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)

Clearance of excess cholesterol from cells by HDL is facilitated by the interaction of HDL apolipoproteins with cell-surface binding sites or receptors, a process that may be important in preventing atherosclerosis. In this study, synthetic peptides containing 18-mer amphipathic helices of the class found in HDL apolipoproteins (class A) were tested for their abilities to remove cholesterol and phospholipid from cultured sterol-laden fibroblasts and macrophages and to interact with cell-surface HDL binding sites. Lipid-free peptides containing two identical tandem repeats of class A amphipathic helices promoted cholesterol and phospholipid efflux from cells and depleted cellular cholesterol accessible for esterification by acyl CoA/cholesterol acyltransferase, similar to what was observed for purified apolipoprotein A-I. Peptide-mediated removal of plasma membrane cholesterol and depletion of acyl CoA/cholesterol acyltransferase-accessible cholesterol appeared to occur by separate mechanisms, as the latter process was less dependent on extracellular phospholipid. The dimeric amphipathic helical peptides also competed for high-affinity HDL binding sites on cholesterol-loaded fibroblasts and displayed saturable high-affinity binding to the cell surface. In contrast, peptides with a single helix had little or no ability to remove cellular cholesterol and phospholipid, or to interact with HDL binding sites, suggesting that cooperativity between two or more helical repeats is required for these activities. Thus, synthetic peptides comprising dimers of a structural motif common to exchangeable apolipoproteins can mimic apolipoprotein A-I in both binding to putative cell-surface receptors and clearing cholesterol from cells.
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PMID:Synthetic amphipathic helical peptides that mimic apolipoprotein A-I in clearing cellular cholesterol. 792 49

Levels of specific antibodies (Ab) against mycobacterial and human heat shock protein (hsp) 65/60 are increased in the sera of patients with atherosclerotic lesions and have been demonstrated to be capable of mediating endothelial cytotoxicity. To clarify the antigen epitopes recognized by these serum Abs, Ab binding to hsp65 deletion mutants (Dms), as well as to overlapping 15-mer and 8-mer hsp65 peptides, was assessed. Western blotting of hsp65 Dms indicated the presence of at least one epitope between amino acid (aa) residues 171 and 276, recognized by both high-titer sera and affinity-purified anti-hsp65/60 Ab. Fluorescence immunoassays using 53 15-mer peptides and Pin ELISA using 526 7-mer peptides demonstrated three distinct, conserved sequences with high affinity to high-titer sera and purified anti-hsp65/60 Ab. Two N-terminal sequences, aa 97-109 and aa 179-187, and one C-terminal sequence, aa 504-512, were identified. These three epitopes recognized by anti-hsp65/60 Ab may serve as autoantigens in certain circumstances in vivo. This phenomenon could contribute to the initiation of atherosclerosis by an autoimmune reaction.
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PMID:Epitope specificity of anti-heat shock protein 65/60 serum antibodies in atherosclerosis. 910 73

Proliferation and migration of vascular smooth muscle cells (VSMCs) are involved in the processes of atherosclerosis and restenosis. The protein product of the growth arrest-specific gene 6 (Gas-6) has recently been identified as a ligand for the Axl/Rse/Mer tyrosine kinase receptor family, which may be involved in proliferation and migration of VSMCs. Here we show that Gas-6 gene expression is increased in proliferating VSMCs in tissue culture (2.5-fold increase by Northern blot) and following neointimal proliferation in a rabbit balloon-injury model (3-fold increase by Western blot). Neither platelet-derived growth factor (PDGF) nor thrombin stimulate the expression of Gas-6 in cultured VSMCs despite the ability of the PDGF, but not thrombin, to stimulate proliferation in growth-arrested cells. These data suggest a role for the Gas-6 regulatory system in VSMC proliferation, which may be a target for therapeutic interventions in the atherosclerotic process and restenosis after angioplasty.
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PMID:Growth arrest-specific gene 6 expression in proliferating rabbit vascular smooth muscle cells in vitro and in vivo. 1127 3

Apolipoprotein (apo) E is a polymorphic plasma protein, synthesized mainly by liver. Here, we evaluate whether synthetic DNA-RNA oligonucleotides (chimeraplasts) can convert a dysfunctional isoform, apoE2 (C --> T, R158C), which causes Type III hyperlipidemia and premature atherosclerosis, into apoE3. First, we treated recombinant Chinese hamster ovary cells stably secreting apoE2 with a 68-mer apoE2 to apoE3 chimeraplast. About one-third of apoE2 was converted to apoE3, and the repair was stable through 12 passages. Subcloning treated cells produced both apoE2 and apoE3 clones. Direct sequencing and reverse transcription polymerase chain reaction confirmed the genotype, whereas phenotypic change was verified by isoelectric focusing and immunoblotting of secreted proteins. Second, we established that the APOE2 gene can be targeted both in vivo, using transgenic mice overexpressing human apoE2, and in chromosomal context, using cultured lymphocytes from a patient homozygous for the epsilon2 allele. We conclude that chimeraplasty has the potential to convert the apoE2 mutation in patients with Type III hyperlipidemia to apoE3.
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PMID:Gene correction of the apolipoprotein (Apo) E2 phenotype to wild-type ApoE3 by in situ chimeraplasty. 1127 48

