IL-15 aggravates atherosclerotic lesion development in LDL receptor deficient mice.

Background: Interleukin 15 (IL-15) is a pro-inflammatory cytokine involved in inflammatory diseases and IL-15 is expressed in atherosclerotic plaques.

Methods: To establish the role of IL-15 in atherosclerosis we studied the effect of IL-15 on atherosclerosis associated cells in vitro and in vivo by neutralizing IL-15 using a DNA vaccination strategy.

Results: Upon feeding a Western type diet LDLr(-/-) mice do express higher levels of IL-15 within the spleen and the number of IL-15 expressing cells among blood leukocytes and spleen cells is increased.

Effect of natural killer T cell activation on the initiation of atherosclerosis.

It has been shown that natural killer T (NKT) cell activation accelerates atherosclerosis in apoE(-/-) mice. ApoE is, however, an important mediator in the presentation of lipids which may complicate conclusions on the role of NKT cells in atherosclerosis. Treatment of LDLr(-/-) mice with alpha-GalCer during Western-type diet feeding is therefore of interest.

Vaccination against TIE2 reduces atherosclerosis.

Background: TIE2(+) cells play a crucial role in processes that are involved in atherosclerosis, such as angiogenesis. Therefore, the specific deletion of TIE2(+) cells by means of DNA vaccination may affect atherosclerosis.

Methods: Cellular immunity against cells that overexpress TIE2 was established in LDLr(-/-) mice by a novel oral DNA vaccination technique, in which an attenuated Salmonella typhimurium strain was used as a carrier for plasmid pcDNA3.

Vaccination against CD99 inhibits atherogenesis in low-density lipoprotein receptor-deficient mice.

Aims: Murine CD99 was recently found to be expressed on leukocytes and endothelial cells, where it is concentrated at inter-endothelial contacts. Blockade of CD99 by specific antibodies inhibits leukocyte extravasation to inflamed sites in vivo. The aim of the present study is to show the role of CD99 in atherosclerosis using a CD99 vaccination protocol to block the function of CD99 during atherosclerosis.

CXCR3 antagonist NBI-74330 attenuates atherosclerotic plaque formation in LDL receptor-deficient mice.

Objective: The chemokine receptor CXCR3 is implicated in migration of leukocytes to sites of inflammation. Antagonizing CXCR3 may be a strategy to inhibit inflammation-induced leukocyte migration and subsequently reduce atherosclerosis. We used the CXCR3 specific antagonist NBI-74330 to block CXCR3-mediated signaling in peritonitis and diet-induced atherosclerosis.

Immunomodulation of the inflammatory response in atherosclerosis.

Purpose Of Review: Cardiovascular disease, as manifested in the formation of atherosclerotic lesions, can be described as a chronic inflammatory autoimmune-like disease that proceeds in the context of enhanced plasma lipid levels. Modulation of the immune response may therefore form a valuable therapy in addition to standardized cholesterol and blood pressure-lowering therapies. The purpose of this review is to describe a number of recent approaches to immunomodulate atherosclerosis: immunization against mediators involved in atherosclerosis, such as cytokines and modified low-density lipoprotein; intervention in cytokine pathways; intervention in co-stimulatory pathways; activation of regulatory T cells; and modulation of natural killer T cells.

Vaccination against VEGFR2 attenuates initiation and progression of atherosclerosis.

Objective: Vascular endothelial growth factor receptor 2 (VEGFR2)-overexpressing cells may form an interesting target for the treatment of atherosclerosis because of their involvement in processes that contribute to this disease, such as angiogenesis.

Methods And Results: We vaccinated mice against VEGFR2 by an orally administered DNA vaccine, comprising a plasmid, encoding murine VEGFR2, carried by live attenuated Salmonella typhimurium. This vaccine induces cellular immunity against cells that overexpress VEGFR2.

KLF2 suppresses TGF-beta signaling in endothelium through induction of Smad7 and inhibition of AP-1.

Objective: The flow-responsive Kruppel-like factor 2 (KLF2) is crucial for maintaining endothelial cell quiescence. Here, we describe its detailed effects on transforming growth factor-beta (TGF-beta) signaling, which normally has proatherogenic effects on endothelium.

Methods And Results: In-depth analysis of genome-wide expression data shows that prolonged lentiviral-mediated overexpression of KLF2 in human umbilical vein endothelial cells (HUVECs) diminishes the expression of a large panel of established TGF-beta-inducible genes.

Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) pathway attenuates atherogenesis in low-density lipoprotein receptor-deficient mice.

Objective: Atherosclerosis is a chronic (auto-)inflammatory disease and T cell activation is an important factor in this process. Tnfrsf4 (OX40) and Tnfsf4 (OX40 ligand) are members of the tumor necrosis factor (TNF) and TNF receptor family and OX40/OX40L mediated signaling is important in co-activation of T cells and facilitates B-T cell interaction. In this study we assessed the role of the OX40/OX40L pathway in atherosclerosis and the effect of interruption of the OX40/OX40L pathway on lesion development.

Microarray analysis indicates an important role for FABP5 and putative novel FABPs on a Western-type diet.

Liver parenchymal cells play a dominant role in hepatic metabolism and thereby total body cholesterol homeostasis. To gain insight into the specific pathways and genes involved in the response of liver parenchymal cells to increased dietary lipid levels under atherogenic conditions, changes in parenchymal cell gene expression upon feeding a Western-type diet for 0, 2, 4, and 6 weeks were determined using microarray analysis in LDL receptor-deficient mice, an established atherosclerotic animal model. Using ABI Mouse Genome Survey Arrays, we were able to detect 7,507 genes (28% of the total number on an array) that were expressed in parenchymal cells isolated from livers of LDL receptor-deficient mice at every time point investigated.

HDL cholesterol levels are an important factor for determining the lifespan of erythrocytes.

Objective: Scavenger receptor class B, type I (SR-BI) is a multifunctional receptor that promotes the selective uptake of cholesteryl esters from high-density lipoprotein (HDL). Disruption of SR-BI in mice results in a dramatic increase in HDL cholesterol. Interestingly, mice lacking SR-BI also develop anemia, as evidenced by accumulation of reticulocytes in the circulation.

HIV entry inhibitor TAK-779 attenuates atherogenesis in low-density lipoprotein receptor-deficient mice.

Objective: HIV combination therapy using protease inhibitors is associated with elevated plasma levels of atherogenic lipoproteins and increased risk for atherosclerosis. We investigated whether the HIV entry inhibitor TAK-779 affects lipoprotein levels and atherogenesis in low-density lipoprotein receptor-deficient mice. TAK-779 is an antagonist for the chemokine receptors CCR5 and CXCR3, which are expressed on leukocytes, especially T-helper 1 cells, and these receptors may be involved in recruitment of these cells to atherosclerotic plaques.

Repopulation of apolipoprotein E knockout mice with CCR2-deficient bone marrow progenitor cells does not inhibit ongoing atherosclerotic lesion development.

Objective: Using bone marrow transplantation, we have previously demonstrated the critical role that hematopoietic CCR2 plays in early atherogenesis. Reconstitution of irradiated apolipoprotein (apo) E3-Leiden mice with CCR2-deficient bone marrow progenitor cells resulted in 86% reduction on overall atherosclerotic lesion development. However, no data on CCR2 in the cause of established atherosclerosis have been reported so far.