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Biomedical subjects

P Libby

Publications and source records attributed to P Libby.

At least 37 records · Page 2Linked to original sources
PubMed2001

The CD40/CD154 receptor/ligand dyad.

Until recently, the expression and primary function of the cell surface receptor CD40 and its ligand CD154 were considered restricted to B and T lymphocytes, and their interactions required for the thymus-dependent humoral response. However, current work from several groups challenges this view of the CD40/CD154 dyad as a mere mediator of lymphocyte communication. A variety of non-lymphocytic cell types express both receptor and ligand, including hematopoetic and non-hematopoetic cells, such as monocytes, basophils, eosinophils, dendritic cells, fibroblasts, smooth muscle, and endothelial cells. Accordingly, ligation of CD40 mediates a broad variety of immune and inflammatory responses, such as the expression of adhesion molecules, cytokines, matrix-degrading enzymes, prothrombotic activities, and apoptotic mediators. Consequently, CD40 signaling has been associated with pathogenic processes of chronic inflammatory diseases, such as autoimmune diseases, neurodegenerative disorders, graft-versus-host disease, cancer, and atherosclerosis. This review focuses on the synthesis and structure of CD40 and outlines CD154/CD40 signaling pathways, and emphasizes the previously unexpected importance of the CD40/CD154 receptor/ligand dyad in a spectrum of immunoregulatory processes and prevalent human diseases.

Animals↗
PubMed2001

Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes.

Inflammation and oxidative stress contribute to the pathogenesis of many human diseases including atherosclerosis. Advanced human atheroma contains high levels of the enzyme myeloperoxidase that produces the pro-oxidant species, hypochlorous acid (HOCl). This study documents increased numbers of myeloperoxidase-expressing macrophages in eroded or ruptured plaques causing acute coronary syndromes. In contrast, macrophages in human fatty streaks contain little or no myeloperoxidase. Granulocyte macrophage colony-stimulating factor, but not macrophage colony-stimulating factor, selectively regulates the ability of macrophages to express myeloperoxidase and produce HOCl in vitro. Moreover, myeloperoxidase-positive macrophages in plaques co-localized with granulocyte macrophage colony-stimulating factor. Pro-inflammatory stimuli known to be present in human atherosclerotic plaque, including CD40 ligand, lysophosphatidylcholine, or cholesterol crystals, could induce release of myeloperoxidase from HOCl production by macrophages in vitro. HOCl-modified proteins accumulated at ruptured or eroded sites of human coronary atheroma. These results identify granulocyte macrophage colony-stimulating factor as an endogenous regulator of macrophage myeloperoxidase expression in human atherosclerosis and support a particular role for the myeloperoxidase-expressing macrophages in atheroma complication and the acute coronary syndromes.

Arteriosclerosis↗
PubMed2001

Host bone-marrow cells are a source of donor intimal smooth- muscle-like cells in murine aortic transplant arteriopathy.

Long-term solid-organ allografts typically develop diffuse arterial intimal lesions (graft arterial disease; GAD), consisting of smooth-muscle cells (SMC), extracellular matrix and admixed mononuclear leukocytes. GAD eventually culminates in vascular stenosis and ischemic graft failure. Although the exact mechanisms are unknown, chronic low-level alloresponses likely induce inflammatory cells and/or dysfunctional vascular wall cells to secrete growth factors that promote SMC intimal recruitment, proliferation and matrix synthesis. Although prior work demonstrated that the endothelium and medial SMCs lining GAD lesions in cardiac allografts are donor-derived, the intimal SMC origin could not be determined. They are generally presumed to originate from the donor media, leading to interventions that target donor medial SMC proliferation, with limited efficacy. However, other reports indicate that allograft vessels may contain host-derived endothelium and SMCs (refs. 8,9). Moreover, subpopulations of bone-marrow and circulating cells can differentiate into endothelium, and implanted synthetic vascular grafts are seeded by host SMCs and endothelium. Here we used murine aortic transplants to formally identify the source of SMCs in GAD lesions. Allografts in beta-galactosidase transgenic recipients showed that intimal SMCs derived almost exclusively from host cells. Bone-marrow transplantation of beta-galactosidase--expressing cells into aortic allograft recipients demonstrated that intimal cells included those of marrow origin. Thus, smooth-muscle--like cells in GAD lesions can originate from circulating bone--marrow-derived precursors.

Animals↗
PubMed2001

Endothelial function and coronary artery disease.