Apolipoprotein A-I (apoA-I) is the major protein associated with high density lipoprotein (HDL), and its plasma levels have been correlated with protection against atherosclerosis. Unfortunately, the structural basis of this phenomenon is not fully understood. Over 25 years of study have produced two general models of apoA-I structure in discoidal HDL complexes. The "belt" model states that the amphipathic helices of apoA-I are aligned perpendicular to the acyl chains of the lipid bilayer, whereas the "picket fence" model argues that the helices are aligned parallel with the acyl chains. To distinguish between the two models, various single tryptophan mutants of apoA-I were analyzed in reconstituted, discoidal HDL particles composed of phospholipids containing nitroxide spin labels at various positions along the acyl chain. We have previously used this technique to show that the orientation of helix 4 of apoA-I is most consistent with the belt model. In this study, we performed additional control experiments on helix 4, and we extended the results by performing the same analysis on the remaining 22-mer helices (helices 1, 2, 5, 6, 7, 8, and 10) of human apoA-I. For each helix, two different mutants were produced that each contained a probe Trp occurring two helical turns apart. In the belt model, the two Trp residues in each helix should exhibit maximal quenching at the same nitroxide group position on the lipid acyl chains. For the picket fence model, maximal quenching should occur at two different levels in the bilayer. The results show that the majority of the helices are in an orientation that is consistent with a belt model, because most Trp residues localized to a position about 5 A from the center of the bilayer. This study corroborates a belt hypothesis for the majority of the helices of apoA-I in phospholipid discs.
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PMID:Apolipoprotein A-I adopts a belt-like orientation in reconstituted high density lipoproteins. 1155 64

Apolipoprotein A-I (apo A-I) is the major protein component of high-density lipoprotein (HDL) particles. Elevated levels of HDL in the bloodstream have been shown to correlate strongly with a reduced risk factor for atherosclerosis. Molecular dynamics simulations have been carried out on three separate model discoidal high-density lipoprotein particles (HDL) containing two monomers of apo A-I and 160 molecules of palmitoyloleoylphosphatidylcholine (POPC), to a time-scale of 1ns. The starting structures were on the basis of previously published molecular belt models of HDL consisting of the lipid-binding C-terminal domain (residues 44-243) wrapped around the circumference of a discoidal HDL particle. Subtle changes between two of the starting structures resulted in significantly different behavior during the course of the simulation. The results provide support for the hypothesis of Segrest et al. that helical registration in the molecular belt model of apo A-I is modulated by intermolecular salt bridges. In addition, we propose an explanation for the presence of proline punctuation in the molecular belt model, and for the presence of two 11-mer helical repeats interrupting the otherwise regular pattern of 22-mer helical repeats in the lipid-binding domain of apo A-I.
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PMID:Molecular dynamics simulations on discoidal HDL particles suggest a mechanism for rotation in the apo A-I belt model. 1246 May 72

To investigate antisense peptide nucleic acid (PNA) as a gene therapy for the arterial proliferative diseases, the authors designed and examined the effects of an antisense PNA targeting platelet-derived growth factor (PDGF) A-chain on expression of PDGF A-chain and growth of vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. A 15-mer antisense PNA complementary to the initiation codon of rat and human PDGF A-chain mRNA was synthesized and purified by high-performance liquid chromatography. Gel-shift assay and biomolecular interaction analysis (BIAcore) revealed that the antisense PNA bound weakly to the target RNA, whereas it bound strongly to the target DNA. Fluorescein-isothiocyanate-labeled antisense PNA to PDGF A-chain was taken up slowly and maintained in VSMCs for a prolonged period of time. Antisense PNA inhibited expression of PDGF A-chain mRNA and protein as well as DNA synthesis in VSMCs in a dose-independent manner. Inhibition of DNA synthesis by the antisense PNA was greater than that by the antisense DNA at a low concentration (0.5 micromol/L). These results suggest that antisense PNA to PDGF A-chain will be used as a gene therapy for vascular proliferative diseases such as hypertensive vascular diseases, restenosis of coronary arteries after angioplasty, and atherosclerosis.
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PMID:Effects of antisense peptide nucleic acid to platelet-derived growth factor A-chain on growth of vascular smooth muscle cells. 1288 26

