The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform
Peter Libby - One of the best experts on this subject based on the ideXlab platform.
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the multifaceted contributions of leukocyte subsets to atherosclerosis lessons from mouse models
Nature Reviews Immunology, 2008Co-Authors: Christian Weber, Alma Zernecke, Peter LibbyAbstract: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.
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inflammation in atherosclerosis
Nature, 2002Co-Authors: Peter LibbyAbstract: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.
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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, 2002Co-Authors: Norbert Gerdes, Peter Libby, Galina K Sukhova, Rebecca S Reynolds, James L Young, Uwe SchonbeckAbstract: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.
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changing concepts of Atherogenesis
Journal of Internal Medicine, 2000Co-Authors: Peter LibbyAbstract:This review discusses three stages in the life history of an atheroma: initiation, progression and complication. Recruitment of mononuclear leucocytes to the intima characterizes initiation of the atherosclerotic lesion. Specific adhesion molecules expressed on the surface of vascular endothelial cells mediate leucocyte adhesion: the selectins and members of the immunoglobulin superfamily such as vascular cell adhesion molecule-1 (VCAM-1). Once adherent, the leucocytes enter the artery wall directed by chemoattractant chemokines such as macrophage chemoattractant protein-1 (MCP-1). Modified lipoproteins contain oxidized phospholipids which can elicit expression of adhesion molecule and cytokines implicated in early Atherogenesis. Progression of atheroma involves accumulation of smooth muscle cells which elaborate extracellular matrix macromolecules. These processes appear to result from an eventual net positive balance of growth stimulatory versus growth inhibitory stimuli, including proteins (cytokines and growth factors) and small molecules (e.g. prostanoids and nitric oxide). The clinically important complications of atheroma usually involve thrombosis. Arterial stenoses by themselves seldom cause acute unstable angina or acute myocardial infarction. Indeed, sizeable atheroma may remain silent for decades or produce only stable symptoms such as angina pectoris precipitated by increased demand. Recent research has furnished new insight into the molecular mechanisms that cause transition from the chronic to the acute phase of atherosclerosis. Thrombus formation usually occurs because of a physical disruption of atherosclerotic plaque. The majority of coronary thromboses result from a rupture of the plaque's protective fibrous cap, which permits contact between blood and the highly thrombogenic material located in the lesion's lipid core, e.g. tissue factor. Interstitial collagen accounts for most of the tensile strength of the plaque's fibrous cap. The amount of collagen in the lesion's fibrous cap depends upon its rate of biosynthesis stimulated by factors released from platelets (e.g. transforming growth factor beta or platelet-derived growth factor), but inhibited by gamma interferon, a product of activated T cells found in plaques. Degradation by specialized enzymes (matrix metalloproteinases) also influences the level of collagen in the plaque's fibrous cap. Such studies illustrate how the application of cellular and molecular approaches has fostered a deeper understanding of the pathogenesis of atherosclerosis. This increased knowledge of the basic mechanisms enables us to understand how current therapies for atherosclerosis may act. Moreover, the insights derived from recent scientific advances should aid the discovery of new therapeutic targets that would stimulate development of novel treatments. Such new treatments could further reduce the considerable burden of morbidity and mortality due to this modern scourge, and reduce reliance on costly technologies that address the symptoms rather than the cause of atherosclerosis.
Garret A Fitzgerald - One of the best experts on this subject based on the ideXlab platform.
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cyclooxygenase 2 in endothelial and vascular smooth muscle cells restrains Atherogenesis in hyperlipidemic mice
Circulation, 2014Co-Authors: Soon Yew Tang, James Monslow, Leslie Todd, John A Lawson, Ellen Puré, Garret A FitzgeraldAbstract: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...
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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, 2012Co-Authors: Irene Crichton, Soon Yew Tang, John A Lawson, Yiqun Hui, Emanuela Ricciotti, Ellen Puré, Mark D Levin, Garret A FitzgeraldAbstract: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.
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Targeted Deletions of Cyclooxygenase-2 and Atherogenesis in Mice
Circulation, 2010Co-Authors: Yiqun Hui, Emanuela Ricciotti, Irene Crichton, Dairong Wang, Jane Stubbe, Miao Wang, Ellen Puré, Garret A FitzgeraldAbstract: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...