The endothelium produces a number of vasodilator and vasoconstrictor substances that not only regulate vasomotor tone, but also the recruitment and activity of inflammatory cells and the propensity towards thrombosis. Endothelial vasomotor function is a convenient way to assess these other functions, and is related to the long-term risk of cardiovascular disease. Lipids (particularly low density lipoprotein cholesterol) and oxidant stress play a major role in impairing these functions, by reducing the bioavailability of nitric oxide and activating pro-inflammatory signalling pathways such as nuclear factor kappa B. Biomechanical forces on the endothelium, including low shear stress from disturbed blood flow, also activate the endothelium increasing vasomotor dysfunction and promoting inflammation by upregulating pro-atherogenic genes. In contrast, normal laminar shear stress promotes the expression of genes that may protect against atherosclerosis. The sub-cellular structure of endothelial cells includes caveolae that play an integral part in regulating the activity of endothelial nitric oxide synthase. Low density lipoprotein cholesterol and oxidant stress impair caveolae structure and function and adversely affect endothelial function. Lipid-independent pathways of endothelial cell activation are increasingly recognized, and may provide new therapeutic targets. Endothelial vasoconstrictors, such as endothelin, antagonize endothelium-derived vasodilators and contribute to endothelial dysfunction. Some but not all studies have linked certain genetic polymorphisms of the nitric oxide synthase enzyme to vascular disease and impaired endothelial function. Such genetic heterogeneity may nonetheless offer new insights into the variability of endothelial function.

Animals↗
PubMed2001

Inflammation and atherothrombosis.

An immune and inflammatory response involving endothelial and smooth muscle cells accompanies the accumulation of lipids and fibrous materials in atheromatous arteries. The inflammatory response involves not only the intrinsic cells of the artery wall, but also circulating leukocytes. Lymphocytes as well as macrophages participate importantly in this disease process. Plaque composition and vulnerability have emerged as more critical determinants of plaque rupture than the degree of lumenal stenosis. Thus, plaque biology has proven more important than gross morphology in determining the clinical consequences of the disease. Rupture of the atherosclerotic plaque, its thrombotic complications, and their sequelae have gained increased recognition as the proximate causes of disability and death due to related syndromes such as acute myocardial infarction. Arterial thromboses occur much more readily in arteries damaged or distorted by the atherosclerotic process. The consequences of a given plaque disruption and subsequent thrombus formation will depend on both "systemic" or fluid phase determinants and local "solid state" factors. The complex heterogeneous structure of thrombi includes fibrin, platelets, erythrocytes, and leukocytes. The local balance of proteases and inhibitors on the fibrin and cell surfaces will determine thrombus stability and persistence. 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.

Animals↗
PubMed2001

Ligation of CD40 onvascular smooth muscle cells mediates loss of interstitial collagen via matrix metalloproteinase activity.

Interstitial collagen constitutes the predominant structural component of the fibrous cap of atherosclerotic plaque. The balance between synthesis and degradation of this extracellular matrix protein probably determines plaque stability and hence the tendency for plaque rupture. The CD40/CD40L signaling dyad has been implicated as an important regulatory pathway of collagen-degrading activity in atherosclerosis via the induction of matrix metalloproteinases (MMPs). However, the role of CD40 signaling in the synthesis of interstitial collagen and thus in the overall rate of collagen turnover has remained unknown. We demonstrate here that CD40 ligation on cultured human vascular smooth muscle cells (SMCs) diminishes the detectable content of de novo synthesized interstitial procollagens. Notably, the loss of collagen is not accompanied by a reduction in collagen transcript expression but can be prevented by MMP inhibition. These data demonstrate that CD40 signaling in human vascular SMC shifts interstitial collagen turnover towards the loss of this extracellular matrix protein by accelerating its degradation without concomitantly diminishing its synthesis. Thus, CD40/CD40L interactions might play a key role in rendering atheromatous lesions prone to rupture.

CD40 Antigens↗
PubMed2001

Induction of endothelial-leukocyte interaction by interferon-gamma requires coactivation of nuclear factor-kappaB.

