Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The low density lipoprotein (LDL) receptor is a cell surface transmembrane protein that mediates the uptake and lysosomal degradation of plasma LDL, thereby providing cholesterol to cells. Mutations disrupting the function of this receptor produce autosomal dominant familial hypercholesterolemia (FH). Affected individuals have elevated plasma levels of LDL, which causes premature coronary atherosclerosis. To date, 71 mutations in the LDL receptor gene have been characterized at a molecular level. In this report, we describe 79 additional mutations and review the insights that all 150 mutations have provided into the structure/function relationship of the receptor protein and the clinical manifestations of FH.
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PMID:Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. 130 56

The localization of proteases to cell surfaces via receptors may facilitate cell migration, invasion, and matrix degradation. Since vascular smooth muscle cell (SMC) migration may be an important event in atherosclerosis and in intimal thickening after vascular injury, we studied the cell surface expression of a receptor for urokinase-type plasminogen activator (u-PAR) in cultured human vascular SMC. Using immunofluorescence microscopy, we demonstrated several staining patterns of SMC u-PAR: at the periphery of the cell membrane, at the leading edge, and at cell-cell contact sites. When migration experiments were performed using a wound assay, one-third of the SMC at the wound edge demonstrated polarization of cell surface u-PAR toward the leading edge of the cell membrane (32 +/- 2%, +/- SEM, n = 7). A similar pattern was seen with an antibody to caveolin, a transmembrane protein found in caveolae, but not with an antibody to 5'-nucleotidase, another cell surface glycophosphatidylinositol-anchored protein, which was homogeneously expressed on the cell surface. Low-density lipoprotein receptor-related protein, which mediates internalization of u-PAR bound ligands, was distributed in a diffuse punctate pattern, not polarized to the leading edge. Double immunofluorescent studies demonstrated codistribution of SMC u-PAR with vinculin and caveolin in migrating SMC at the leading edge in a wound assay. Polarization of cell surface u-PAR was not observed in either nonwounded or subconfluent cultures, despite random migratory behavior. These studies suggest that in response to wounding, human vascular SMC polarize and concentrate cell surface u-PAR to their leading edge, perhaps facilitating directional migration.
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PMID:Migrating vascular smooth muscle cells polarize cell surface urokinase receptors after injury in vitro. 786 16

Tissue factor (TF) is a transmembrane protein that serves as the major initiator of the blood coagulation cascade. The overexpression of TF antigen and mRNA has previously been reported in advanced atherosclerotic lesions. Recently TF procoagulant activity has also been identified in these lesions. However, localization and activity of TF in various stages of atherosclerosis have not yet been reported. We studied TF localization and its activity in three stages of the human atherosclerotic lesions (diffuse intimal thickening, fatty streak, and atheromatous plaque). The thoracic aortas were obtained from 23 autopsy cases and were examined immunohistochemically using an anti-human TF polyclonal antibody and biotinylated factor VIIa (FVIIa) as a probe to test the FVIIa-binding ability of TF. In addition, the TF-mediated activation of factor X (FX) was quantitatively assessed using a chromogenic assay. In lesions of the diffuse intimal thickening and the fatty streak, almost all of intimal smooth muscle cells (SMCs), macrophages, and endothelial cells were positive for TF. In the atheromatous plaques, TF antigen was detected extensively in the extracellular matrix as well as in the intimal cells. TF in all stages of atherosclerotic lesions had the ability to bind biotinylated FVIIa. TF activity was detected in each lesion and was more prominent in fatty streaks and atheromatous plaques than in the diffuse intimal thickening. These results indicate that active TF is expressed in the early stage of atherosclerotic lesions as well as in the advanced stage, and it contributes to the thrombotic property of human atherosclerotic lesions.
Atherosclerosis 1997 Sep
PMID:Localization and activity of tissue factor in human aortic atherosclerotic lesions. 929 81

