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)

Atherosclerotic plaques contain a significant number of macrophage foam cells and are associated with an inflammatory state. Inflammation induces the secretion from monocytes and other cells of cytokines, reactive oxygen species, proteinases and proteinase inhibitors among many other molecular species. AAT is prominent among the serine proteinase inhibitors and is an important regulator of leukocyte elastase and proteinase-3. It has been shown that the stable AAT-proteinase complex can upregulate AAT biosynthesis, and we have shown that the shorter, carboxyl terminal peptide (C-36) resulting from proteinase cleavage of AAT polymerizes, and in its fibrillar form alters cellular metabolism. To test for a possible link between the inflammation-generated C-36 peptide and cellular processes associated with atherogenesis, we have studied the effects of the fibrillar form of this peptide at varying concentrations on human monocytes in culture. We have found that fibrillar C-36 at concentrations of greater than or equal to 5 micromol/l in monocyte cultures for 24 h significantly increases LDL binding and uptake, upregulates LDL receptors, induces cytokine production and glutathione reductase activity, and upregulates AAT synthesis. The expression of CD36 protein, LDL Scavenger receptor, is also upregulated by fibrillar C-36 and native LDL in the presence of C-36-activated monocytes is more oxidized than with unactivated control monocytes. The majority of monocytes cultured for 24 h in the presence of C-36 fibrils were transformed morphologically into macrophages. These data establish a direct molecular link, mediated by C-36 peptide of AAT, between inflammation and the oxidation and accumulation of lipid in monocyte-derived macrophages. This may be important for an understanding of the events conducive to atherogenesis.
Atherosclerosis 1999 Dec
PMID:Atherogenic properties of human monocytes induced by the carboxyl terminal proteolytic fragment of alpha-1-antitrypsin. 1055 12

Oxidized low-density lipoproteins (oxLDL) play a role in the genesis of atherosclerosis. OxLDL are able to induce apoptosis of vascular cells, which is potentially involved in the formation of the necrotic center of atherosclerotic lesions, plaque rupture, and subsequent thrombotic events. Because oxLDL may induce structural modifications of cell protein and altered proteins may impair cell viability, the present work aimed to evaluate the extent of protein alterations, the degradation of modified proteins through the ubiquitin-proteasome system (a major degradative pathway for altered and oxidatively modified proteins) and their role during apoptosis induced by oxLDL. This paper reports the following: 1) oxLDL induce derivatization of cell proteins by 4-hydroxynonenal (4-HNE) and ubiquitination. 2) Toxic concentrations of oxLDL elicit a biphasic effect on proteasome activity. An early and transient activation of endogenous proteolysis is followed rapidly by a subsequent decay (resulting probably from the 26S proteasome inhibition) and followed later by the inhibition of the 20S proteasome (as assessed by inhibition of sLLVY-MCA hydrolysis). 3) Specific inhibitors of proteasome (lactacystin and proteasome inhibitor I) potentiated considerably the toxicity of oxLDL (nontoxic doses of oxLDL became severely toxic). The defect of the ubiquitination pathway (in temperature-sensitive mutants) also potentiated the toxicity of oxLDL. This suggests that the ubiquitin-proteasome pathway plays a role in the cellular defenses against oxLDL-induced toxicity. 4) Dinitrophenylhydrazine (DNPH), an aldehyde reagent, prevented both the oxLDL-induced derivatization of cell proteins and subsequent cytotoxicity. Altogether, the reported data suggest that both derivatization of cell proteins (by 4-HNE and other oxidized lipids) and inhibition of the proteasome pathway are involved in the mechanism of oxLDL-induced apoptosis.
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PMID:Oxidized LDLs alter the activity of the ubiquitin-proteasome pathway: potential role in oxidized LDL-induced apoptosis. 1069 69

