PETER W LIBBY

..In particular, we tested the involvement in cardiac allografts of thrombospondin-1 (TSP-1), a matrix glycoprotein that inhibits angiogenesis and facilitates smooth muscle cell (SMC) proliferation...

..Thus, physicians must continue to educate their patients regarding an optimal balance of drug therapy and personal behavior...

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..Inflammation regulates aspects of plaque biology that trigger the thrombotic complications of atherosclerosis. Translation of these discoveries to humans has enabled both novel mechanistic insights and practical clinical advances...

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..The concept of "interventional cardiology" must expand beyond mechanical revascularization to embrace preventive interventions that forestall future events...

..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...

..The potential vascular protective effects of metformin, demonstrated by the UK Prospective Diabetes Study, may complement other strategies within such a framework...

..Thus, the time has come to embrace inflammation as a common pathway for atherogenic risk factors and for providing new opportunities for therapeutic intervention...

..Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets...

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..This article examines recent experimental approaches aimed at elucidating these antiatherogenic, HDL-mediated mechanisms...

..This article reviews the evolution of the concept of plaque stabilization and reexamines the evidence for the role of statins in that process...

..Treatment of vulnerable patients should include measures to stabilize plaques and to lessen the thrombotic consequences of plaque disruptions...

..Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications...

..The goals for the years to come must include translation of the experimental work to visualization of these appealing biologic targets in humans...

..The clinical use of biomarkers of inflammation may provide the practitioner with a tool to help gauge residual risk, and chart a course for its optimal management...

..Inflammation is thus moving from a theoretical concept to a tool that provides practical clinical utility in risk assessment and targeting of therapy...

..This convergence of clinical and pathological observations highlighted the importance of understanding the mechanisms of disruption of plaques that can precipitate thromboses...

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..This review provides an update of the role of inflammation in atherogenesis and highlights how translation of these advances in basic science promises to change clinical practice...

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..Novel molecular imaging strategies may permit visualization of proteinase activity in vivo, providing a new functional window on pathophysiology...

..Therefore, we propose that early alloresponses, without CD40-CD40L costimulation, induce allospecific tolerance but may trigger allo-independent mechanisms that ultimately result in graft vasculopathy...

..Thus, MCP-1 plays a unique and crucial role in the initiation of atherosclerosis and may provide a new therapeutic target in this disorder...

..CONCLUSIONS: This study showed that statins can reduce MMP expression in atheroma and that cell-permeant statins can decrease SMC number and collagen gene expression in vivo...

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..CONCLUSIONS: These data point to MMP-8 as a previously unsuspected participant in collagen breakdown, an important determinant of the vulnerability of human atheroma...

..7+/-4.7% for animals on standard chow; P<0.001). CONCLUSIONS: Biomechanical strain induces SRA expression by monocyte/macrophages, suggesting a novel mechanism for promotion of atherosclerosis in hypertensive patients...

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..This study shows that sodium cholate is not necessary for the formation of atherosclerosis in LDLR(-/-) mice and that precisely defined semipurified diets are a valuable tool for the examination of diet-gene interactions...

..These data support the involvement of inflammatory pathways in atherosclerosis and indicate a role for CD40 signalling during atherogenesis in hyperlipidaemic mice...

..The present study investigated PPARalpha expression in human ECs and their regulation of vascular cell adhesion molecule-1 (VCAM-1)...

..Accordingly, CD40/CD154 interactions have advanced as a potential therapeutic target for these diseases, whereby two opposing strategies, interruption as well as enhancement of CD40 signaling, are explored for beneficial outcomes...

..The indefinite survival of allografts into B7-1/B7-2-/- recipients further shows that the absence of B7 costimulation alone is sufficient to prevent rejection...

..Continued probing of the basic mechanisms of endothelial dysfunction and its treatment may lead to new therapies that offer clinical benefits in patients with atherosclerosis, including reductions in coronary events...

..Rather than attempting a comprehensive overview, we will focus primarily on selected examples where new information sheds light on potential molecular mechanisms underlying these pathologic processes...

..Tissue factor (TF) overexpressed in atheroma may accelerate thrombus formation at the sites of plaque disruption. A cell surface cytokine CD40 ligand (CD40L) enhances TF expression in vitro...

..This pathophysiologic mechanism may play a role in the anatomic localization of some inflammatory skin diseases, such as psoriasis, which occurs more commonly in locations where the dermis is subjected to repetitive stretch or trauma...

..These results suggest potential mechanisms by which lipid lowering reduces acute coronary events in patients by decreasing proteolytic and prothrombotic activity within the atheroma...

