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)

In previous studies, it was shown that a lysine deficient diet reduces the severity of aortic cholesterol atherosclerosis in rabbits. Feeding 1-amino-3-imino N,N' propene diacetate (AIPD) produced 2 metabolic by products with active aldehyde groups 1-amino propenal acetic acid (APA) and malonyldialdehyde (MDA) that transiently block the lysine epsilon-amino groups of all proteins and lipoproteins in vivo. This paper reports the effects of blocking the lysine free epsilon-amino groups of all lipoproteins on 2 different types of cholesterol atherosclerosis; (1) A proliferative-type cholesterol atherosclerosis containing a high proportion of spindle-shaped myogenic foam cells rich in collagen and alcian blue-stainable material produced by feeding a diet containing cholesterol, peanut oil, ethanol and butylated hydroxyanisole and (2) cholesterol atherosclerosis containing a high proportion of polyhedral-shaped nonmyogenic macrophage-type foam cells produced by feeding cholesterol and oleic acid. After 14 weeks on the diets the mean +/- SD percent of intimal aortic area covered with the myogenic-type atherosclerosis in the control peanut oil-fed group was 34 +/- 6% and this was reduced to 13 +/- 3% in the peanut oil AIPD group. In contrast, after 14 weeks in the control oleic acid group the severity of atherosclerosis was 14 +/- 4% and this was increased to 36 +/- 7% in the oleic acid AIPD group. Aortic cholesterol concentration was decreased in the AIPD peanut oil group relative to its control but was increased in the AIPD oleic acid group relative to its control group. A higher concentration of AIPD metabolites accumulated in the atherosclerotic lesions of the oleic AIPD group than in the peanut oil AIPD group indicating that a larger amount of lysine blocked lipoprotein accumulated in the macrophage-rich lesions of the oleic acid AIPD group than in the myogenic-rich lesions of the peanut oil AIPD group. Blocking lysine epsilon-amino groups in vivo by feeding AIPD did not modify DNA synthesis in the aortae of either AIPD group relative to their control groups.
Atherosclerosis 1985 Oct
PMID:Modification of two types of cholesterol atherosclerosis in rabbits by blocking lipoprotein lysine epsilon-amino groups. 393 26

Progress in the understanding of blood cell--endothelial cell interactions has been achieved by the development of in-vitro model systems. We describe adhesion properties of the recently established human monocytic cell line Mono Mac 6. These cells showed increased adherence to unstimulated and tumour necrosis factor (TNF)-alpha (50 U/ml) stimulated human umbilical vein endothelial cells (HUVEC) (9.4% +/- 0.4% and 56.5% +/- 3.3%), as compared to U937 cells (2.6% +/- 0.8% and 40.0% +/- 8.4%). The values were similar to freshly isolated human blood monocytes (18.8% +/- 7.5% and 55.7% +/- 9.3%, respectively). Maximal binding was 6.2 +/- 0.6 Mono Mac 6 cells per HUVEC, which was 34% less than U937 cells (8.9 +/- 0.3). The lower number of adherent Mono Mac 6 cells per HUVEC could be due to their larger size, as assessed by flow cytometry. Blocking experiments with monoclonal antibody (mAb) directed against E-selectin, VCAM-1 and ICAM-1 on HUVEC and CD11b or CD14 on Mono Mac 6 cells demonstrated the contribution of these molecules to Mono Mac 6 adherence. Reduced binding after 24 h parallels the decline of E-selectin expression in HUVEC. Linearity of cell binding was confirmed from 0.2 x 10(6) to 1.0 x 10(6) Mono Mac 6 cells. Expression of CD11b and CD14 in Mono Mac 6 cells and in isolated human monocytes but not in U937 cells leading to interaction with ICAM-1 on HUVEC appears to be responsible for the increased adhesion of Mono Mac 6, as compared to U937 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1995 Feb
PMID:Adhesion properties of Mono Mac 6, a monocytic cell line with characteristics of mature human monocytes. 753 62