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acceleration of Atherogenesis by cox 1 dependent prostanoid formation in low density lipoprotein receptor knockout mice
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Domenico Pratico, Cyrus Tillmann, Zhibing Zhang, Garret A FitzgeraldAbstract:The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substantially in humans. Because deletion of the PGI(2) receptor accelerates Atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate Atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF(1alpha) by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI(2) biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of Atherogenesis. Despite their divergent effects on Atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during Atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to Atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.
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vitamin e suppresses isoprostane generation in vivo and reduces atherosclerosis in apoe deficient mice
Nature Medicine, 1998Co-Authors: Domenico Pratico, Rajendra K Tangirala, Daniel J Rader, Joshua Rokach, Garret A FitzgeraldAbstract:Oxidative modification of low density lipoprotein (LDL) has been implicated in Atherogenesis 1 . Evidence consistent with this hypothesis includes the presence of oxidized lipids in atherosclerotic lesions 2, 3 , the newly discovered biological properties conferred on LDL by oxidation 1, 4 and the acceleration of Atherogenesis by in vivo delivery of the gene for 15-lipoxygenase 5 , an oxidizing enzyme present in atherosclerotic lesions 6 . However, it is still unknown whether oxidative stress actually coincides with the evolution of the disease or whether it is of functional relevance to Atherogenesis in vivo . Isoprostanes are products of arachidonic acid catalyzed by free radicals, which reflect oxidative stress and lipid peroxidation in vivo 7 . Elevation of tissue and urinary isoprostanes is characteristic of human atherosclerosis 8, 9 . Here, deficiency in apolipoprotein E in the mouse (apoE –/– ) resulted in Atherogenesis and an increase in iPF 2α -VI, an F 2 -isoprostane 10 , in urine, plasma and vascular tissue. Supplementation with vitamin E significantly reduced isoprostane generation, but had no effect on plasma cholesterol levels in apoE –/– mice. Aortic lesion areas and iPF 2α -VI levels in the arterial wall were also reduced significantly by vitamin E. Our results indicate that oxidative stress is increased in the apoE –/– mouse, is of functional importance in the evolution of atherosclerosis and can be suppressed by oral administration of vitamin E.
Martin A Schwartz - One of the best experts on this subject based on the ideXlab platform.
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a mechanosensory complex that mediates the endothelial cell response to fluid shear stress
Nature, 2005Co-Authors: Eleni Tzima, Mohamad Iranitehrani, William B Kiosses, E Dejana, David A Schultz, Britta Engelhardt, Horace M Delisser, Martin A SchwartzAbstract: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.
Dianqing Wu - One of the best experts on this subject based on the ideXlab platform.
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lack of a significant role of p rex1 a major regulator of macrophage rac1 activation and chemotaxis in Atherogenesis
Prostaglandins & Other Lipid Mediators, 2008Co-Authors: Zhenglong Wang, Xuemei Dong, Jonathan D. Smith, Zhong Li, Dianqing WuAbstract:Abstract Background Rho GTPases are known to play important roles in regulating multiple cellular processes that include cell polarization and migration. Among these Rho GTPases, Rac has been shown to be essential for F actin formation and cell migration. P-Rex1 is a guanine nucleotide exchange factor (GEF) that was previously found to mediate the activation of Rac2, but not Rac1, in mouse neutrophils. Objectives Here we examined the role of P-Rex1 in mouse macrophages and Atherogenesis. Methods and results PBD (p21 binding domain) pull down assay was performed to compare the Rac1 activation in WT and P-Rex1-deficient macrophage. In addition, transwell assay was conducted to compare chemotaxis of WT and P-Rex1-deficient macrophage. We found that P-Rex1 is a major Rac1 regulator in mouse macrophages as its deficiency significantly compromises macrophage chemotaxis, superoxide production (SOD), and Rac1 activation in response to chemoattractants. The potential role of P-Rex1 in Atherogenesis is also investigated by transferring P-Rex1-deficient bone marrow cells to LDLR deficient mice. Contrary to our prediction, P-Rex1 deficiency did not alter Atherogenesis, suggesting chemoattractant-induced macrophage migration may not have a significant role in Atherogenesis. Conclusions P-Rex1 is one of the major GEFs in macrophage regulating Rac1 activation and chemotaxis.
