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Atherogenesis

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Peter Libby – One of the best experts on this subject based on the ideXlab platform.

  • the multifaceted contributions of leukocyte subsets to atherosclerosis lessons from mouse models
    Nature Reviews Immunology, 2008
    Co-Authors: Christian Weber, Alma Zernecke, Peter Libby

    Abstract:

    Chronic inflammation drives the development of atherosclerosis, and details regarding the involvement of different leukocyte subpopulations in the pathology of this disease have recently emerged. This Review highlights the surprising contribution of granulocyte subsets and mast cells to early Atherogenesis and subsequent plaque instability, and describes the complex, double-edged role of monocyte, macrophage and dendritic-cell subsets through crosstalk with T cells and vascular progenitor cells. Improved understanding of the selective contributions of specific cell types to Atherogenesis will pave the way for new targeted approaches to therapy.

  • inflammation in atherosclerosis
    Nature, 2002
    Co-Authors: Peter Libby

    Abstract:

    Abundant data link hypercholesterolaemia to Atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early Atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.

  • expression of interleukin il 18 and functional il 18 receptor on human vascular endothelial cells smooth muscle cells and macrophages implications for Atherogenesis
    Journal of Experimental Medicine, 2002
    Co-Authors: Norbert Gerdes, Peter Libby, Galina K Sukhova, Rebecca S Reynolds, James L Young, Uwe Schonbeck

    Abstract:

    Although considerable evidence implicates the cytokine interferon (IFN)-γ in Atherogenesis, the proximal inducers and the range of sources of its expression remain unknown. This study tested the hypothesis that interleukin (IL)-18 regulates IFN-γ expression during Atherogenesis. Indeed, human atheroma in situ expressed IL-18 and elevated levels of its receptor subunits, IL-18Rα/β, compared with nondiseased arterial tissue. IL-18 occurred predominantly as the mature, 18-kD form and colocalized with mononuclear phagocytes (MO), while endothelial cells (ECs), smooth muscle cells (SMCs), and MO all expressed IL-18Rα/β. Correspondingly in vitro, only MO expressed IL-18, while all three cell types displayed the IL-18Rα/β complex constitutively, exhibiting enhanced expression upon stimulation with LPS, IL-1β, or tumor necrosis factor (TNF)-α. IL-18 signaling evoked effectors involved in Atherogenesis, e.g., cytokines (IL-6), chemokines (IL-8), intracellular adhesion molecules (ICAM)-1, and matrix metalloproteinases (MMP-1/-9/-13), demonstrating functionality of the receptor on ECs, SMCs, and MO. Finally, IL-18, particularly in combination with IL-12, induced the expression of IFN-γ in cultured MO and, surprisingly, in SMCs (but not in ECs). The expression of functional IL-18 and IL-18 receptor on human atheroma-associated ECs, SMCs, and MO, and its unexpected ability to induce IFN-γ expression in SMCs, suggests a novel paracrine proinflammatory pathway operating during Atherogenesis.

Garret A Fitzgerald – One of the best experts on this subject based on the ideXlab platform.

  • cyclooxygenase 2 in endothelial and vascular smooth muscle cells restrains Atherogenesis in hyperlipidemic mice
    Circulation, 2014
    Co-Authors: Soon Yew Tang, John A Lawson, James Monslow, Leslie Todd, Ellen Puré, Garret A Fitzgerald

    Abstract:

    Background—Placebo-controlled trials of nonsteroidal anti-inflammatory drugs selective for inhibition of cyclooxygenase-2 (COX-2) reveal an emergent cardiovascular hazard in patients selected for low risk of heart disease. Postnatal global deletion of COX-2 accelerates Atherogenesis in hyperlipidemic mice, a process delayed by selective enzyme deletion in macrophages. Methods and Results—In the present study, selective depletion of COX-2 in vascular smooth muscle cells and endothelial cells depressed biosynthesis of prostaglandin I2 and prostaglandin E2, elevated blood pressure, and accelerated Atherogenesis in Ldlr knockout mice. Deletion of COX-2 in vascular smooth muscle cells and endothelial cells coincided with an increase in COX-2 expression in lesional macrophages and increased biosynthesis of thromboxane. Increased accumulation of less organized intimal collagen, laminin, α-smooth muscle actin, and matrix-rich fibrosis was also apparent in lesions of the mutants. Conclusions—Although Atherogenesis

