UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelins (ETs) are 21-amino-acid peptides produced in many cells and tissues. The vascular ET system is represented mainly by ET-1 produced in endothelial cells. PreproET-1 gene expression is regulated by transactivating signals dependent on cooperative interaction of GATA-2 and AP-1 sites. ProET-1 is acted on by a furin-like enzyme to generate big ET-1, a 38-39-amino-acid peptide, which is converted to the mature 21-amino-acid peptide ET-1 by ET-converting enzyme (ECE) in endothelial cells, both intracellularly and on the cell membrane, and on the surface of underlying smooth muscle cells. The mature peptide ET-1 acts in a paracrine manner on smooth muscle cell ET(A) and ET(B) receptors to induce contraction and growth, and in an autocrine or paracrine manner on endothelial cells to induce production of the vasorelaxant and growth-inhibitory agents nitric oxide (NO) and prostacyclin. ET receptors are G-protein-coupled, resulting in activation of phospholipase C and generation of two second messengers, inositol triphosphate and diacylglycerol, which respectively stimulate calcium release and protein kinase C activation. Phospholipase D activation with generation of diacylglycerol, phospholipase A2 stimulation with release of arachidonic acid, activation of the Na+/H+ exchanger, and activation of tyrosine kinases and MAP kinases, are other pathways that contribute to contraction and growth induced by ET receptor stimulation. ET receptors may be downregulated by ET, especially under conditions in which large amounts of ET are being produced in the vasculature. This has been demonstrated in some models of experimental hypertension and in some forms of human hypertension. Some of the effects of angiotensin II, particularly growth of the smooth muscle media of blood vessels, have been shown under some conditions to be mediated by ET-1 via ET(A) receptors. Many ET-induced effects on smooth muscle cells can be blocked by ET(A)-selective ET antagonists, which makes possible an identification of the physiologic and pathophysiologic roles of the ET system in cardiovascular diseases such as hypertension, heart failure, atherosclerosis, coronary heart disease, restenosis after angioplasty, primary pulmonary hypertension, and other pathologic conditions.
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PMID:Vascular biology of endothelin. 988 41

Inorganic phosphate (Pi) is required for cellular function and skeletal mineralization. Serum Pi level is maintained within a narrow range through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, and renal tubular reabsorption. The crucial regulated step in Pi homeostasis is the transport of Pi across the renal proximal tubule. Type II sodium-dependent phosphate (Na/Pi) cotransporter (NPT2) is the major molecule in the renal proximal tubule and is regulated by Pi, parathyroid hormone and by 1,25-dihydroxyvitamin D. Recent studies of inherited and acquired hypophosphatemia [X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced rickets/osteomalacia (TIO)], which exhibit similar biochemical and clinical features, have led to the identification of novel genes, PHEX and FGF23, that play a role in the regulation of Pi homeostasis. The PHEX gene, which is mutated in XLH, encodes an endopeptidase, predominantly expressed in bone and teeth, but not in kidney. FGF-23 may be a substrate of this endopeptidase and may therefore accumulate in patients with XLH. In the case of ADHR mutations in the furin cleavage site, which prevent the processing of FGF-23 into fragments, lead to the accumulation of a "stable" circulating form of the peptide which also inhibits renal Pi reabsorption. In the case of TIO, ectopic overproduction of FGF-23 overwhelms its processing and degradation by PHEX, leading to the accumulation of FGF-23 in the circulation and inhibition of renal Pi reabsorption. Mice homozygous for severely hypomorphic alleles of the Klotho gene exhibit a syndrome resembling human aging, including atherosclerosis, osteoporosis, emphysema, and infertility. The KLOTHO locus is associated with human survival, defined as postnatal life expectancy, and longevity, defined as life expectancy after 75. In considering the relationship of klotho expression to the dietary Pi level, the klotho protein seemed to be negatively controlled by dietary Pi.
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PMID:Inorganic phosphate homeostasis and the role of dietary phosphorus. 1525 67

Integrins are heterodimeric alpha/beta receptors that link the cytoskeleton with the extracellular matrix, thereby regulating several cell functions important in atherosclerosis. In vitro, the subtilisin/kexin-like proprotein convertases (PCs), namely PC5 and furin, have been shown to be responsible for the endoproteolytic activation of the alpha(v) integrin subunit. Based on their cleavage activity, these PCs are potential targets in atherosclerosis. In the present study, we investigated the localization of furin and PC5 in different stages of human atherosclerosis. Immunohistochemical analysis of furin and PC5 revealed their presence in vascular smooth-muscle cells and endothelial cells in atherosclerotic and non-atherosclerotic lesions. However, in the more advanced lesions, furin and PC5 staining was significantly expressed in macrophages/foam cells. In vitro, THP-1 derived macrophages contained furin and PC5, and maturation of monocytes to macrophages was accompanied by enhanced alpha(v)beta3 cell-surface expression. Inhibition of furin/PC5 with the specific pharmacological furin-like PC-inhibitor dec-CMK inhibited alpha(v) endoproteolytic activation but did not abolish alpha(v)beta3 cell-surface expression. This indicates that furin/PC5 is required for alpha(v) endoproteolytic activation but not for alpha(v) routing and sorting to the cell surface. In conclusion, our study demonstrates that furin and PC5 are significantly expressed in mononuclear cells in advanced human atherosclerotic lesions, where they regulate alpha(v) endoproteolytic activation.
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PMID:Immunohistochemical localization of subtilisin/kexin-like proprotein convertases in human atherosclerosis. 1575 93