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Lack of a significant role of P-Rex1, a major regulator of macrophage Rac1 activation and chemotaxis, in Atherogenesis.
Prostaglandins & other lipid mediators, 2008Co-Authors: Zhenglong Wang, Xuemei Dong, Jonathan D. Smith, Zhong Li, Dianqing WuAbstract:Rho GTPases are known to play important roles in regulating multiple cellular processes that include cell polarization and migration. Among these Rho GTPases, Rac has been shown to be essential for F actin formation and cell migration. P-Rex1 is a guanine nucleotide exchange factor (GEF) that was previously found to mediate the activation of Rac2, but not Rac1, in mouse neutrophils. Here we examined the role of P-Rex1 in mouse macrophages and Atherogenesis. PBD (p21 binding domain) pull down assay was performed to compare the Rac1 activation in WT and P-Rex1-deficient macrophage. In addition, transwell assay was conducted to compare chemotaxis of WT and P-Rex1-deficient macrophage. We found that P-Rex1 is a major Rac1 regulator in mouse macrophages as its deficiency significantly compromises macrophage chemotaxis, superoxide production (SOD), and Rac1 activation in response to chemoattractants. The potential role of P-Rex1 in Atherogenesis is also investigated by transferring P-Rex1-deficient bone marrow cells to LDLR deficient mice. Contrary to our prediction, P-Rex1 deficiency did not alter Atherogenesis, suggesting chemoattractant-induced macrophage migration may not have a significant role in Atherogenesis. P-Rex1 is one of the major GEFs in macrophage regulating Rac1 activation and chemotaxis.
Soon Yew Tang - One of the best experts on this subject based on the ideXlab platform.
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myeloid cell microsomal prostaglandin e synthase 1 fosters Atherogenesis in mice
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Lihong Chen, Guangrui Yang, James Monslow, Leslie Todd, David P Cormode, Jun Tang, Gregory R Grant, Jonathan H Delong, Soon Yew Tang, John A LawsonAbstract:Microsomal prostaglandin E synthase-1 (mPGES-1) in myeloid and vascular cells differentially regulates the response to vascular injury, reflecting distinct effects of mPGES-1–derived PGE2 in these cell types on discrete cellular components of the vasculature. The cell selective roles of mPGES-1 in Atherogenesis are unknown. Mice lacking mPGES-1 conditionally in myeloid cells (Mac-mPGES-1-KOs), vascular smooth muscle cells (VSMC-mPGES-1-KOs), or endothelial cells (EC-mPGES-1-KOs) were crossed into hyperlipidemic low-density lipoprotein receptor-deficient animals. En face aortic lesion analysis revealed markedly reduced Atherogenesis in Mac-mPGES-1-KOs, which was concomitant with a reduction in oxidative stress, reflective of reduced macrophage infiltration, less lesional expression of inducible nitric oxide synthase (iNOS), and lower aortic expression of NADPH oxidases and proinflammatory cytokines. Reduced oxidative stress was reflected systemically by a decline in urinary 8,12-iso-iPF2α-VI. In contrast to exaggeration of the response to vascular injury, deletion of mPGES-1 in VSMCs, ECs, or both had no detectable phenotypic impact on Atherogenesis. Macrophage foam cell formation and cholesterol efflux, together with plasma cholesterol and triglycerides, were unchanged as a function of genotype. In conclusion, myeloid cell mPGES-1 promotes Atherogenesis in hyperlipidemic mice, coincident with iNOS-mediated oxidative stress. By contrast, mPGES-1 in vascular cells does not detectably influence Atherogenesis in mice. This strengthens the therapeutic rationale for targeting macrophage mPGES-1 in inflammatory cardiovascular diseases.
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cyclooxygenase 2 in endothelial and vascular smooth muscle cells restrains Atherogenesis in hyperlipidemic mice
Circulation, 2014Co-Authors: Soon Yew Tang, James Monslow, Leslie Todd, John A Lawson, Ellen Puré, Garret A FitzgeraldAbstract: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...
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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, 2012Co-Authors: Irene Crichton, Soon Yew Tang, John A Lawson, Yiqun Hui, Emanuela Ricciotti, Ellen Puré, Mark D Levin, Garret A FitzgeraldAbstract: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.