Authors examined concentration of the leukocyte elastase (LE) in serum and walls of atherosclerotic abdominal aorta, ruptured and nonruptured aneurysms of abdominal aorta. Control group included LE level in normal abdominal aortas from multi organ donors. For trial 12589 PMN ELASTASE (2th Version) MERCK IMMUNOASSAY was using. From November of 1994 to December 1997 87 patients were explorated. Our study presents highest level of the LE in sequence: ruptured aneurysms, nonruptured aneurysms, atherosclerotic aortas and normal aortas. We did not confirm any statistic dependence between serum LE levels. Analysis between aneurysms diameter and their LE level, evaluated mutual dependence. Exploration proved connection between expansion and inflammatory genesis of atherosclerosis disease (activity of the PMN-elastasis in vessels wall).
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PMID:[Examination of elastase concentration in the wall of abdominal aortic aneurysms]. 1108 23

Oxidized low density lipoproteins (oxLDL) are thought to play a major role in atherosclerosis. OxLDL act in part through alteration of intracellular signalling pathways in cells of the vascular wall. We recently reported that the EGF receptor (EGFR) signalling pathway is activated by lipid peroxidation products (among them 4-hydroxynonenal, 4-HNE) contained in oxLDL. The use of phenolic antioxidants, such as trolox, alpha-tocopherol, caffeic acid and tyrphostins A-25, A-46 or A-1478, showed that the oxLDL-induced EGFR activation is constituted by two separate components, the first (early) one being antioxidant-insensitive, the second (late) being antioxidant-sensitive. 4-HNE derivatization of EGFR and EGFR activation induced by exogenous 4-HNE, suggest that the early (0.5 - 3 h) component of oxLDL-induced EGFR activation is mediated (at least in part) by 4-HNE (and possibly by other oxidized lipids). This early component is antioxidant-insensitive. The second component (4 - 5 h) of the oxLDL-induced EGFR activation is antioxidant-sensitive, since it is blocked by antioxidants such as trolox, caffeic acid or PDTC, which act by blocking the cellular oxidative stress (H(2)O(2) generation) evoked by oxLDL. Conversely, exogenous H(2)O(2) induced EGFR autophosphorylation (thus mimicking the second component) and was also inhibited by antioxidants. This effect is mediated in part through inhibition by oxidative stress of protein tyrosine phosphatases involved in EGFR dephosphorylation.
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PMID:Phenolic antioxidants trolox and caffeic acid modulate the oxidized LDL-induced EGF-receptor activation. 1130 50

The aim of the study was to demonstrate an activation of polymorpho-nuclear leukocytes (PMNs) in chronic progressive atherosclerosis (ATH). A group of patients with ATH, and a group of ATH patients under aspirin (ASA) therapy were compared with control persons without atherosclerotic alterations (healthy controls). Each group comprised 15 male age-matched subjects. The following inflammatory parameters related to PMN activities were measured: the polymorphonuclear leukocyte (PMN) blood count; blood PMN migration and reactive oxygen species release in vitro; the blood levels of PMN elastase, malondialdehyde, antibodies to oxidized LDL and soluble ICAM-1. In ATH patients, the PMN blood counts and the share of blood PMNs migrating upon platelet activating factor and leukotriene B4 stimulation were significnatly above the values of the healthy controls, while the other parameters were not significantly altered. ASA treatment attenuated the inflammatory response and reduced the differences between ATH and the healthy controls. It can be concluded that, in patients with chronic progressive atherosclerosis, PMNs are involved in the inflammatory process underlying the disease.
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PMID:Blood polymorphonuclear leukocyte activation in atherosclerosis: effects of aspirin. 1132 59