Platelet-derived growth factor-B (PDGF-B) is important for normal tissue growth and maintenance and its overexpression has been linked to several diseases, including cancer, fibrotic disease and atherosclerosis. Here, we show that synthesized as a precursor, proPDGF-B is converted to a mature form by proteolytic cleavage at two sites and its N-terminal cleavage is a prerequisite for processing at its C-terminus. The first cleavage occurs at residues RGRR81/, and the second cleavage close to residues ARPVT190, just before the C-terminal amino-acid sequence crucial for PDGF-B retention to cell surface. Cotransfection of a Furin-deficient cell line LoVo-C5 with proPDGF-B and different PC members revealed that Furin, PACE4, PC5, and PC7 are candidate proPDGF-B convertases. This finding is consistent with the in vitro digestions of a synthetic peptide mimicking the cleavage site of proPDGF-B. The processing of proPDGF-B is blocked by site-directed mutagenesis of the RGRR81/ sequence and by various PC inhibitors. Mutation of the PDGF-A and/or PDGF-B convertase sites, revealed that processing of both A and B chains is required for the formation of mature PDGF-B dimers and that the processing of the B chain controls the level of secreted and matrix-bound PDGF-BB forms. Our findings emphasize the importance of the convertase-directed processing of proPDGF-B at the RGRR81/ sequence for PDGF-B maturation and secretion.
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PMID:Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases. 1600 51

Several growth factors, chemokines, adhesion molecules, and proteolytic enzymes important for cell-cell/cell-matrix interactions in atherosclerosis and restenosis are initially synthesized as inactive precursor proteins. Activation of proproteins to biologically active molecules is regulated by limited endoproteolytic cleavage at dibasic amino acid residues. This type of activation typically requires the presence of suitable proprotein convertases (PCs). The PC-isozymes furin and PC5 are expressed in human atherosclerotic lesions and have been found to be up-regulated, following vascular injury in animal models in vivo. In vitro, these PCs can regulate vascular smooth muscle cell and macrophage functions and signaling events, through activation of pro-alpha-integrins and/or pro-membrane-type matrix metalloproteinases. Integrins link the cytoskeleton with the extracellular matrix and mediate bidirectional signaling and mechanotransduction, whereas matrix metalloproteinases are the major matrix-degrading enzymes. Both activities are required for cell recruitment to the intima. Furthermore, cleavage of extracellular matrix molecules by matrix metalloproteinases potentially contributes to weakening of the fibrous cap, promoting plaque rupture. Based on these recent in vitro and in vivo data, furin and PC5 are potential contributors to the initiation, progression, and complications of atherosclerosis and restenosis. Targeting these PCs may provide future anti-atherosclerotic therapies.
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PMID:Proprotein convertases furin and PC5: targeting atherosclerosis and restenosis at multiple levels. 1624 76

The physiological role of the subtilisin/kexin-like proprotein convertases (PCs) in rodents has been examined through the use of knockout mice. This review will summarize the major in vivo defects that result from the disruption of the expression of their genes. This includes abnormal embryonic development, hormonal disorder, infertility, and/or modified lipid/sterol metabolism. Members of the PC family play a central role in the processing of various protein precursors ranging from hormones and growth factors to bacterial toxins and viral glycoproteins. Proteolysis occurring at basic residues is mediated by the basic amino acid-specific proprotein convertases, namely: PC1/3, PC2, furin, PACE4, PC4, PC5/6, and PC7. In contrast, proteolysis at nonbasic residues is performed by the subtilisin/kexin-like isozyme-1 (SKI-1/S1P) and the newly identified neural apoptosis-regulated convertase-1 (PCSK9/NARC-1). In addition to their requirement for many physiological processes, these enzymes are also involved in various pathologies such as cancer, obesity, diabetes, lipid disorders, infectious diseases, atherosclerosis and neurodegenerative diseases.
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PMID:Proprotein convertases: lessons from knockouts. 1701 47

Familial hypercholesterolemia (FH) is characterized by raised serum LDL cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease. FH results from defects in the hepatic uptake and degradation of LDL via the LDL-receptor pathway, commonly caused by a loss-of-function mutation in the LDL-receptor gene (LDLR) or by a mutation in the gene encoding apolipoprotein B (APOB). FH is primarily an autosomal dominant disorder with a gene-dosage effect. An autosomal recessive form of FH caused by loss-of-function mutations in LDLRAP1, which encodes a protein required for clathrin-mediated internalization of the LDL receptor by liver cells, has also been documented. The most recent addition to the database of genes in which defects cause FH is one encoding a member of the proprotein convertase family, PCSK9. Rare dominant gain-of-function mutations in PCSK9 cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype. Expression of PCSK9 normally downregulates the LDL-receptor pathway by indirectly causing degradation of LDL-receptor protein, and loss-of-function mutations in PCSK9 result in low plasma LDL levels. Thus, PCSK9 is an attractive target for new drugs aimed at lowering serum LDL cholesterol, which should have additive lipid-lowering effects to the statins currently used.
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PMID:Mechanisms of disease: genetic causes of familial hypercholesterolemia. 1738 Jan 67

