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)

Hyperinsulinemia has been shown to be associated with diabetic angiopathy. Migration and proliferation of vascular smooth muscle cells (VSMC) are the processes required for the development of atherosclerosis. In this study, we attempted to determine whether insulin affects mitogenic signaling induced by platelet-derived growth factor (PDGF) in a rat VSMC cell line (A10 cells). PDGF stimulated DNA synthesis which was totally dependent on Ras, because transfection of dominant negative Ras resulted in complete loss of PDGF-stimulated DNA synthesis. Initiation of DNA synthesis was preceded by activation of Raf-1, MEK and MAP kinases (Erk 1 and Erk2). Treatment of the cells with PD98059, an inhibitor of MAPK kinase (MEK) attenuated but did not abolish PDGF-stimulated DNA synthesis, suggesting that MAPK is required but not essential for DNA synthesis. PDGF also stimulated phosphorylation of protein kinase B (Akt/PKB) and p70 S6Kinase (p70S6K) in a wortmannin-sensitive manner. Rapamycin, an inhibitor of p70S6K, markedly suppressed DNA synthesis. Low concentrations of insulin (1-10 nmol/l) alone showed little mitogenic activity and no significant effect on MAPK activity. However, the presence of insulin enhanced both DNA synthesis and MAPK activation by PDGF. The enhancing effect of insulin was not seen in cells treated with PD98059. Insulin was without effect on PDGF-stimulated activations of protein kinase B (Akt/PKB) and p70S6K. We conclude that insulin, at pathophysiologically relevant concentrations, potentiates the PDGF-stimulated DNA synthesis, at least in part, by potentiating activation of the MAPK cascade. These results are consistent with the notion that hyperinsulinemia is a risk factor for the development of atherosclerosis.
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PMID:Potentiation of mitogenic activity of platelet-derived growth factor by physiological concentrations of insulin via the MAP kinase cascade in rat A10 vascular smooth muscle cells. 1199 Nov 99

Advanced glycation end products (AGEs) play an important role in the development of angiopathy in diabetes mellitus and atherosclerosis. Here, we show that adducts of N(epsilon)-(carboxymethyl)lysine (CML), a major AGE, and bovine serum albumin (CML-BSA) stimulated gamma-glutamylcysteine synthetase (gamma-GCS), which is a key enzyme of glutathione (GSH) synthesis, in RAW264.7 mouse macrophage-like cells. CML-BSA stimulated the expression of gamma-GCS heavy subunit (h) time- and dose-dependently and concomitantly increased GSH levels. CML-BSA also stimulated DNA-binding activity of activator protein-1 (AP-1) within 3h, but the stimulatory effect decreased in 5h, and nuclear factor-kappaB (NF-kappaB) with a peak activity at 1h and the stimulatory effect diminished in 3h. Studies of luciferase activity of the gamma-GCSh promoter showed that deletion and mutagenesis of the AP-1-site abolished CML-BSA-induced up-regulation, while that of NF-kappaB-site did not affect CML-BSA-induced activity. CML-BSA also stimulated the activity of protein kinase C, Ras/Raf-1, and MEK/ERK1/2. Inhibition of ERK1/2 abolished CML-BSA-stimulated AP-1 DNA-binding activity and gamma-GCSh mRNA expression. Our results suggest that induction of gamma-GCS by CML adducts seems to increase the defense potential of cells against oxidative stress produced during glycation processes.
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PMID:Nepsilon-(Carboxymethyl)lysine induces gamma-glutamylcysteine synthetase in RAW264.7 cells. 1214 23

Although oxidized lipoproteins may play an important role in the progression of atherosclerosis, no report has mentioned the significance of oxidized lipoprotein (a) (Lp[a]) in the pathogenesis of cardiovascular disease. Initially, we compared the mitogenic actions of Lp(a) and oxidized Lp(a) on human vascular smooth muscle cells (VSMC). Lp(a) significantly stimulated the growth of human VSMC in a dose-dependent manner, whereas oxidized Lp(a) showed a stronger stimulatory action on VSMC growth than native Lp(a). Interestingly, antioxidants probucol and fluvastatin inhibited the oxidation of Lp(a). Moreover, the stimulatory effect of oxidized Lp(a) on human VSMC growth was significantly inhibited by probucol. Finally, we elucidated the molecular mechanisms of how Lp(a) stimulated the growth of VSMC. Extracellular signal-regulated kinase (ERK), as those controlled by kinases, modulate critical cellular functions such as cell growth, differentiation, and apoptosis, was transiently phosphorylated by oxidized Lp(a) as well as native Lp(a) from 5 minutes, and the phosphorylation disappeared within 30 minutes. The degree of ERK phosphorylation by oxidized Lp(a) was much higher than that by native Lp(a). Administration of a specific inhibitor of MEK, PD 98059, significantly attenuated VSMC growth induced by native Lp(a) or oxidized Lp(a) in a dose-dependent manner (P<0.01). The current study demonstrated that oxidized Lp(a) is more potent than native Lp(a) in stimulating VSMC growth. Oxidized Lp(a) may play an important role in the pathogenesis of vascular disease.
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PMID:Mitogenic activity of oxidized lipoprotein (a) on human vascular smooth muscle cells. 1221 72

A key event in neointima formation and atherogenesis is the migration of vascular smooth muscle cells (VSMCs) into the intima. This is controlled by cytokines and extracellular matix (ECM) components within the microenvironment of the diseased vessel wall. At present, these signals have only been partially identified. In this study, we demonstrate that Met, the receptor tyrosine kinase for hepatocyte growth factor (HGF), is expressed on VSMCs isolated from the intima of atherosclerotic plaques of carotid arteries. Stimulation with HGF led to activation of Met as well as to activation of PI3-K, PKB/Akt, MEK, and the MAP kinases Erk1 and -2. Moreover, HGF induced lamellipodia formation, a characteristic feature of motile cells, and promoted VSMC migration across fibronectin-coated filters. The HGF-induced cell migration was mediated by beta1 integrins and required PI3-K activation. Our results suggest a role for the HGF-Met signaling pathway in the pathogenesis of atherosclerosis and restenosis.
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PMID:Hepatocyte growth factor triggers signaling cascades mediating vascular smooth muscle cell migration. 1237 23