CD40 ligand, a type II transmembrane protein recently renamed CD154, was originally considered restricted to activated T lymphocytes, functioning as a mediator of T cell-dependent B cell activation, proliferation, and differentiation. However, the spectrum of CD154 expression and function has broadened considerably during recent years, establishing new roles as a central mediator of immunity and inflammation for this member of the tumor necrosis factor (TNF) gene superfamily. The emerging picture indicates that ligation of the receptor CD40 via CD154, most potently in its trimeric form, functions in two ways. CD154 modulates physiologic processes, such as T cell-mediated effector functions and general immune responses required for appropriate host defense, but also triggers the expression of pro-inflammatory mediators, such as cytokines, adhesion molecules, and matrix degrading activities, all of which are associated with the pathogenesis of chronic inflammatory diseases, e.g., autoimmune disorders, arthritis, atherosclerosis, and cancer. 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.
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PMID:CD154 (CD40 ligand). 1085 99

Endoglin is a transmembrane protein that is found in association with transforming growth factor-beta (TGF-beta) superfamily receptor complexes and has an expression pattern that appears to be restricted primarily to endothelial cells, activated macrophages, trophoblasts, and fibroblasts. Since mutations in endoglin have been shown to be linked to hereditary hemorrhagic telangiectasia type 1, a disease manifested as vascular malformations characterized by excessive layers of vascular smooth muscle cells (VSMC), the expression of endoglin was investigated in VSMC. In vivo, the majority of SMC in human atherosclerotic plaques expressed high levels of endoglin, while endoglin was not detected in SMC from samples of the normal arterial wall. In vitro studies demonstrate that human aortic smooth muscle cells (HASMC) express the L-isoform of endoglin. Like endothelial cells, HASMC express endoglin protein as a dimer on the cell surface that binds TGF-beta1. In vitro, endoglin expression by HASMC is upregulated in response to TGF-beta1, suggesting that the presence of this factor in the atherosclerotic plaque might be responsible for the increased expression of endoglin. The demonstration of increased levels of endoglin in VSMC in human atherosclerotic plaques suggests a role for SMC endoglin in the maintenance of vascular integrity and in the response of the vessel wall to injury.
Atherosclerosis 2000 Dec
PMID:Endoglin, a TGF-beta receptor-associated protein, is expressed by smooth muscle cells in human atherosclerotic plaques. 1116 21

Murine macrosialin (MS), a scavenger receptor family member, is a heavily glycosylated transmembrane protein expressed predominantly in macrophage late endosomes. MS is also found on the cell surface where it is suggested, on the basis of ligand blotting, to bind oxidized LDL (oxLDL). Here we report on the regulation of MS by an atherogenic high-fat diet and oxLDL, and on the inability of MS in transfected cells to bind oxLDL. MS expression was markedly increased in the livers of atherosclerosis-susceptible C57BL/6 and atherosclerosis-resistant C3H/HeJ mice fed an atherogenic high-fat diet. In resident-mouse peritoneal macrophages, treatment with oxLDL upregulated MS mRNA and protein expression 1.5- to 3-fold. MS, overexpressed in COS-7 cells through adenovirus mediated gene transfer, bound oxLDL by ligand blotting. However, no binding of oxLDL to MS was observed in intact transfected COS-7 and Chinese hamster ovary cells, despite significant cell surface expression of MS. Furthermore, inhibition of MS through gene silencing did not affect the binding of oxLDL to macrophages. We conclude that although MS expression in macrophages and Kupffer cells is responsive to a proatherogenic inflammatory diet and to oxLDL, MS does not function as an oxLDL receptor on the cell surface.
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PMID:Lack of a direct role for macrosialin in oxidized LDL metabolism. 1256 41

For three decades, low-density lipoprotein (LDL) dominated research into cholesterol metabolism and atherosclerosis, whereas scant attention was paid to high-density lipoprotein (HDL), an equally important risk factor for cardiovascular disease. This low interest reflected the lack of knowledge about physiological HDL receptors. As a result, our understanding of HDL-cell interactions failed to develop alongside that of LDL, and mechanisms through which atheroprotective HDL promoted clearance of cholesterol from peripheral cells remained poorly-defined. Interest was kindled with the recognition that scavenger receptor class B, type I is the cell-surface protein in hepatocytes and steroidogenic tissues which selectively extracts cholesteryl esters from HDL. Greater impetus still was given by the discovery that mutations in the gene encoding the ATP-binding cassette transporter, class A1 (ABCA1) are the cause of Tangier disease, a rare recessive disorder with near-absent plasma HDL. The ABCA1 transmembrane protein is crucial for efficient efflux of cellular cholesterol and HDL maturation and has emerged as a promising therapeutic target for cardiovascular disease. The hope is that new drugs, regulating ABCA1 activity and HDL homeostasis, will accelerate cholesterol efflux from lipid-laden foam cells and thus promote regression of atherosclerotic lesions.
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PMID:ATP-binding cassette A1 protein and HDL homeostasis. 1257 59