..The findings highlight a potentially important role for imbalance between cysteine proteases and cystatin C in arterial wall remodeling and establish that cystatin C deficiency occurs in vascular disease...

..Such genetic heterogeneity may nonetheless offer new insights into the variability of endothelial function...

..The effects of the op mutation on atherogenesis may have resulted from decreased circulating monocytes, reduced tissue macrophages, or diminished arterial M-CSF...

..These findings suggest that factors that activate NF-kappaB can synergize with IFN-gamma in promoting endothelial-leukocyte interaction...

..It is unknown, however, whether elevations of circulating sCD40L precede the onset of acute cardiovascular symptoms...

..Lipid lowering with HMG-CoA reductase inhibitors reduces acute coronary events...

..These data demonstrate that mechanical deformation increases specific vascular smooth muscle cell proteoglycan synthesis and aggregation, indicating a highly coordinated extracellular matrix response to biomechanical stimulation...

..We hypothesize that lipid-lowering reduces clinical events, as shown in recent trials, by stabilizing lesions in part by reversing some of the maladaptive functions of macrophages described above...

..Degradation and weakening of the collagenous extracellular matrix at these critical high-stress regions may play a role in the pathogenesis of plaque rupture and acute ischemic syndromes...

..These findings establish a new, anti-inflammatory function of TFPI-2 of potential pathophysiological significance for human diseases, including atherosclerosis...

..The local production of MCSF during atherogenesis may contribute to macrophage survival and proliferation or activate specific macrophage functions such as expression of the scavenger receptor and secretion of apo E...

..Thus, development of GAD, but not parenchymal rejection, requires IFN-gamma. Reduced expression of MHC antigens and leukocyte adhesion molecules may contribute to the lack of coronary arteriopathy in hearts allografted into GKO mice...

..Thus, CD40/CD40L interactions might play a key role in rendering atheromatous lesions prone to rupture...

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..This study lends further support to the importance of this specific inflammatory signaling pathway in atherosclerosis and its complications...

..Thus, smooth-muscle--like cells in GAD lesions can originate from circulating bone--marrow-derived precursors...

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..Studies in rabbits with diet-induced atherosclerosis have shown that reducing cholesterol consumption indeed decreases inflammation in atheroma and improves those features of plaques associated with stability...

..Plaque progression was seen with maintenance of high-cholesterol diet. MRI is a promising noninvasive technology for directly imaging atherosclerosis and its response to therapeutic interventions...

..These results demonstrate a novel function of endothelium-derived Cat S in angiogenesis...

..These studies support the conclusion that M-CSF participates critically in fatty streak formation and progression to a complex fibrous lesion...

..The decrease in collagen accumulation and the enhanced expression of other MMPs suggest that MMP-9 plays a prominent role in extracellular matrix remodeling after MI...

..Enhanced understanding of the processes involved in the development and progression of atherosclerosis and its complications will surely provide areas that can be targeted in the treatment of the disease...

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..To examine whether a lack of prostaglandin E receptor 4 (EP4) on bone marrow-derived cells would increase local inflammation and enhance the formation of abdominal aortic aneurysm (AAA) in vivo...

..Imaging of macrophages and protease activity should provide an important adjunct to understanding pathophysiology in vivo, evaluating the effects of interventions, and ultimately aiding clinical care...

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..This effort will hasten the translation of research discoveries to promote health of the heart and blood vessels at home and abroad. ..

..The observations point to distinct mechanisms mediating acute vs. chronic allograft pathologies, and suggest that different therapeutic interventions will be uniquely applicable to each. ..

..5. We will explore a putative functional role of a novel prostaglandin E2 receptor EP4 interacting protein (EPRAP) in endogenous anti-inflammatory pathways. ..

..Together, this project should help in understanding the mechanisms of extracellular matrix remodeling during atherogenesis, a key determinant of the clinical expression of this disease. ..

..In this application we propose to continue our longstanding record (documented within) or preparing a talented pool of fellows for successful academic careers. ..

..Delineation of such pathways will help to understand the mechanisms that modulate undesirable amplification of local inflammatory related to SMC growth...

..Finally, we will correlate results of these immunologic studies with angiographic evidence of vascular dysfunction or injury determined at the time of flood drawing in the same patients...

..The results of this study should help unravel mechanisms of arterial pathology, to understand normal vascular homeostasis, and to aid the rational design of therapies for prevalent vascular diseases...

..This project should help in understanding the mechanisms of arterial remodeling during atherogenesis. These complementary studies will translate further preclinical findings into clinical preventive cardiovascular medicine. ..