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)

Cultured mouse peritoneal macrophages secrete a growth-promoting activity that stimulates 3 types of nonlymphoid mesenchymal cells in vitro: fibroblasts, vascular smooth muscle, and vascular endothelium. Production of this macrophage-derived growth factor (MDGF) is directly related to the number of viable macrophages and their time in culture, and is independent of platelet- or plasma-derived serum growth factors. Treatment of cultured macrophages with latex, bacterial lipopolysaccharide, or phorbol myristate acetate results in increased growth factor activity. Preliminary biochemical characterization of MDGF indicates that it is a heat labile (100 degrees C, 2 min), non-dialyzable protein, which contains at least 1 essential disulfide bond. Growth-promoting activity is not adsorbed by CM-Sephadex chromatography, under conditions that effectively remove platelet-derived growth factor(s). Serine protease activity is not required for the action of MDGF. Secretion of macrophage-derived growth factor may be relevant to the function of mononuclear phagocytes in several pathologic processes, including the neovascularization and fibroplasia of wound healing, smooth muscle hyperplasia in atherosclerosis, and proliferative glomerulonephritis.
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PMID:Stimulation of nonlymphoid mesenchymal cell proliferation by a macrophage-derived growth factor. 720 74

Familial hypercholesterolemia (FH) has a higher prevalence in central Tunisia together with a milder clinical expression than in western countries. The molecular basis of FH in Tunisia remains unknown. Our aim was to identify FH-causing mutations in three unrelated families (21 subjects) from the area of Souassi (central Tunisia). In probands with a presentation of homozygous FH, the promoter and 18 exons of the low density lipoprotein (LDL)-receptor gene were sequenced in both orientations. A novel complex frameshift mutation was identified in exon 10, nucleotides 1477-1479 (TCT) at Serine 472 were replaced by an insertion of seven nucleotides (AGAGACA), producing a premature termination codon 43 amino acids downstream. Binding of 125I-labelled LDL at 4 degrees C to cultured fibroblasts from two probands showed <2% normal LDL-receptor activity. AvaII digestion of PCR amplified genomic DNA identified this unique mutation in all families; homozygotes n=11, heterozygotes n=10. All mutation carriers shared the same haplotype (7 RFLPs), suggesting that they had a common ancestor. Despite high plasma LDL levels (m=16.0+/-3.0 mmol/l) and extravascular cholesterol deposits, most homozygotes were diagnosed after puberty and had a delayed onset of cardiovascular complications. Moreover, most heterozygotes were free of clinical signs and had plasma LDL cholesterol in the normal range (4.7+/-1.3 mmol/l) without taking any lipid-lowering medication. This mild clinical phenotype which contrasted with the severity of the mutation, could not be explained by specific apolipoprotein E or lipoprotein lipase alleles.
Atherosclerosis 2001 Feb 15
PMID:Fh-Souassi: a founder frameshift mutation in exon 10 of the LDL-receptor gene, associated with a mild phenotype in Tunisian families. 1125 56

The effects of the lipoprotein lipase (LPL) Serine 447 Stop (S447X) polymorphism on high-density lipoprotein cholesterol (HDLC) and triglycerides (TG) have been demonstrated. However, little is known about its effect on the tracking of HDLC and TG over time and familial risk of coronary artery disease (CAD). This aspect was examined in black and white individuals (n=829) aged 5-18 year at baseline, followed on average 18.8 yr. The frequency of the X447 allele was lower in Blacks than Whites (0.043 vs. 0.087, P=0.002). Carriers vs. noncarriers of the X447 allele had lower TG (99.3 vs 122.1 mg/dl, P<0.01) and higher HDLC (51.1 vs. 49.7 mg/dl, P<0.05) in adulthood, but not in childhood. The trends in genotype-specific means of childhood and adulthood levels of HDLC and TG in sex or race subgroups were similar to those in the total sample. With respect to tracking over time, of those in the bottom quartile of HDLC in childhood, 46.1% of the noncarriers vs. 23.1% of the carriers remained in this lowest quartile into adulthood (P=0.03); corresponding values for the top quartile of HDLC were 37.5% for the noncarriers vs. 57.1% for the carriers (P=0.03). Although TG tended to track better among the carriers in the bottom quartile and among the noncarriers in the top quartile, this trend was not significant. Carriers showed lower prevalence of parental history of CAD than noncarriers (6.9% vs. 14.1%, P=0.02) independently of lipoprotein variables, adiposity, blood pressure, age, sex and race. Thus, the X447 allele of the LPL gene is associated with an increase in HDLC and a decrease in TG in adults, tracking of HDLC since childhood, and a lower family history of CAD.
Atherosclerosis 2001 Dec
PMID:Influence of lipoprotein lipase serine 447 stop polymorphism on tracking of triglycerides and HDL cholesterol from childhood to adulthood and familial risk of coronary artery disease: the Bogalusa heart study. 1173 Aug 16