The tumor necrosis factor (TNF) superfamily member TNF-like weak inducer of apoptosis (TWEAK) was initially described in a 1997 publication co-authored by investigators from the biotechnology company Biogen (now Biogen-Idec) and the University of Geneva. Four years later, researchers at the biotechnology company Immunex (now part of Amgen) reported the cloning and characterization of the human TWEAK receptor. A sequence database search revealed that the predicted TWEAK receptor amino acid sequence was identical to that of fibroblast growth factor-inducible 14 (Fn14), a small transmembrane protein described one year earlier in a publication from investigators at the American Red Cross Holland Laboratory. Recent studies have revealed that the TWEAK-Fn14 ligand-receptor pair likely plays an important role in a variety of cellular processes and in the pathogenesis of several human diseases, including atherosclerosis, stroke, rheumatoid arthritis and cancer. In this paper, we first summarize the general properties of these two proteins and then review the available data implicating TWEAK and Fn14 in multiple aspects of tumor biology.
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PMID:Role of TWEAK and Fn14 in tumor biology. 1712 78

Under usual conditions, the role of IGF-I in vascular cell types is to maintain cellular protein synthesis and cell size, and even excess IGF-I does not stimulate proliferation. In pathophysiologic states, such as hyperglycemia, smooth muscle cells (SMC) dedifferentiate and change their responsiveness to IGF-I. During hyperglycemia IGF-I stimulates both SMC migration and proliferation. Our laboratory has investigated the molecular mechanism by which this change is mediated. During hyperglycemia SMC secrete increased concentrations of thrombospondin, vitronectin and osteopontin, ligands for the integrin alphaVbeta3. Activation of alphaVbeta3 stimulates recruitment of a tyrosine phosphatase, SHP-2. Exposure of SMC to IGF-I results in phosphorylation of the transmembrane protein, SHPS-1, which provides a docking site for alphaVbeta3-associated SHP-2. After IGF-I stimulation SHP-2 associates with Src kinase, which associates with the signaling protein Shc. Src phosphorylates Shc, resulting in activation of MAP kinases, which are necessary both for stimulation of cell proliferation and migration. Blocking activation of alphaVbeta3 results in an inability of IGF-I to stimulate Shc phosphorylation. Under conditions of normoglycemia, there are insufficient alphaVbeta3 ligands to recruit SHP-2, and no increase in Shc phosphorylation can be demonstrated in SMC. In contrast, if alphaVbeta3 ligands are added to cells in normal glucose, the signaling events that are necessary for Shc phosphorylation can be reconstituted. Therefore when SMC are exposed to normal glucose they are protected from excessive stimulation of mitogenesis by IGF-I. With hyperglycemia there is a marked increased in alphaVbeta3 ligands and Shc phosphorylation in response to IGF-I is sustained. These findings indicate that in SMC hyperglycemic stress leads to altered IGF-I signaling, which allows the cells to undergo a mitogenic response, and which may contribute to the development of atherosclerosis.
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PMID:Role of the integrin alphaVbeta3 in mediating increased smooth muscle cell responsiveness to IGF-I in response to hyperglycemic stress. 1741 27

Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis and obesity. A well-known cause is the deficiency of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride hydrolysis. Mice carrying the combined lipase deficiency (cld) mutation show severe hypertriglyceridemia owing to a decrease in the activity of LPL and a related enzyme, hepatic lipase (HL), caused by impaired maturation of nascent LPL and hepatic lipase polypeptides in the endoplasmic reticulum (ER). Here we identify the gene containing the cld mutation as Tmem112 and rename it Lmf1 (Lipase maturation factor 1). Lmf1 encodes a transmembrane protein with an evolutionarily conserved domain of unknown function that localizes to the ER. A human subject homozygous for a deleterious mutation in LMF1 also shows combined lipase deficiency with concomitant hypertriglyceridemia and associated disorders. Thus, through its profound effect on lipase activity, LMF1 emerges as an important candidate gene in hypertriglyceridemia.
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PMID:Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia. 1804 26


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