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)

Oxidized low-density lipoprotein (OxLDL) is a risk factor in atherosclerosis and stimulates multiple signaling pathways, including activation of phosphatidylinositol 3-kinase (PI3-K)/Akt and p42/p44 mitogen-activated protein kinase (MAPK), which are involved in mitogenesis of vascular smooth muscle cells (VSMCs). We therefore investigated the relationship between PI3-K/Akt and p42/p44 MAPK activation and cell proliferation induced by OxLDL. OxLDL stimulated Akt phosphorylation in a time- and concentration-dependent manner, as determined by Western blot analysis. Phosphorylation of Akt stimulated by OxLDL and epidermal growth factor (EGF) was attenuated by inhibitors of PI3-K (wortmannin and LY294002) and intracellular Ca2+ chelator (BAPTA/AM) plus EDTA. Pretreatment of VSMCs with pertussis toxin, cholera toxin, and forskolin for 24 h also attenuated the OxLDL-stimulated Akt phosphorylation. In addition, pretreatment of VSMCs with wortmannin or LY294002 inhibited OxLDL-stimulated p42/p44 MAPK phosphorylation and [3H]thymidine incorporation. Furthermore, treatment with U0126, an inhibitor of MAPK kinase (MEK)1/2, attenuated the p42/p44 MAPK phosphorylation, but had no effect on Akt activation in response to OxLDL and EGF. Overexpression of p85-DN or Akt-DN mutants attenuated MEK1/2 and p42/p44 MAPK phosphorylation stimulated by OxLDL and EGF. These results suggest that the mitogenic effect of OxLDL is, at least in part, mediated through activation of PI3-K/Akt/MEK/MAPK pathway in VSMCs.
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PMID:OxLDL induces mitogen-activated protein kinase activation mediated via PI3-kinase/Akt in vascular smooth muscle cells. 1281 Aug 18

Various growth factors such as the platelet derived growth factor (PDGF), insulin-like growth factor (IGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) transduce their mitogenic signals through the activation of tyrosine kinase receptors (RTKs). Since enhanced RTK activity has been associated with the development of proliferative diseases such as atherosclerosis and cancer, there has been an increased interest recently in the development of small molecule RTK inhibitors for the prevention/treatment of the aforementioned diseases. Many cell culture and animal studies have shown that catechins, the main compounds of the green tea leaves, are potent natural inhibitors of several RTKs. In the present article we review the various molecular and cellular mechanisms through which catechins inhibit the growth factor-RTK-mediated signal transduction pathways and exert their antiproliferative/apoptotic effects.
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PMID:Molecular mechanisms explaining the preventive effects of catechins on the development of proliferative diseases. 1507 40

Reactive oxygen species (ROS) have been shown to mediate the effects of several growth factors and vasoactive peptides, such as epidermal growth factor, platelet-derived growth factor, and angiotensin II (AII). Endothelin-1 (ET-1) is a vasoactive peptide which also exhibits mitogenic activity in vascular smooth muscle cells (VSMCs), and is believed to contribute to the pathogenesis of vascular abnormalities such as atherosclerosis, hypertension, and restenosis after angioplasty. However, a possible role for ROS generation in mediating the ET-1 response on extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase B (PKB), and protein tyrosine kinase 2 (Pyk2), key components of the growth-promoting and proliferative signaling pathways, has not been examined in detail. Our aim was to investigate the involvement of ROS in ET-1-mediated activation of ERK1/2, PKB, and Pyk2 in A-10 VSMCs. ET-1 stimulated ERK1/2, PKB, and Pyk2 phosphorylation in a dose- and time-dependent manner. Pretreatment of A-10 VSMCs with diphenyleneiodonium (DPI), an inhibitor of reduced nicotinamide adenine dinucleotide phosphate oxidase, attenuated ET-1-enhanced ERK1/2, PKB, and Pyk2 phosphorylation. In addition, in parallel with an inhibitory effect on the above signaling components, DPI also blocked ET-1-induced protein synthesis. ET-1 was also found to increase ROS production, which was suppressed by DPI treatment. N-Acetylcysteine, a ROS scavenger, exhibited a response similar to that of DPI and inhibited ET-1-stimulated ERK1/2, PKB, and Pyk2 phosphorylation. These results demonstrate that ROS are critical mediators of ET-1-induced signaling events linked to growth-promoting proliferative and hypertrophic pathways in VSMCs.
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PMID:Reactive oxygen species mediate Endothelin-1-induced activation of ERK1/2, PKB, and Pyk2 signaling, as well as protein synthesis, in vascular smooth muscle cells. 1520 92