Bacterial cell-wall lipopolysaccharide (LPS) is the main endotoxin contributing to local inflammation and systemic toxicity during Gram-negative infections and induces aortic endothelial injury with or without cell death and replication followed by increased leukocyte adhesion. Heat-shock protein (hsp) 60 is under study in our laboratory as a potential antigen inducing immunologic attack to endothelial cells in atherogenesis. To investigate the mechanism of LPS-induced endothelial injury and the phenotypes of adhering cells, Lewis rats were treated in vivo or, in aortic organ cultures, with LPS to determine the expression of intercellular-adhesion molecule-1 (ICAM-1) and hsp60 on aortic endothelium and to characterize phenotypes of adhering leukocytes. Increased ICAM-1 expression by aortic endothelium was observed as early as 3 hr after LPS injection and persisted up to 72 hr, whereas elevated levels of hsp60 were found between 6 and 48 hr. In vitro application of various types of stress, such as LPS, H2O2, and high temperature, not only stimulated endothelial expression of hsp60 but, concomitantly, that of ICAM-1. The number of adhering leukocytes was significantly increased on aortic endothelium 6 hr after LPS administration, and the predominant leukocytes adhering to stressed endothelium were monocytes (80%) and T lymphocytes (8 to 20%). In organ cultures of rat aortic intimal, LPS, and H2O2 evoked increased leukocyte adhesion, which proved to be selective, because adherent leukocytes were mostly Ia+ monocytes and T cells, i.e., activated. Adhering T cells were gamma/delta antigen-receptor positive in 8 to 16% after LPS stress, whereas these cells amount to only 2 to 4% of peripheral blood T cells. Blocking of adhesion molecules ICAM-1, LFA-1 alpha, and/or LFA-1 beta reduced adhesion up to 34%. Increased coordinated LPS-dependent expression of hsp60 and ICAM-1 correlates with monocyte and T-cell adhesion to aortic endothelium. These observations may be significant for elucidating the mechanism of the initiating events in the development of atherosclerosis.
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PMID:Coexpression of heat-shock protein 60 and intercellular-adhesion molecule-1 is related to increased adhesion of monocytes and T cells to aortic endothelium of rats in response to endotoxin. 856 88

Thrombin's proteolytically activated "tethered-ligand" receptor is widely expressed and mediates many of thrombin's actions on cells. Its central role in thrombin-stimulated human platelet activation and vascular smooth muscle proliferation as well as location in atherosclerotic plaques suggests receptor involvement in arterial thrombosis and atherosclerosis. Thrombin receptor antagonists, should they be effective, could be more selective than thrombin active site inhibitors in antithrombotic therapy as well as other indications. Blocking antibodies to peptides derived from the thrombin receptor have been used as prototypical thrombin receptor antagonists in vitro and have been useful in implicating this receptor in thrombin's actions on a variety of cell types. These antibodies have also shown the involvement of the receptor in arterial thrombosis models in nonhuman primates. Amino acid substitution studies have shown the structural requirements for receptor activation of peptides homologous to the new NH2-terminus. Peptide-based partial agonists and antagonists have been synthesized by NH2-terminal replacements of the serine in the receptor activating peptides. Current thrombin receptor antagonists lack potency and some are partial agonists; however, it is expected that more potent compounds will result from further investigation. The potency limitations are important to overcome before serious evaluation of their efficacy can be determined.
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PMID:Thrombin receptor antagonists. 883 6

The urokinase-type plasminogen activator (UPA) and its receptor are expressed in the vasculature and are involved in cell migration and remodeling of the extracellular matrix in the neointima. Vessels with atherosclerosis or neointimal hyperplasia, when compared with normal vessels, contain high UPA activity as well as increased levels of UPA receptor. In this study, we have identified the stimulation of vascular smooth muscle cell proliferation as a novel activity for UPA in the vessel wall. High-molecular-weight-UPA (12-200 nmol/L range) stimulated DNA synthesis and cell proliferation, which was half that induced by fetal calf serum or by platelet-derived growth factor-BB. UPA did not induce growth of endothelial cells, and tissue-type plasminogen activator showed no activity on either cell type. Induction of proliferation required the complete UPA molecule but was independent of the proteolytic activity of UPA, whereas neither the amino-terminal fragment nor the catalytic domain by itself was mitogenic. UPA also stimulated c-fos/c-myc mRNA expression and mitogen-activated protein kinase activity in smooth muscle cells. Blocking monoclonal antibodies against the UPA receptor and the enzymatic removal of receptors were ineffective in inhibiting the mitogenic effect of UPA, suggesting a UPA receptor-independent mechanism. Thus, we provide evidence for a novel function of UPA on vascular smooth muscle cell proliferation that, together with its previously documented involvement in regulating pericellular proteolysis-related events and cell migration, provides additional evidence for a role in the pathogenesis of atherosclerosis/restenosis.
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PMID:Induction of vascular SMC proliferation by urokinase indicates a novel mechanism of action in vasoproliferative disorders. 940 65

The incubation of human macrophages with antigen antibody complexes prepared with rabbit anti-LDL and human LDL (LDL-IC) is followed by ingestion of those immune complexes (IC), massive cholesterol ester accumulation, cytokine release and overexpression of the LDL receptor. The massive accumulation of cholesterol esters and overexpression of the native LDL receptor are specifically induced by immune complexes containing native or modified LDL, but not by any other type of IC. We report the results of a series of experiments aimed at defining the receptor preferentially involved in LDL-IC uptake. Flow cytometry studies using CD16, CD32 and CD64 monoclonal antibodies showed a sharp reduction on the expression of CD64 (Fc gamma RI) both by human monocyte-derived macrophages and THP-1 cells after incubation with LDL-IC, suggesting preferential engagement of this type of Fc receptor. Blocking experiments with aggregate-free IgG1 and CD32 monoclonal antibody confirmed that blocking Fc gamma RI prevented both LDL-IC uptake and the upregulation of LDL receptors on THP-1 cells. In contrast, blocking Fc gamma RII did not affect either the uptake of LDL-IC or the expression of LDL receptors on the same cells. The preferential engagement of Fc gamma R-I by LDL-IC suggests a biological difference of LDL-IC relative to other types of IC and opsonized particles. The precise molecular mechanism(s) responsible for the paradoxical upregulation of LDL receptor after the uptake of LDL-IC remain to be elucidated.
Atherosclerosis 1997 Dec
PMID:The uptake of LDL-IC by human macrophages: predominant involvement of the Fc gamma RI receptor. 943 Mar 65