To determine whether nuclear factor (NF)-kappaB is necessary to confer endothelial cell responsiveness to interferon (INF)-gamma in terms of vascular cell adhesion molecule (VCAM)-1 expression and leukocyte adhesion, human endothelial cells were treated with IFN-gamma in the presence of low concentrations (LCs) of interleukin (IL)-1alpha (</=100 pg/mL), which activates NF-kappaB but does not induce VCAM-1 expression. Although IFN-gamma induced major histocompatibility complex class II antigen expression and although a high concentration of IL-1alpha (10 ng/mL) induced leukocyte adhesion and VCAM-1 expression, neither IFN-gamma nor LC IL-1alpha was able to induce VCAM-1 expression or leukocyte adhesion. However, the combination of IFN-gamma and LC IL-1alpha induced VCAM-1 expression and increased leukocyte adhesion (67% and 49% of high-concentration IL-1alpha, respectively). Electrophoretic mobility shift assays and immunoblotting of nuclear extracts showed that IFN-gamma activated signal transducers and activators of transcription (STAT)-1alpha and interferon regulatory factor (IRF)-1 but not NF-kappaB, whereas LC IL-1alpha activated NF-kappaB but not STAT-1alpha or IRF-1. Nuclear run-on studies showed that LC IL-1alpha is necessary but not sufficient for inducing VCAM-1 gene transcription and that the combination of IFN-gamma and LC IL-1alpha is required for full VCAM-1 gene transcription. These findings suggest that factors that activate NF-kappaB can synergize with IFN-gamma in promoting endothelial-leukocyte interaction.

Animals↗
PubMed2001

Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis.

Degradation of ECM, particularly interstitial collagen, promotes plaque instability, rendering atheroma prone to rupture. Previous studies implicated matrix metalloproteinases (MMPs) in these processes, suggesting that dysregulated MMP activity, probably due to imbalance with endogenous inhibitors, promotes complications of atherosclerosis. We report here that the serine proteinase inhibitor tissue factor pathway inhibitor-2 (TFPI-2) can function as an MMP inhibitor. TFPI-2 diminished the ability of the interstitial collagenases MMP-1 and MMP-13 to degrade triple-helical collagen, the primary load-bearing molecule of the ECM within human atheroma. In addition, TFPI-2 also reduced the activity of the gelatinases MMP-2 and MMP-9. In contrast to the "classical" tissue inhibitors of MMPs (TIMPs), TFPI-2 expression in situ correlated inversely with MMP levels in human atheroma. TFPI-2 colocalized primarily with smooth muscle cells in the normal media as well as the plaque's fibrous cap. Conversely, the macrophage-enriched shoulder region, the prototypical site of matrix degradation and plaque rupture, stained only weakly for TFPI-2 but intensely for gelatinases and interstitial collagenases. Evidently, human mononuclear phagocytes, an abundant source of MMPs within human atheroma, lost their ability to express this inhibitor during differentiation in vitro. These findings establish a new, anti-inflammatory function of TFPI-2 of potential pathophysiological significance for human diseases, including atherosclerosis.

Aorta↗
PubMed2001

Peroxisome proliferator-activated receptors (PPARs) and their role in the vessel wall: possible mediators of cardiovascular risk?

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that regulate gene expression in response to activation by specific ligands including insulin sensitizing thiazolidinedione and lipid-lowering fibrates. Recent work has identified PPARalpha and PPARgamma expression in vascular cells and established a role for these receptors in the regulation of genes relevant to atherogenesis. The following review will focus on the role of PPAR activation in the vasculature and discuss the potential clinical implications of these findings.

Arteriosclerosis↗
PubMed2000

Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: using genomic technology to identify a potential novel pathway of vascular inflammation.

BACKGROUND: Unstable atherosclerotic lesions typically have an abundant inflammatory cell infiltrate, including activated T cells, macrophages, and mast cells, which may decrease plaque stability. The pathophysiology of inflammatory cell recruitment and activation in the human atheroma is incompletely described. METHODS AND RESULTS: We hypothesized that differential gene expression with DNA microarray technology would identify new genes that may participate in vascular inflammation. RNA isolated from cultured human aortic smooth muscle cells treated with tumor necrosis factor-alpha (TNF-alpha) was examined with a DNA microarray with 8600 genes. This experiment and subsequent Northern analyses demonstrated marked increases in steady-state eotaxin mRNA (>20 fold), a chemokine initially described as a chemotactic factor for eosinophils. Because eosinophils are rarely present in human atherosclerosis, we then studied tissue samples from 7 normal and 14 atherosclerotic arteries. Immunohistochemical analysis demonstrated overexpression of eotaxin protein and its receptor, CCR3, in the human atheroma, with negligible expression in normal vessels. Eotaxin was predominantly located in smooth muscle cells. The CCR3 receptor was localized primarily to macrophage-rich regions as defined by immunopositivity for CD 68; a minority of mast cells also demonstrated immunopositivity for the CCR3 receptor. CONCLUSIONS: Eotaxin and its receptor, CCR3, are overexpressed in human atherosclerosis, suggesting that eotaxin participates in vascular inflammation. These data demonstrate how genomic differential expression technology can identify novel genes that may participate in the stability of atherosclerotic lesions.