The extracellular matrix provides a structural framework essential for the functional properties of vessel walls. The three dimensional organization of the extracellular matrix molecules--elastin, collagens, proteoglycans and structural glycoproteins--synthesized during fetal development--is optimal for these functions. Early in life, the vessel wall is subjected to injury: lipid deposition, hypoxia, enzyme secretion and reactive oxygen species production during inflammatory processes, and the extracellular matrix molecules are hydrolyzed by proteases--matrix metalloproteinases, leukocyte elastase, etc. In uninjured arteries and veins, some proteases are constitutively expressed, but through the control of their activation and/or their inhibition by inhibitors, these proteases have a very low activity. During the occurrence of vascular pathologies--atherosclerosis, hypertension, varicosis, restenosis, etc.--the balance between proteases and their inhibitors is temporally destroyed through the induction of matrix metalloproteinase gene expression or the secretion of enzymes by inflammatory cells. Smooth muscle cells, the most numerous cells in vascular walls, have a high ability to respond to injury through their ability to synthesize extracellular matrix molecules and protease inhibitors. However, the three dimensional organization of the newly synthesized extracellular matrix is never functionally optimal. In some other pathologies--aneurysm--the injury overcomes the responsive capacity of smooth muscle cells and the quantity of extracellular matrix decreases. In conclusion, care should be taken to maintain the vascular extracellular matrix reserve and any therapeutic manipulation of the protease/inhibitor balance must be perfectly controlled, because an accumulation of abnormal extracellular matrix may have unforeseen adverse effects.
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PMID:Extracellular matrix remodeling in the vascular wall. 1142 68

Oxidized lipoproteins inhibit TNF-alpha secretion by human THP-1 macrophages due, at least in part, to aldehydes derived from the oxidation of polyunsaturated fatty acids. This study extends these findings by investigating the effect of three aldehydes (2,4-decadienal (2,4-DDE), hexanal and 4-hydroxynonenal (4-HNE)) on TNF-alpha and IL-1beta mRNA expression. The 2,4-DDE and 4-HNE showed considerable biological activity which induced cytotoxicity on THP-1 macrophages at concentration of 50 microM. Hexanal, on the other hand, had a lower cytotoxic capacity and concentration of 1000 microM was needed for the effect to be observed. Exposure of THP-1 macrophages to aldehydes for 24 h inhibited TNF-alpha mRNA expression but increased or did not affect IL-1beta mRNA levels. The inhibitory action of 2,4-DDE was dose dependent and began at 5 microM (46%, P<0.001). The effect of 4-HNE was less inhibitory than 4-DDE but only when cytotoxic concentrations were used (50 microM). Very high concentrations of hexanal (200 microM) were needed to inhibit TNF-alpha expression (23%, P<0.001). This downregulation of TNF-alpha gene expression by 2,4-DDE was parallel to a lower protein production. These data indicate that low levels of 2,4-DDE may modulate inflammatory action by inhibiting TNF-alpha mRNA gene expression and that the biological activity of 2,4-DDE may be involved in the development of atherosclerosis.
Atherosclerosis 2001 Sep
PMID:2,4-Decadienal downregulates TNF-alpha gene expression in THP-1 human macrophages. 1150 Jan 79

In the vessel wall, macrophages are among the cells that upon activation contribute to the atherosclerotic process. Low density lipoproteins (LDL) can mediate this activation but only after enzymatic or oxidative modification. Lipoprotein(a) (Lp(a)) is an LDL variant that has been shown to have an atherogenic potential by no clearly established mechanisms. In the present study we examined whether native Lp(a) can activate macrophages and, if so, identify the structural elements involved in this action. For this purpose, we utilized human THP-1 macrophages, prepared by treating THP-1 monocytes with phorbol ester, and we exposed them to Lp(a) and its two derivatives, apo(a)-free LDL (Lp(a-)) and free apo(a). We also studied apo(a) fragments, F1 (N terminus) and F2 (C terminus) and subfragments thereof, obtained by leukocyte elastase digestion. By Northern blot analyses, Lp(a), but not Lp(a-), caused up to a 12-fold increase in interleukin 8 (IL-8) mRNA as compared with untreated cells. Free apo(a) also induced the production of IL-8 mRNA; however, the effect was 3-4-fold higher than that of Lp(a). The increase in mRNA was associated with the accumulation of IL-8 protein in the culture medium. F1 had only a minimal effect, whereas F2 was 1.5-2-fold more potent than apo(a), an activity mostly contained in the Kringle V-protease region. A monoclonal antibody specific for Kringle V inhibited the apo(a)-mediated effect on IL-8. We conclude that Lp(a) via elements contained in the C-terminal domain of apo(a) causes in THP-1 macrophages an increased production of IL-8, a chemokine with pro-inflammatory properties, an event that may be relevant to the process of atherosclerosis.
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PMID:Stimulation of interleukin-8 production in human THP-1 macrophages by apolipoprotein(a). Evidence for a critical involvement of elements in its C-terminal domain. 1159 15

