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Biomedical subjects

P Libby

Publications and source records attributed to P Libby.

267 records · Page 15Linked to original sources
PubMedDate not supplied

Omega-3 fatty acids and endothelial leukocyte adhesion molecules.

Although dietary fatty acids can modulate atherogenesis and inflammation, the mechanisms by which this occurs are poorly understood. Induction in endothelial cells of adhesion molecules for circulating leukocytes and of inflammatory mediators by cytokines likely contributes to early phases of atherogenesis and inflammation. We report here that incorporation into cellular lipids of one specific fatty acid of the omega-3 family, docosahexaenoic acid (DHA), decreases cytokine-induced expression of endothelial leukocyte adhesion molecules, secretion of inflammatory mediators, and leukocyte adhesion to endothelial cells. These properties of DHA may contribute to antiatherogenic and antiinflammatory effects of omega-3 fatty acids.

Adult↗
PubMedDate not supplied

The molecular bases of restenosis.

Studies on the fundamental mechanisms of restenosis after arterial intervention have undergone upheaval. The rat carotid artery has provided perhaps the most widely used experimental preparation for the study of the response to acute arterial injury and gave rise to the multiwave model of restenosis. However, simple arterial injury differs substantially from angioplasty to diseased human vessels. The human intimal lesion already contains abundant smooth muscle cells and leukocytes. Therefore, although the rat carotid injury preparation has provided keen insight into the biology of the response to injury, it mimics human restenosis poorly, if at all. The first wave and second wave of the response to arterial injury so well delineated in rats (medial smooth muscle cell proliferation and migration from media into intima) may not apply to clinical angioplasty injury at all. Smooth muscle proliferation, a constant in injury to animal arteries, may be indolent in human restenosis. Accumulation of extracellular matrix probably explains in part the dissociation between intimal thickening and smooth muscle replication. Also, failure to "remodel" outwards to maintain the increased caliber produced by interventional arterial dilatation, may prove more important than intimal thickening in determining ultimate intimal caliber. Despite a rather disappointing decade of translation of laboratory findings to the clinic, some grounds for optimism in approaching the complications of arterial intervention have emerged. Our appreciation for the biological complexities underlying the restenosis problem have increased. In interventional cardiology we can now proceed, more experienced and wiser, to longer range solutions to help our patients based on mechanistic insights.

Angioplasty, Balloon↗
PubMedDate not supplied

Atheromas that cause fatal thrombosis are usually large and frequently accompanied by vessel enlargement.

Several lines of clinical evidence show that AMI frequently occurs at sites with mild to moderate degree of coronary stenosis. The degree of luminal stenosis depends on plaque deposition and degree of vessel remodeling, features poorly assessed by coronary angiography. This postmortem study tested the hypothesis that the size of coronary atheroma and the type of remodeling distinguish culprit lesion responsible for fatal AMI from equi-stenotic nonculprit lesion in the same coronary tree. The main coronary branches from 36 consecutive patients with fatal AMI were studied. The culprit lesion (Group 1) and an equi-stenotic nonculprit segment (Group 2) obtained in measurements of another coronary branch from the same patient were compared. Morphometry and plaque composition was assessed in both groups. Compared to Group 2, Group 1 had larger areas of: plaque 9.6 vs. 4.7 mm(2), vessel 12.7 vs. 7.4 mm(2) and lumen 1.7 vs. 1.2 mm(2); (P< .01). Positive remodeling was more frequent in Group 1 than Group 2: 21/30 (70%) vs. 8/26 (31%). Plaque area correlated positively with lipid core and macrophages and negatively with fibrosis and smooth muscle cells. Atherosclerotic plaques that cause fatal thrombosis are more frequently positively remodeled and tend to be larger than nonculprit plaques with the same degree of cross-sectional stenosis. We tested whether arterial remodeling and plaque size vary between segments containing a fatal thrombosed plaque versus an equi-stenotic nonculprit plaque. Culprit vessel segments had higher cross-sectional areas of intimal plaque and of vessel wall than equi-stenotic nonculprit plaques. The cross-sectional area of the vessel correlated positively with both the lipid core area and CD68(+) macrophage content, and negatively with fibrosis area and smooth muscle cell content. These results add elements explaining limitations of angiography in identifying plaques and provide new insights into the role of remodeling in plaque instability.

Antigens, CD↗
PubMedDate not supplied

Expression of monocyte chemotactic protein and interleukin-8 by cytokine-activated human vascular smooth muscle cells.