Primary hypobetalipoproteinemia (HBL) includes a group of genetic disorders: abetalipoproteinemia (ABL) and chylomicron retention disease (CRD), with a recessive transmission, and familial hypobetalipoproteinemia (FHBL) with a co-dominant transmission. ABL and CRD are rare disorders due to mutations in the MTP and SARA2 genes, respectively. Heterozygous FHBL is much more frequent. FHBL subjects often have fatty liver and, less frequently, intestinal fat malabsorption. FHBL may be linked or not to the APOB gene. Most mutations in APOB gene cause the formation of truncated forms of apoB which may or may be not secreted into the plasma. Truncated apoBs with a size below that of apoB-30 are not detectable in plasma; they are more frequent in patients with the most severe phenotype. Only a single amino acid substitution (R463W) has been reported as the cause of FHBL. Approximately 50% of FHBL subjects are carriers of pathogenic mutations in APOB gene; therefore, a large proportion of FHBL subjects have no apoB gene mutations or are carriers of rare amino acid substitutions in apoB with unknown effect. In some kindred FHBL is linked to a locus on chromosome 3 (3p21) but the candidate gene is unknown. Recently a FHBL plasma lipid phenotype was observed in carriers of mutations of the PCSK9 gene causing loss of function of the encoded protein, a proprotein convertase which regulates LDL-receptor number in the liver. Inactivation of this enzyme is associated with an increased LDL uptake and hypobetalipoproteinemia. HBL carriers of PCSK9 mutations do not develop fatty liver disease.
Atherosclerosis 2007 Dec
PMID:Molecular diagnosis of hypobetalipoproteinemia: an ENID review. 2718 Jun 45

Major reproductive events such as menstruation, ovulation, implantation, and cervical ripening are characterized by an increased number of invading leukocytes in the tissues. Sex steroid hormones, particularly estrogens, play an important role in these dynamic changes in the female reproductive tract. Estrogens have also been implicated in the pathogenesis of many common pathological conditions associated with leukocyte infiltration and immunological dysfunction, such as auto-immune diseases and atherosclerosis. Although the two estrogen receptor (ER) subtypes, ERalpha and ERbeta, have been found in different leukocyte populations in tissues and in peripheral blood, there is still very little known about functional activity and importance of ERs in blood cells. To elucidate the different roles for ERalpha and ERbeta in peripheral blood leukocytes, we used microarray gene expression profiling of rat peripheral blood leukocytes subjected to in vivo treatment with estradiol (E2), the selective ERalpha agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), and the selective ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN). We report the identification of genes that were commonly regulated by E2, PPT, and DPN, and genes that were regulated either by the ERalpha or ERbeta agonist. Further confirmatory analyses of the selected regulated genes 12-lipoxygenase, fibulin-1, furin, and calgranulin B are also presented. These results were then compared with those from the uterine tissue of the same animals. Our study demonstrates that peripheral blood leukocytes are responsive to estrogens. E2 and selective ERalpha and ERbeta agonists regulate a number of genes that may contribute to inflammation and remodeling of the extracellular matrix.
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PMID:Studies on estrogen receptor (ER) alpha and beta responses on gene regulation in peripheral blood leukocytes in vivo using selective ER agonists. 1759 25

Familial hypercholesterolaemia (FH), defined as the heritable occurrence of severe hypercholesterolaemia with cholesterol deposits in tendons and premature heart disease, is caused by at least four genes in sterol and lipoprotein pathways and displays varying gene-dose effects. The genes are the low-density lipoprotein (LDL) receptor, apolipoprotein (apo) B, proprotein convertase subtilisin/kexin 9, and the autosomal recessive hypercholesterolaemia (ARH) adaptor protein. All of these disorders have in common defective clearance of LDL within a complex system of lipid and lipoprotein metabolism and regulation. Normal cellular cholesterol and lipoprotein metabolism is reviewed before describing the disorders, their metabolic derangements and their clinical effects. FH is classified as two simplified phenotypes of disease according to the severity of the metabolic derangement. The dominantly inherited heterozygous phenotype comprises defects in the LDL receptor, apoB100, and neural apoptosis regulatory cleavage protein. The homozygous phenotype is co-dominant in defects of the LDL receptor, and occurs also as the ARH of adapter protein mutations. Defective binding of apoB100 does not result in a significant gene dose effect, but enhances the severity of heterozygotes for LDL receptor mutations. The genetic diagnosis of FH has provided greater accuracy in definition and detection of disease and exposes information about migration of populations. All of these disorders pose a high risk of atherosclerosis, especially in the homozygous phenotype. Studies of influences on the phenotype and responses to treatment are also discussed in the context of the metabolic derangements.
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PMID:Familial hypercholesterolaemia. 1851 3

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