Nitric oxide (NO) induced by bacterial lipopolysaccharide (LPS) plays a critical role in various patho-physiological implications, such as atherosclerosis, vasculitis and septic shock. In addition, cAMP-responsive element binding protein (CREB), an important transcription factor for cell differentiation, has been shown to be involved in atherosclerogenesis in VSMCs. Here we investigated the possibility whether LPS-induced NO signaling led to phosphorylation of cAMP-responsive element binding protein on Serine-133 (CREBSer-133) in cultured vascular smooth muscle cells (VSMCs) from rats. Addition of LPS (1-10 microg/ml) for 48 hours increased not only the production NO, but also the phosphorylation of CREBSer-133. The use of NOS inhibitor (100-500 microM L-NAME) blocked the magnitudes of both LPS-induced NO production and CREBSer-133 phosphorylation. In addition, either a guanylyl cyclase (GC) inhibitor (30 microM ODQ) or a cGMP-dependent protein kinase (PKG) inhibitor (20 microM (Rp)-8-pCPT-cGMPs) significantly attenuated the magnitudes of LPS-induced CREBSer-133 phosphorylation, suggesting the involvement of NO-GC-PKG signaling. Thus, the present study suggests that NO-mediated signaling activated by bacterial LPS, at least in part, enhance CREBSer-133 phosphorylation in cultured VSMCs. The findings here may provide not only signaling pathway involved in VSMC differentiation during inflammatory response, but also new insight into possible therapeutic intervention.
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PMID:Enhancement of CREBSerine-133 phosphorylation through nitric oxide-mediated signaling induced by bacterial lipopolysaccharide in vascular smooth muscle cells from rats. 1281 20

Serine proteases are attractive targets for the design of enzyme inhibitors since they are involved in the etiology of several diseases. Within the class of serine proteases, HLE is one of the most destructive enzymes in the body. It is implicated in the promotion or exacerbation of a number of diseases including pancreatitis, acute respiratory syndrome, rheumatoid arthritis, atherosclerosis, pulmonary emphysema, and cystic fibrosis. Thrombin, a trypsin-like serine protease, plays a dual role in thrombogenesis, including fibrin formation and platelet activation. As a result, thrombin constitutes one of the most widely studied targets for antithrombotic strategy. Numerous inhibitors of serine proteases have been reported during the past three decades. Among them, coumarin-type molecules displayed a high inhibitory potency towards various serine proteases. At that time, halomethyl dihydrocoumarins have been shown to behave as the first general suicide inhibitors of serine protease. These molecules inhibit several proteases such as human leucocyte elastase, porcine pancreatic elastase, thrombin, urokinase and human plasmin. Isocoumarins are very effective as mechanism-based inhibitors of serine proteases. Pharmacomodulation on the 3-alkoxy-4-chloroisocoumarins and the 3-alkoxy-7-amino-4-chloroisocoumarins led to strong inhibitors of numerous serine proteases such as HLE, human factor XIa and XIIa, thrombin, urokinase and kallikrein. Recently, a series of coumarins characterised by an alkyl, aryl ester, amide, thioester or ketone in the position 3 and an electrophilic chloromethyl moiety in the position 6 have been developed. These compounds were found to be high inhibitors of alpha-chymotrypin, HLE and human thrombin.
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PMID:Coumarin and isocoumarin as serine protease inhibitors. 1557 71

Serine protease inhibitors, termed serpins, are key regulators of numerous biological pathways that initiate inflammation, coagulation, angiogenesis, apoptosis, extra-cellular matrix composition and complement activation responses. Viruses have encoded serpins to guard themselves from host immune attack. The myxoma virus which infects rabbits secretes a highly potent anti-inflammatory serpin, Serp-1, which targets thrombolytic and thrombotic proteases as a means to fend off coagulation and inflammatory reactions to viral infection. These reactions act as a defense, produced by the host, to counter viral infection and invasion. When infused in animals after vascular injury, Serp-1 elicits exceptional anti-inflammatory activity, whereas the mammalian serpin, plasminogen activator inhibitor-1 (PAI-1), which also targets thrombotic and thrombolytic proteases can induce a pro-thrombotic response. During arterial injury, PAI-1 is highly expressed and increased PAI-1 concentration can result in acute thrombosis after aortic transplant in mouse models. The reactive center loop amino acid sequence is a fingerprint for serpin function and this function is highly sequence specific such that modification in this sequence can markedly alter activity. For instance, the alteration of the serpin reactive site loop P1-P1I amino acid sequence nullified the anti-inflammatory activity of Serp-1 and modification of P2-P7 initiated a pro-inflammatory response with vascular remodeling with aneurysm formation. Furthermore Serp-1 has demonstrated the capacity to utilize a mammalian serine protease receptor, the urokinase-type plasminogen activator receptor (uPAR), to alter cellular signaling in part through the actin binding protein cytoskeletal system (via filamin B). In this review, the molecular mechanisms relating inflammation and coagulation pathways to atherosclerosis and how the viral serpin, Serp-1, modifies these pathways in order to exhibit this profound anti-inflammatory activity without associated adverse thrombosis are discussed. Viral and vascular serpins targeting the thrombolytic cascade represent a potential new and untapped therapeutic resource.
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PMID:Serpins, the vasculature, and viral therapeutics. 1614 96