Connective tissue growth factor (CTGF) is a 38-kd protein involved in several human fibrotic disorders including atherosclerosis and skin and renal fibrosis. Although it has been shown that human and experimental liver fibrosis is associated with CTGF expression through up-regulation of CTGF mRNA by hepatic stellate cells (HSC), the role of CTGF in the liver has not yet been determined. The aim of the present study was to assess the effects of CTGF on rat primary HSC and its regulation in a well-established model of in vitro liver fibrogenesis. Incubation of primary HSC with recombinant CTGF induced a significant migratory (2.3-fold, 50 ng/ml CTGF) and proliferative effect (1.8-fold, 100 ng/ml CTGF). Type I collagen mRNA expression, as assessed by a real-time RT-PCR procedure, was also increased when cells were incubated in the presence of CTGF (2-fold, 50 ng/ml). Transforming growth factor-beta1 (TGF-beta1) strongly stimulated CTGF mRNA expression, a direct mechanism observed in the absence of any intermediate protein synthesis. Furthermore, spontaneous activation of HSC plated on plastic and stimulation by vascular endothelial growth factor, lipid peroxidation products (HNE, MDA), acetaldehyde, and platelet-derived growth factor (PDGF)-BB significantly up-regulated CTGF mRNA expression in HSC. PDGF-induced CTGF stimulation might be related in part to TGF-beta1 secretion because CTGF mRNA up-regulation observed after PDGF-BB stimulation was abrogated in the presence of neutralizing TGF-beta1 antibody. In conclusion, this study extends the role of CTGF in HSC activation and suggests that CTGF up-regulation might be a central pathway during HSC activation.
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PMID:Effects and regulation of connective tissue growth factor on hepatic stellate cells. 1206 87

Oxidized lipids, such as 13-hydroperoxyoctadecadienoic acid (13-HPODE), have been implicated in the pathogenesis of atherosclerosis. 13-HPODE, a constituent of oxidized low-density lipoproteins, can induce cytotoxicity of vascular smooth muscle cells (SMC), which may facilitate plaque destabilization and/or rupture. 13-HPODE-induced cytotoxicity has been linked to oxidative stress, although the mechanisms by which this occurs are unknown. In the present study, we show that 13-HPODE and 9-HPODE (10-30 microM) increased superoxide (O2*-) production and induced cytotoxicity in SMC. The 13-HPODE-induced increase in O2*- was blocked by transfecting the cells with antisense oligonucleotides against p22phox, suggesting that the O2*- was produced by NAD(P)H oxidase. Similar concentrations of the corresponding HPODE reduction products, 13-hydroxyoctadecadienoic acid (13-HODE) and 9-HODE, neither increased O2*- production nor induced cytotoxicity, while 4-hydroxy nonenal (4-HNE), an unsaturated aldehyde lipid peroxidation product, induced cytotoxicity without increasing O2*- production. Treatment with superoxide dismutase or Tiron to scavenge O2*-, or transfection with p22phox antisense oligonucleotides to inhibit O2*- production, attenuated 13-HPODE-induced cytotoxicity, but not that induced by 4-HNE. These findings suggest that activation of NAD(P)H oxidase, and production of O2*-, play an important role in lipid hydroperoxide-induced smooth muscle cytotoxicity.
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PMID:Activation of NAD(P)H oxidase by lipid hydroperoxides: mechanism of oxidant-mediated smooth muscle cytotoxicity. 1265 83


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