We examined the mechanisms by which insulin may be atherogenic during aging. We postulated that an increase in insulin secretion during aging produces growth factor effects on vascular smooth muscle cells (VSMCs), promoting these cells to synthesize collagen and to migrate. We have previously demonstrated that insulin stimulates collagen synthesis and release in senescent VSMCs that were obtained from a human organism with high levels of insulin secretion. Using the same experimental model, we now study the effects of insulin on VSMC migration. We demonstrate that insulin has a chemoattractant effect on VSMCs which occurs through insulin binding to its own specific receptors as opposed to its effect on collagen production. Blocking the insulin receptor significantly eliminates the insulin effect on cell migration. At the same molarity, the chemotactic effect of insulin is less pronounced than that of insulin-like growth factor-1. In spite of different mechanisms, there is a remarkable correlation between the insulin effects on collagen secretion and cell migration (r2 = 97%, p < 0.0005). Our results indicate that distinct but closely related mechanisms may exist by which insulin becomes atherogenic. Our results also suggest the importance of normal aging processes in the development of atherosclerosis.
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PMID:Phenotypic changes in vascular smooth muscle cells during aging: insulin effect on migration. 959 86

Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical-producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO-LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl-2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF-2, ELK-1, CREB, AP-1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL-induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical-sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.
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PMID:Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells. 1102 84

Intracellular Ca2+ transients have been shown to control several transition points within the eukaryotic cell cycle. We focus here on the G1-to-S phase transition triggered by an increase in the intracellular Ca2+ concentration ([Ca2+](i)) in rodent vascular smooth muscle cells (VSMC) and its potential targeting for the treatment of vaso-occlusive processes such as atherosclerosis, hypertension and post-angioplasty restenosis. The transcription factor c-Myb generates a G1/S transition-specific Ca2+ transient via its regulation of a high affinity Ca2+ efflux pump, the plasma membrane Ca2+ ATPase-1 (PMCA1). The cell cycle-associated repression of PMCA1 is mediated by two c-Myb binding sites in the PMCA1 promoter. As c-Myb levels increase in late G1 phase of proliferating VSMC, transcription from the PMCA1 promoter is reduced, expression of the PMCA1 gene falls, and the resultant reduced rate of Ca2+ efflux underlies a G1/S-associated increase in [Ca2+](i). Blocking either the upregulation of c-Myb levels, or the down regulation in expression of the efflux pump, leads to significant reductions in S phase entry and proliferation of VSMC. A search for functional c-Myb sites within the promoters of other Ca2+ transporters has been undertaken in order to extend the molecular framework of the G1/S-specific Ca2+ signal mediated by the c-Myb transcription factor. Animal studies with c-myb antisense oligodeoxynucleotides and an anti-c-myb ribozyme as well as in vitro results with dominant negative c-Myb mutants and a doxycycline-inducible c-Myb neutralizing antibody point to the potential of c-Myb-targeted gene therapy for treating pathologic VSMC proliferation and highlight the need for clinical trials in this field.
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PMID:Cell cycle dependent regulation of intracellular calcium concentration in vascular smooth muscle cells: a potential target for drug therapy. 1276 62

Blocking intestinal bile acid absorption by inhibiting the apical sodium codependent bile acid transporter (ASBT) is a target for increasing hepatic bile acid synthesis and reducing plasma LDL cholesterol. SC-435 was identified as a potent inhibitor of ASBT (IC50 = 1.5 nM) in cells transfected with the human ASBT gene. Dietary administration of 3 mg/kg to 30 mg/kg SC-435 to apolipoprotein E-/- (apoE-/-) mice increased fecal bile acid excretion by >2.5-fold. In vivo inhibition of ASBT also resulted in significant increases of hepatic mRNA levels for cholesterol 7alpha-hydroxylase and HMG-CoA reductase. Administration of 10 mg/kg SC-435 for 12 weeks to apoE-/- mice lowered serum total cholesterol by 35% and reduced aortic root lesion area by 65%. Treatment of apoE-/- mice also resulted in decreased expression of ileal bile acid binding protein and hepatic nuclear hormone receptor small heterodimer partner, direct target genes of the farnesoid X receptor (FXR), suggesting a possible role of FXR in SC-435 modulation of cholesterol homeostasis. In dogs, SC-435 treatment reduced serum total cholesterol levels by </=12% and, in combination with atorvastatin treatment, caused an additional reduction of 25%. These results suggest that specific inhibition of ASBT is a novel therapeutic approach for treatment of hypercholesterolemia resulting in a decreased risk for atherosclerosis.
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PMID:Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE-/- mice by SC-435. 1281 Aug 16


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