Actins↗
PubMed2000

Coronary artery injury and the biology of atherosclerosis: inflammation, thrombosis, and stabilization.

Conventional concepts of the pathogenesis of acute coronary syndromes are changing. High-risk lesions are not necessarily the angiographically "tight" stenoses. Rather, unstable vulnerable lesions have large lipid cores and thin fibrous caps. Plaque instability relates closely to the development of inflammation within the intima. Acute coronary syndromes usually result from rupture of a vulnerable atherosclerotic plaque mechanistically linked to the inflammatory process. Stabilization of lesions, rather than percutaneous or surgical procedures, provides a new therapeutic target. Lipid lowering may stabilize lesions by mitigating the inflammatory response.

Acute Disease↗
PubMed2000

Matrix matters.

Explore the source record for details and available documents.

Animals↗
PubMed2000

Host CD40 ligand deficiency induces long-term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis.

Although interruption of CD40-CD40L interactions via their respective mAbs yields prolonged allograft survival, the relative importance of CD40 or CD40L on donor or host cells remains unknown. Moreover, it is uncertain whether any allospecific tolerance occurring with CD40-CD40L blockade will also prevent allograft arteriopathy, the major long-term limitation to transplantation. Therefore, we performed cardiac transplantations using CD40L-deficient (CD40L-/-) mice to investigate the mechanisms underlying prolonged allograft survival. Without immunosuppression, wild-type (WT) hosts rejected allo-mismatched WT or CD40L-/- heart allografts within 2 wk. Conversely, allografts in CD40L-/- hosts beat vigorously for 12 wk. Anti-CD40 treatment did not induce graft failure in CD40L-/- recipients. Although graft-infiltrating cells were reduced approximately 50% in CD40L-/- hosts, the relative percentages of macrophages and T cell subsets were comparable to WT. IFN-gamma, TNF-alpha, and IL-10 were diminished commensurate with the reduced cellular infiltrate; IL-4 was not detected. CD40L-/- recipients did not develop IgG alloantibodies and showed diminished B7 and CD28 expression on subsets of graft-infiltrating cells. CD40L-/- transplant recipients developed allospecific tolerance to the donor haplotype; second set donor skin grafts engrafted well, whereas third-party skin grafts were vigorously rejected. By MLR, splenocytes from CD40L-/- allograft recipients also demonstrated allo-specific hyporesponsiveness. Nevertheless, allografts in CD40L-/- hosts developed significant graft arteriosclerosis by 8-12 wk posttransplant. 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.

Animals↗
PubMed2000

Lipid lowering improves endothelial functions.

The healthy endothelium usually provides an anticoagulant, vasodilatory and anti-inflammatory spectrum of functions that are central in vascular homeostasis. Dysfunction of the endothelium is a common feature of all phases of atherosclerosis. Hypercholesterolemia provokes many aspects of endothelial dysfunction before and during the development of atheroma. For example, a high cholesterol diet leads to the formation of a fatty streak and the recruitment and binding of blood leukocytes to the artery wall. This process requires expression by the endothelial cells of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1). In rabbits that are fed an atherogenic diet, the aortic endothelium, which usually expresses little VCAM-1, shows foci of VCAM-1 expression soon after initiating this diet. Furthermore, lowering plasma cholesterol by diet or drugs down-regulates the expression of VCAM-1 and reduces the density of inflammatory cells in the atherosclerotic plaque. Hypercholesterolemia also attenuates normal vasodilatation to several stimuli such as exercise and acetylcholine. In healthy subjects, the vascular endothelium produces the vasodilator nitric oxide. In atherosclerosis, however, nitric oxide bioavailability is impaired. As a result, atherosclerotic coronary arteries commonly display a vasoconstrictor response when challenged with acetylcholine. Lipid lowering appears to favorably influence endothelial vasomotor and inflammatory functions in ways that may benefit patients with coronary artery disease. 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.

Animals↗