  • disruption of the 5 lipoxygenase pathway attenuates Atherogenesis consequent to cox 2 deletion in mice
    Proceedings of the National Academy of Sciences of the United States of America, 2012
    Co-Authors: Irene Crichton, John A Lawson, Soon Yew Tang, Yiqun Hui, Emanuela Ricciotti, Ellen Puré, Mark D Levin, Garret A Fitzgerald

    Abstract:

    Suppression of cyclooxygenase 2 (COX-2)–derived prostacyclin (PGI2) is sufficient to explain most elements of the cardiovascular hazard from nonsteroidal antinflammatory drugs (NSAIDs). However, randomized trials are consistent with the emergence of cardiovascular risk during chronic dosing with NSAIDs. Although deletion of the PGI2 receptor fosters Atherogenesis, the importance of COX-2 during development has constrained the use of conventional knockout (KO) mice to address this question. We developed mice in which COX-2 was deleted postnatally, bypassing cardiorenal defects exhibited by conventional KOs. When crossed into ApoE-deficient hyperlipidemic mice, COX-2 deletion accelerated Atherogenesis in both genders, with lesions exhibiting leukocyte infiltration and phenotypic modulation of vascular smooth muscle cells, as reflected by loss of α-smooth muscle cell actin and up-regulation of vascular cell adhesion molecule-1. Stimulated peritoneal macrophages revealed suppression of COX-2–derived prostanoids and augmented 5-lipoxygenase product formation, consistent with COX-2 substrate rediversion. Although deletion of the 5-lipoxygenase activating protein (FLAP) did not influence Atherogenesis, it attenuated the proatherogeneic impact of COX-2 deletion in hyperlipidemic mice. Chronic administration of NSAIDs may increasingly confer a cardiovascular hazard on patients at low initial risk. Promotion of Atherogenesis by postnatal COX-2 deletion affords a mechanistic explanation for this observation. Coincident inhibition of FLAP may offer an approach to attenuating such a risk from NSAIDs.

  • Targeted Deletions of Cyclooxygenase-2 and Atherogenesis in Mice
    Circulation, 2010
    Co-Authors: Yiqun Hui, Emanuela Ricciotti, Irene Crichton, Dairong Wang, Jane Stubbe, Miao Wang, Ellen Puré, Garret A Fitzgerald

    Abstract:

    Background— Although the dominant product of vascular Cyclooxygenase-2 (COX-2), prostacyclin (PGI2), restrains Atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX-2 in macrophages and T cells (TCs) to Atherogenesis. Methods and Results— Deletion of macrophage–COX-2 (Mac–COX-2KOs) was attained with LysMCre mice and completely suppressed lipopolysaccharide-stimulated macrophage prostaglandin (PG) formation and lipopolysaccharide-evoked systemic PG biosynthesis by ≈30%. Lipopolysaccharide-stimulated COX-2 expression was suppressed in polymorphonuclear leukocytes isolated from MacKOs, but PG formation was not even detected in polymorphonuclear leukocyte supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic low-density lipoprotein receptor knockouts. Deletion of Mac–COX-2 appeared to remove a restraint on COX-2 expression in l…

Martin A Schwartz – One of the best experts on this subject based on the ideXlab platform.

  • a mechanosensory complex that mediates the endothelial cell response to fluid shear stress
    Nature, 2005
    Co-Authors: Eleni Tzima, Martin A Schwartz, Mohamad Iranitehrani, William B Kiosses, E Dejana, David A Schultz, Britta Engelhardt, Horace M Delisser

    Abstract:

    Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and Atherogenesis1, but the mechanisms of transduction are poorly understood. Previous work showed that the conversion of integrins to a high-affinity state mediates a subset of shear responses, including cell alignment and gene expression2,3,4. Here we investigate the pathway upstream of integrin activation. PECAM-1 (which directly transmits mechanical force), vascular endothelial cell cadherin (which functions as an adaptor) and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) comprise a mechanosensory complex. Together, these receptors are sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-κB and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in Atherogenesis.