treatment Is Vasoprotective in High-Fat-Fed ApoE−/−Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Asha Ford ◽  
Mohammad Al-Magableh ◽  
Tracey A. Gaspari ◽  
Joanne L. Hart
Keyword(s):  
High Fat Diet ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Atherosclerotic Lesion ◽  
Vascular Changes ◽  
High Fat ◽  
Superoxide Generation ◽  
Atherosclerotic Lesions ◽  
Atherosclerotic Lesion Development

Hydrogen sulfide is emerging as an important mediator of vascular function that has antioxidant and cytoprotective effects. The aim of this study was to investigate the role of endogenous H2S and the effect of chronic exogenous H2S treatment on vascular function during the progression of atherosclerotic disease. ApoE−/−mice were fed a high-fat diet for 16 weeks and treated with the H2S donor NaHS or the cystathionine-γ-lyase (CSE) inhibitor D,L-propargylglycine (PPG), to inhibit endogenous H2S production for the final 4 weeks. Fat-fed ApoE−/−mice displayed significant aortic atherosclerotic lesions and significantly impaired endothelial function compared to wild-type mice. Importantly, 4 weeks of NaHS treatment significantly reduced vascular dysfunction and inhibited vascular superoxide generation. NaHS treatment significantly reduced the area of aortic atherosclerotic lesions and attenuated systolic blood pressure. Interestingly, inhibiting endogenous, CSE-dependent H2S production with PPG did not exacerbate the deleterious vascular changes seen in the untreated fat-fed ApoE−/−mice. The results indicate NaHS can improve vascular function by reducing vascular superoxide generation and impairing atherosclerotic lesion development. Endogenous H2S production via CSE is insufficient to counter the atherogenic effects seen in this model; however exogenous H2S treatment has a significant vasoprotective effect.

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.

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