The present study was designed to investigate the capacity of human vascular smooth muscle cells (SMCs) to produce a cytokine chemotactic for monocytes (monocyte chemotactic protein [MCP]) and by way of comparison, a related polypeptide activator of neutrophils (known as interleukin-8 [IL-8] or neutrophil activating protein-1 [NAP-1]. On exposure to IL-1, SMCs released high levels of chemotactic activity for monocytes, which could be removed by absorption with anti-MCP antibodies. MCP production by activated SMCs was comparable to that of IL-1-stimulated umbilical vein endothelial cells. Activated SMCs released appreciable levels of IL-8, as determined by a specific enzyme-linked immunosorbent assay, but little chemotactic activity for neutrophils. IL-1-treated SMCs expressed high levels of both MCP and IL-8 mRNA transcripts, as assessed by Northern blot analysis. Tumor necrosis factor and bacterial lipopolysaccharide but not IL-6 also induced MCP and IL-8 gene expression in SMCs. Nuclear runoff analysis revealed that IL-1 augmented transcription of the MCP and IL-8 genes. The capacity of SMCs to produce a cytokine (MCP) that recruits and activates circulating mononuclear phagocytes may be of considerable importance in the pathogenesis of vascular diseases (e.g., vasculitis and atherosclerosis) that are characterized by monocyte infiltration of the vessel wall.

Blotting, Northern↗
PubMedDate not supplied

Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells.

Human atheromas accumulate extracellular matrix proteins such as collagen types I and III. We tested whether cytokines or growth factors produced by cells found in human atherosclerotic plaques alter collagen gene expression in vascular smooth muscle cells (VSMCs), which produce the blood vessel matrix. Interleukin-1 (IL-1, 1-10 ng/ml) modestly increased the synthesis of collagens I and III (measured by tritiated proline incorporation into specific electrophoretic bands), whereas transforming growth factor-beta (TGF-beta) or platelet-derived growth factor (PDGF) markedly stimulated production of these interstitial collagens. Interferon gamma (IFN-gamma), a product of activated T cells found in atheromas, selectively alters several VSMC functions. For example, this cytokine reduces growth of VSMCs, decreases alpha-actin gene expression, and induces VSMC expression of class II histocompatibility antigens. We report here that IFN-gamma also inhibits basal as well as IL-1-, PDGF-, or TGF-beta-stimulated collagen I and III synthesis by human VSMCs. TGF-beta, the most potent stimulator of collagen synthesis studied here, raised the level of collagen III mRNA in VSMCs 4.8-fold (determined by densitometry of Northern blots), whereas exposure to both TGF-beta and IFN-gamma reduced this mRNA to 0.5 of basal level. Locally produced cytokines and growth factors may thus modify matrix accumulation during atherogenesis by stimulating or suppressing expression of interstitial collagen mRNA and protein by VSMCs.

Arteriosclerosis↗
PubMedDate not supplied

Differential effects of human interleukin-1 on growth of human fibroblasts and vascular smooth muscle cells.

Monocyte products probably play a role in the initiation of smooth muscle cell proliferation in the arterial wall early in atherogenesis. Several groups have described mitogenic activity for arterial smooth muscle cells that is elaborated by mononuclear phagocytes (macrophage-derived growth factor). However, the biochemical nature of this mitogenic activity is unknown. Interleukin-1 (IL-1) is a well-characterized monocyte product that activates the growth of mitogen-stimulated lymphocytes and promotes the growth of fibroblasts. We tested whether IL-1 also affects the growth of arterial smooth muscle cells and might account for some of the mitogenic activity produced by activated monocytes. Highly purified human IL-1 did stimulate the growth of human fibroblasts of either adult or fetal origin. However, under identical conditions, IL-1 lacked significant mitogenic effects on human, bovine, rabbit, or canine arterial smooth muscle cells. This mediator also failed to stimulate the growth of cultured human or bovine vascular endothelial cells, another cell type that may respond to macrophage-derived growth factor. Interleukin-1 did not render smooth muscle cells competent to divide in the presence of plasma factors such as insulin (10(-6) M), or when growth of muscle cells was limited by incubation in a low (2%) concentration of serum. This monokine also failed to increase the mitogenic effect of purified platelet-derived growth factor on arterial smooth muscle cells incubated in serum-free medium. Thus, cultured human arterial smooth muscle cells differ from fibroblasts and lymphocytes in their response to human IL-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Regulation of major histocompatibility gene expression in human vascular smooth muscle cells.