Sphingolipids play a very important role in cell membrane formation, signal transduction, and plasma lipoprotein metabolism, and all these functions may have an impact on atherosclerotic development. Serine palmitoyl-CoA transferase (SPT) is the key enzyme in sphingolipid biosynthesis. To evaluate in vivo SPT activity and its role in sphingolipid metabolism, we applied homologous recombination to embryonic stem cells, producing mice with long chain base 1 (Sptlc1) and long chain base 2 (Sptlc2), two subunits of SPT, gene deficiency. Homozygous Sptlc11 and Sptlc2 mice are embryonic lethal, whereas heterozygous versions of both animals (Sptlc1(+/-), Sptlc2(+/-)) are healthy. Analysis showed that, compared with WT mice, Sptlc1(+/-) and Sptlc2(+/-) mice had: (1) decreased liver Sptlc1 and Sptlc2 mRNA by 44% and 57% (P<0.01 and P<0.0001, respectively); (2) decreased liver Sptlc1 mass by 50% and Sptlc2 mass by 70% (P<0.01 and P<0.01, respectively), moreover, Sptlc1 mass decreased by 70% in Sptlc2(+/-) mouse liver, while Sptlc2 mass decreased by 53% in Sptlc1(+/-) mouse liver (P<0.001 and P<0.01, respectively); (3) decreased liver SPT activity by 45% and 60% (P<0.01, respectively); (4) decreased liver ceramide (22% and 39%, P<0.05 and P<0.01, respectively) and sphingosine levels (22% and 31%, P<0.05 and P<0.01, respectively); (5) decreased plasma ceramide (45% and 39%, P<0.01, respectively), sphingosine-1-phosphate (31% and 32%, P<0.01, respectively) and sphingosine levels (22.5% and 25%, P<0.01, respectively); (6) dramatically decreased plasma lysosphingomyelin (17-fold and 16-fold, P<0.0001, respectively); and (7) no change of plasma sphingomyelin, triglyceride, total cholesterol, phospholipids, and liver sphingomyelin levels. These results indicated that both Sptlc1 and Sptlc2 interactions are necessary for SPT activity in vivo, and that SPT activity directly influences plasma sphingolipid levels. Furthermore, manipulation of SPT activity might well influence the course of such diseases as atherosclerosis.
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PMID:Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice. 1621 50

Cardiovascular (CV) disease is increased in patients with chronic inflammatory disease, including rheumatoid arthritis (RA). Furthermore it has become clear at a pathophysiological level, that atherosclerosis has striking similarities with autoimmune disease. This realization has come at a time of paradigm shift in how rheumatologists manage RA, with the availability of biological agents targeting key inflammatory cytokines. This review will focus on the possible causes of increased vascular disease in RA, including the role of traditional CV risk factors. Mechanisms potentially at play, such as C-reactive protein (CRP), altered coagulation, and cyclooxygenase (COX)-2 inhibitors will be covered in brief. The receptor for advanced glycation end products (RAGE) has been identified as a candidate molecule influencing response to ongoing inflammation and autoimmunity. There will be a focus on the role of RAGE in CV disease and RA. As has been the case with many novel molecules, functional polymorphisms are thought to alter disease expression and assist us in coming to terms with the biological activities of the parent molecule. The review will conclude with a discussion of the potential role of the RAGE Glycine 82 Serine polymorphism.
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PMID:Rheumatoid arthritis: links with cardiovascular disease and the receptor for advanced glycation end products. 1646 13

Serine proteinases (trypsin and chymotrypsin) cause destruction of apolipoprotein B-100 on the surface of human blood LDL. Incubation of LDL with these enzymes increases the mean size of LDL particles. Proteolysis of apolipoprotein B-100 induces changes in surface structure, destabilizes LDL particles, and reduces their association resistance. Presumably, this proteolytic modification of LDL with subsequent association of these particles plays an important role in accumulation of cholesterol in the vascular wall and in the development of early stages of atherosclerosis.
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PMID:Proteolysis of apoprotein B-100 impairs its topography on LDL surface and reduces LDL association resistance. 1675 14

Atherosclerosis is initially a chronic inflammatory disease as it involves inflammatory cells such as macrophages, T-lymphocytes and mast cells. At later stages, when plaques manifest clinically, thrombosis, coagulation and fibrinolysis contribute to the escalation of the disease, which culminates in acute cardiovascular syndromes. Serine proteases are instrumental in all of these processes, rendering their inhibition of clinical interest for the prevention of atherosclerotic plaque progression. Viral serine protease inhibitors, specifically engineered by pathogens to evade the host's defense system, not only display profound anti-inflammatory activity but also inhibit a range of serine proteases implicated in cardiovascular disease. In this review, the potential of viral serine protease inhibitors in anti-atherosclerotic therapy is discussed.
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PMID:Viral serine protease inhibitors as anti-atherosclerotic therapy. 1772 84


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