The recruitment of peripheral monocytes to the sub-endothelial space, their development into macrophages and subsequent proliferation are critical events during atherosclerosis. Receptors for epidermal growth factor (EGF) have been identified on cells of the myeloid lineage, but a role for them in atherogenesis has yet to be described. We have identified functional EGF receptors (EGFR, ErbB1/HER-1) on peripheral blood monocytes and monocyte-derived macrophages. Uniquely, these receptors were found to mediate both chemotaxis in monocytes and macrophages and proliferation in macrophages. EGFR mRNA was detected in atherosclerotic plaques, but not in morphologically normal aortae and EGFR receptor staining co-localised with macrophage staining in these plaques. The identification of receptors for EGF on peripheral blood monocytes, macrophages and atherosclerotic lesions, together with their transduction of two functionally important cellular events, heightens the potential importance of members of the EGF super-family in atherogenesis and other chronic inflammatory processes.
Atherosclerosis 2004 Sep
PMID:EGF mediates monocyte chemotaxis and macrophage proliferation and EGF receptor is expressed in atherosclerotic plaques. 1530 70

The endothelium of the adult vasculature is normally quiescent, with the exception of the vasculature of the female reproductive system. However, in response to appropriate stimuli (ie, wound healing, atherosclerosis, tumor growth and metastasis, arthritis) the vasculature becomes activated and grows new capillaries through angiogenesis. We have recently identified a novel endothelial-restricted gene, Egfl7, that encodes a 41-kd secreted protein (Fitch MJ, Campagnolo L, Kuhnert F, Stuhlmann H: Egfl7, a novel epidermal growth factor-domain gene expressed in endothelial cells. Dev Dyn 2004, 230:316-324). Egfl7 is expressed at high levels early during mouse embryonic development and is strictly associated with the vascular bed. In this study, we investigated Egfl7 expression in the quiescent adult vasculature, in the pregnant uterus, and in two different models of arterial injury, namely ballooning and ferric chloride injury. By RNA in situ hybridization, Egfl7 expression in the vasculature was found to be restricted to the endothelium of the capillaries and mature vessels. In the pregnant uterus, increased vascularization was accompanied by up-regulation of Egfl7. On arterial injury, Egfl7 expression was up-regulated in the regenerating endothelium, but not in the neointima. Importantly, the EGFL7 protein acted as a chemoattractant for embryonic endothelial cells and fibroblasts in a cell migration assay. Together, these results suggest that Egfl7 functions in the formation and maintenance of endothelial integrity and that its up-regulation may be a critical component in the reorganization of the vascular bed in response to angiogenic stimuli.
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PMID:EGFL7 is a chemoattractant for endothelial cells and is up-regulated in angiogenesis and arterial injury. 1597 71

Berberine, an alkaloid isolated from Chinese medicinal herbs, long been known for its anti-microbial activity and used to treat various infectious disorders in traditional Chinese medicine. In the present study, we have tested the hypothesis that berberine could inhibit vascular smooth muscle cell (VSMC) proliferation as it did in endothelial cells or cancer cells. Our results show that berberine significantly inhibits growth factor, mainly angiotensin II (AngII) and heparin binding epidermal growth factor (HB-EGF), induced VSMC proliferation and migration in vitro, and this effect is achieved by delaying or partially suppressing activation of Akt pathway rather than ERK pathway. Furthermore, we have examined its effect in vivo using a rat carotid artery injury model. A 28 days of chronic berberine treatment using an osmotic pump (100 microg kg(-1)d(-1), 2 weeks before and 2 weeks after the injury) improved neointima formation. The Neointima/Media ratio for control group and berberine treated group were 1.14+/-0.11 and 0.85+/-0.06 (p<0.05), respectively, and the reduction was approximately 25%. The result of the present study suggests a possibility of berberine being a potent agent to control restenosis after balloon angioplasty and warrants further study to gain a more complete understanding of its underlying mechanisms at a cellular level.
Atherosclerosis 2006 May
PMID:Berberine inhibits rat vascular smooth muscle cell proliferation and migration in vitro and improves neointima formation after balloon injury in vivo. Berberine improves neointima formation in a rat model. 1609 30