Human atheromata, but not normal blood vessels, contain numerous smooth muscle cells (SMC) that bear class II major histocompatibility (MHC) antigens. These lesions also contain leukocytes that can secrete cytokines, which may modulate SMC functions. Because of morphologic evidence for immune-activated (class II+) SMC in vascular lesions, we studied the regulation by cytokines of MHC gene expression in SMC cultured from human vessels. Under basal conditions, these SMC contained mRNA for class I MHC (detected by Northern blotting with a cDNA probe for HLA-B7) and expressed surface class I MHC product determined by enzyme-linked immunoassay with monoclonal antibody (MAb) W6/32. Unstimulated SMC contained little or no class II MHC mRNA (probed with HLA-DR alpha cDNA) or surface antigen (examined using MAb I2). Secretory products of activated human leukocytes (the cell-free supernatant of a mixed leukocyte reaction) induced class II MHC antigen expression by SMC after 3 days. Treatment of SMC with interferon (IFN)-alpha or -beta (1000 U/ml for 72 hours) increased class I MHC mRNA content and surface antigen but did not alter class II expression. Immune IFN (IFN-gamma), a leukocyte product known to induce class II MHC expression in classical antigen presenting cells as well as epithelial and endothelial cells, not only increased class I MHC expression by SMC but also induced substantial levels of class II MHC mRNA and surface antigen. IFN-gamma (ED50 approximately 10 U/ml) increased class II MHC mRNA maximally after 2 to 3 days and surface expression linearly from 1 to 4 days. Immunohistochemical study demonstrated few class II+ SMC in cultured human SMC under basal conditions but homogeneous expression of high levels of DR antigen after exposure to IFN-gamma for 3 days. Neither interleukin-1 (IL-1 alpha or beta), tumor necrosis factor alpha (TNF), nor endotoxin altered class II expression by SMC. Local secretion of IFN-gamma by activated leukocytes may account for the presence of HLA-DR+ SMC in the human atheroma. Immune activation of SMC might participate in the pathogenesis of vasculitis and arteriosclerosis, particularly in the form found in the coronary arteries of transplanted hearts.

Antigens, Surface↗
PubMedDate not supplied

Death of smooth muscle cells and expression of mediators of apoptosis by T lymphocytes in human abdominal aortic aneurysms.

BACKGROUND: Thinning of the tunica media and rarefaction of smooth muscle cells (SMCs) characterize aneurysmal aortas. Apoptosis determines the cellularity and morphogenesis of tissue. Macrophages and T lymphocytes infiltrate the wall of abdominal aortic aneurysms (AAAs) and produce death-promoting proteins (perforin, Fas, and FasL). This study investigated whether apoptosis occurs in association with the expression of these proteins. METHODS AND RESULTS: We examined signs of apoptosis and expression of death-promoting mediators in segments of AAAs from patients undergoing elective repair (n=20). Anti-alpha-actin immunostaining showed a reduced number of SMCs in AAAs. In situ terminal transferase-mediated dUTP nick end-labeling (TUNEL) showed higher levels of DNA fragmentation in AAAs than in controls (n=5). The AAA walls contained more cells bearing markers of apoptosis than normal aorta (P<0.05, Student's t test). Double immunostaining identified SMCs and macrophages as the principal cell types displaying fragmented DNA. Immunohistochemistry revealed that AAAs but not normal aorta contained CD4(+) and CD8(+) T cells that expressed well-characterized cytotoxic mediators: perforin, which produces membrane damage, and Fas, which acts by ligand-receptor interaction. Double immunostaining also identified SMCs that expressed Fas. Immunoblotting confirmed the presence and, in the case of Fas, activation of these proteins in aneurysmal tissue. CONCLUSIONS: Many medial SMCs in AAAs bear markers of apoptosis and signals capable of initiating cell death. Apoptotic death may contribute to the reduction of cellularity and to the impaired repair and maintenance of the arterial extracellular matrix in AAAs. Macrophages and T lymphocytes infiltrate the wall of AAAs, where they can produce cytotoxic mediators such as cytokines, perforin, and Fas/FasL. These death-promoting products of activated immune cells may contribute to elimination of SMCs, a source of elastin and collagen, during the pathogenesis of AAAs.

Aged↗
PubMedDate not supplied

Transcriptional profile of mechanically induced genes in human vascular smooth muscle cells.

Vascular smooth muscle cells must monitor and respond to their mechanical environment; however, the molecular response of these cells to mechanical stimuli remains incompletely defined. By applying a highly uniform biaxial cyclic strain to cultured cells, we used DNA microarray technology to describe the transcriptional profile of mechanically induced genes in human aortic smooth muscle cells. We first identified vascular endothelial growth factor (VEGF) as a mechanically induced gene in these cells; VEGF served as a positive control for these experiments. We then used a DNA microarray with 5000 genes with putative functions to identify additional mechanically induced genes. Surprisingly, relatively few genes are mechanically induced in human aortic smooth muscle cells. Only 3 transcripts of 5000 were induced >2.5-fold: cyclooxygenase-1, tenascin-C, and plasminogen activator inhibitor-1. Downregulated transcripts included matrix metalloproteinase-1 and thrombomodulin. The transcriptional profile of mechanically induced genes in human aortic smooth muscle cells suggests a response of defense against excessive deformation. These data also demonstrate that in addition to identifying large clusters of genes that respond to a given stimulus, DNA microarray technology may be used to identify a small subset of genes that comprise a highly specific molecular response.

Cells, Cultured↗
PubMedDate not supplied

Potential infectious etiologies of atherosclerosis: a multifactorial perspective.

Coronary heart disease (CHD) contributes substantially to illness and death worldwide. Experimental studies demonstrate that infection can stimulate atherogenic processes. This review presents a spectrum of data regarding the link between CHD and infection. In addition, the need for improved diagnostic tools, the significance of multiple pathogens, and potential intervention strategies are discussed.

Animals↗