Insulin-like growth factors (IGFs) play a central role in the integration of proliferative and survival responses of most mammalian cell types. IGF-binding protein-3 (IGFBP-3) influences IGF action directly as a carrier of IGFs but also modulates these actions indirectly via independent mechanisms involving interactions with plasma, extracellular matrix and cell surface molecules, conditional proteolysis, cellular uptake, and nuclear transport. Here we demonstrate that a short C-terminal metal-binding domain (MBD) of IGFBP-3 mediates binding to metals. MBD epitopes, sequestered in the intact molecule, are unmasked by incubation in the presence of ferrous (but not ferric or zinc) ions. An isolated 14-mer MBD peptide triggered apoptotic effects in stressed HEK293 cells as effectively as IGFBP-3. The MBD, which encompasses a nuclear localization sequence and an adjacent putative caveolin-binding sequence, mobilizes rapid cellular uptake and nuclear localization of unrelated proteins such as green fluorescent protein and streptavidin-horseradish peroxidase conjugate. Metal ions stimulate MBD-mediated cellular/nuclear uptake in vivo. Cross-linking studies showed a direct physical interaction of MBD with integrins alphav and beta1, caveolin-1, and transferrin receptor. MBD-mediated protein mobilization and pro-apoptotic effects are inhibited by nystatin but not chlorpromazine, suggesting an involvement of caveolar-mediated endocytosis. However, MBD effects are inhibited by antibodies to transferrin receptor or integrins. These results are discussed with particular reference to the cell target specificity of IGFBP-3 in disease processes such as cancer and atherosclerosis.
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PMID:Insulin-like growth factor-independent effects mediated by a C-terminal metal-binding domain of insulin-like growth factor binding protein-3. 1457 63

Although the VEGF-Flk-1-pathway has been known as the major driving force of angiogenesis, new evidence has shown that VEGFR-1/Flt-1 plays important roles during the neovascularization under pathological conditions including tumor, atherosclerosis and arthritis. In search of Flt-1 receptor antagonizing peptides, we screened a phage display 12-mer-peptide library with recombinant Flt-1 protein. Seven candidate peptides were identified that specifically bound to VEGF receptor Flt-1, of which peptide F56 (WHSDMEWWYLLG) almost abolished VEGF binding to receptor Flt-1 in vitro. In vivo, F56 fused with DHFR (DHFR-F56) inhibited angiogenesis in a CAM assay. Moreover, DHFR-F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC-803 in BALB/c nude mice. Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with DHFR-F56. In the severe combined immunodeficiency disease (SCID) mouse model for studying metastasis of the human breast cancer cell line BICR-H1, synthetic peptide F56 significantly inhibited tumor growth and lung metastases. Taken together, our results have demonstrated that peptide F56, as a Flt-1 receptor antagonist, fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between VEGF and receptor Flt-1. Thus, short peptide F56 may have clinical potential in tumor therapy.
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PMID:Suppression of tumor growth and metastasis by a VEGFR-1 antagonizing peptide identified from a phage display library. 1519 67

Macrophage apoptosis and the ability of phagocytes to clear these apoptotic cells are important processes in advanced atherosclerosis. Phagocytic clearance not only disposes of dead cells but usually elicits an anti-inflammatory response. To study this process in a model of advanced lesional macrophage death, macrophages rendered apoptotic by free cholesterol loading (FC-AMs) were incubated briefly with fresh macrophages ("phagocytes"). FC-AMs were promptly ingested by the phagocytes, which was dependent upon actin polymerization and the phagocyte Mer receptor. Surprisingly, this brief exposure to FC-AMs triggered a modest proinflammatory response in the phagocytes: tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta were induced, whereas the levels of transforming growth factor-beta and IL-10 were not increased. This response required cell contact between the FC-AMs and phagocytes but not FC-AM ingestion. TNF-alpha and IL-1beta induction required one or more proteins on the FC-AM surface and was dependent on signaling through extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase and nuclear factor-kappaB in the phagocytes. TNF-alpha production was markedly greater when Mer-defective phagocytes were used, indicating that Mer attenuated the inflammatory response. Interestingly, a more typical anti-inflammatory response was elicited when phagocytes were exposed to macrophages rendered apoptotic by oxidized low density lipoprotein or UV radiation. Thus, the proinflammatory milieu of advanced atherosclerotic lesions may be promoted, or at least not dampened, by contact between FC-induced apoptotic macrophages and neighboring phagocytes prior to apoptotic cell ingestion.
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PMID:Cholesterol-induced apoptotic macrophages elicit an inflammatory response in phagocytes, which is partially attenuated by the Mer receptor. 1638 Mar 74


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