High-throughput genomic technology identified an association between a single nucleotide polymorphism (SNP), a proline (P387) rather than the predominant alanine (A387) at position 387 in thrombospondin-4 (TSP-4) and premature myocardial infarction. The inflammatory hypothesis of atherosclerosis invokes a prominent role of leukocytes and cytokines in pathogenesis. As the expression of TSP-4 by vascular cells permits its exposure to circulating leukocytes, the interactions of human neutrophils (polymorphonuclear leukocytes [PMNs]) with both TSP-4 variants were investigated. Phorbol 12-myristate 13-acetate (PMA)-stimulated PMNs adhered and migrated well and equally on the TSP-4 variants. Integrin alpha(M)beta2 was identified as the TSP-4 receptor mediating these responses, and the 3 epidermal growth factor (EGF)-like domains of TSP-4 harboring the SNPs interacted with the alpha(M)I-domain. Despite the similarity in these responses, the P387 variant induced more robust tyrosine phosphorylation of the stress-related mitogen-activated protein kinases (MAPKs): p38MAPK and c-Jun NH2-terminal kinase (JNK), as well as signal transducer and activator of transcription-1 (STAT1) and heat shock protein 27 (HSP27) than the A387 variant. Additionally, cells adherent to P387 TSP-4 variant released 4-fold more H2O2 and secreted 2-fold more interleukin 8 (IL-8) as compared with the A387. H2O2 release and p38MAPK activation were totally inhibited by blockade of alpha(M)beta2. Thus, alpha(M)beta2 plays a central role in proinflammatory activities of TSP-4 (P387) and may contribute to the prothrombotic phenotype associated with this variant.
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PMID:Mechanism and effect of thrombospondin-4 polymorphisms on neutrophil function. 1609 85

Platelets, macrophages, endothelial cells, and smooth muscle cells can all contribute to atherosclerosis. To investigate the molecular events leading to atherosclerosis involving platelets, macrophages, endothelial cells, and smooth muscle cells, we carried out suppression subtractive hybridization (SSH) to generate a profile of genes overexpressed in the aorta and blood cells in high fat diet rats. From 85 random SSH-cDNA clones, we have screened 23 clones by Northern blotting, which were scored as overexpressed in the aorta and blood cells in high fat diet rats compared to normal diet rats. Sequencing showed that the gene corresponded to the known gene in the public databases, previously shown to be overexpressed in atherosclerosis, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), and local production was seen in vascular smooth muscle and endothelial cells by RT-PCR and Western blotting. These results show that SSH provides a very efficient means to produce a profile of differentially expressed genes in atherosclerosis. The identified gene may provide novel points of therapeutic intervention and pathophysiological mechanisms in atherosclerosis.
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PMID:Profile of differentially expressed genes in blood vessels and blood cells of hyperlipidemia rats using suppression subtractive hybridization. 1619 94

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of hepatic low density lipoprotein receptors (LDLR), the major route of clearance of circulating cholesterol. Gain-of-function mutations in PCSK9 cause hypercholesterolemia and premature atherosclerosis, whereas loss-of-function mutations result in hypocholesterolemia and protection from heart disease. Recombinant human PCSK9 binds the LDLR on the surface of cultured hepatocytes and promotes degradation of the receptor after internalization. Here we localized the site of binding of PCSK9 within the extracellular domain of the LDLR and determined the fate of the receptor after PCSK9 binding. Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR. Similar binding specificity was observed between PCSK9 and purified EGF-A. Binding to EGF-A was calcium-dependent and increased dramatically with reduction in pH from 7 to 5.2. The addition of PCSK9, but not heat-inactivated PCSK9, to the medium of cultured hepatocytes resulted in redistribution of the receptor from the plasma membrane to lysosomes. These data are consistent with a model in which PCSK9 binding to EGF-A interferes with an acid-dependent conformational change required for receptor recycling. As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded.
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PMID:Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. 1745 16

Heparin binding-epidermal growth factor-like growth factor (HB-EGF) is one of the EGF receptor ligands and possesses several functional domains. It is involved in diverse biological processes, including wound healing, blast implantation, atherosclerosis and tumor formation, through its interactions with various molecules. We have reported that HB-EGF gene expression is significantly elevated in human ovarian cancer, and further demonstrated that HB-EGF plays key roles in the acquisition of malignant phenotypes, such as cell survival in peritoneal fluid, cell adhesion on extracellular matrices, invasion, angiogenesis, tumorigenicity, and chemoresistance in ovarian cancer. Thus, HB-EGF was considered as a promising target for cancer therapy. In vitro as well as in vivo experiments have revealed that cross-reacting material 197 (CRMI97), a specific inhibitor of HB-EGF, or a small interfering RNA for HB-EGF can block each step involved in peritoneal dissemination. According to these pieces of evidence, the development of targeting tools against HB-EGF, such as CRM197, could allow us to improve the prognosis of cancer patients.
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PMID:New approach to cancer therapy: heparin binding-epidermal growth factor-like growth factor as a novel targeting molecule. 1797 33


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