We investigated the effects of high concentrations of glucose on plasminogen activator inhibitor-1 (PAI-1) gene expression in cultured rat vascular smooth muscle cells (VSMC). In response to a high glucose concentration (27.5 mM), PAI-1 mRNA increased within 2 h, peaked at 4 h, remained elevated for another 4 h, then decreased to basal levels at 24 h. On the other hand, mannose at the same concentration (22.5 mM mannose plus 5.5 mM glucose) as an osmotic control had little effect on PAI-1 mRNA expression. The expression of PAI-1 mRNA that was also increased by H(2)O(2), angiotensin II, or phorbol myristate acetate, was reversed by the MAPK kinase (MEK) inhibitor PD98059 or the specific protein kinase C (PKC) inhibitor GF109203X. High glucose appeared to activate MAPK and PKC in VSMC judging from Elk-1 and AP-1 activation, respectively. PD98059 inhibited and GF109203X prevented subsequent PAI-1 induction by glucose. These results suggest that glucose at high concentrations induces PAI-1 gene expression in VSMC at least partially via MAPK and PKC activation. This direct effect of glucose might have important implications for the increased plasma concentrations of PAI-1 and possibly atherosclerosis that are associated with diabetes.
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PMID:Glucose upregulates plasminogen activator inhibitor-1 gene expression in vascular smooth muscle cells. 1240 45

Hepatocyte growth factor (HGF) is a potent mitogen for vascular endothelial cells (EC); however, signal transduction pathways for HGF-stimulated EC growth remain unclear. In the present study we investigated the role of Src family kinases and nitric oxide (NO) in HGF-stimulated EC growth. Human umbilical vein endothelial cells (HUVEC) were stimulated with HGF and NO was measured by an NOx analyzing HPLC system. Activation of ERK1/2 and p38 MAPK was assessed by Western blot. NO production in HUVEC increased 1.8-fold by HGF. A Src family kinases inhibitor PP1 inhibited HGF-stimulated NO production by 71%. HUVEC growth increased 1.9-fold in cell number by HGF. PP1 and Nitro-L-arginine methylester (L-NAME) inhibited HGF-stimulated HUVEC growth by 51 and by 71%. ERK1/2 and p38 MAPK were phosphorylated by HGF and a MEK inhibitor PD98059 and a p38 MAPK inhibitor SB203580 inhibited HGF-stimulated HUVEC growth by 66% and by 58%; however, HGF-induced phosphorylation of ERK1/2 and p38 MAPK was not inhibited by L-NAME, indicating that NO is not an upstream activator of ERK1/2 and p38 MAPK. These findings demonstrated that Src family kinases regulate HGF-stimulated NO production in HUVEC and that HGF stimulates HUVEC growth through NO-dependent and NO-independent pathways.
Atherosclerosis 2003 Mar
PMID:Src family kinases and nitric oxide production are required for hepatocyte growth factor-stimulated endothelial cell growth. 1261 72

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

Early growth response-1 (Egr-1) regulates expression of proinflammatory and procoagulant genes in acute cell stress. Experimental evidence suggested that Egr-1 transcripts were upregulated in human atherosclerotic plaques versus adjacent unaffected tissue. To test the impact of Egr-1 in chronic vascular stress, we examined its role in a murine model of atherosclerosis. Real-time PCR analysis of aortae retrieved from apoE-/- mice demonstrated increased Egr-1 transcripts in an age-dependent manner, compared with aortae retrieved from C57BL/6 control animals. Therefore, homozygous Egr-1-/- mice were bred into the apoE-/- background. Homozygous double-knockout mice (Egr-1-/-/apoE-/-) in the C57BL/6 background were maintained on normal chow diet. At age 14 and 24 weeks, atherosclerotic lesion area and complexity at the aortic root were strikingly decreased in mice deficient in both Egr-1 and apoE compared with mice deficient in apoE alone. In parallel, transcripts for genes regulating the inflammatory/prothrombotic response were diminished in Egr-1-/-/apoE-/- aortae versus apoE-/-. In vitro, oxidized low-density lipoprotein (OxLDL), a key factor inciting atherogenic mechanisms in the vasculature, upregulated Egr-1 expression in monocytes via the MEK-ERK1/2 pathway. We conclude that Egr-1 broadly regulates expression of molecules critically linked to atherogenesis and lesion progression.
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PMID:Early growth response-1 promotes atherogenesis: mice deficient in early growth response-1 and apolipoprotein E display decreased atherosclerosis and vascular inflammation. 1467 Aug 37

Platelet-derived growth factors (PDGFs), potent mitogens and chemoattractants for mesenchymal cell types, play essential roles in development of several organs including blood vessels, kidney, and lung, and are also implicated in the pathogenesis of atherosclerosis and malignancies. Blood lipid mediator sphingosine 1-phosphate (S1P) regulates migration, proliferation, and apoptosis in a variety of cell types through multiple G protein-coupled receptors of the Edg family, and is necessary for vascular formation at the developmental stage. We found in the present study that S1P induced severalfold increases in the mRNA and protein levels of PDGF-A and -B chains in vascular smooth muscle cells and neointimal cells. S1P stimulation of PDGF mRNA and protein expression was abolished by the small interfering RNA duplexes targeting S1P(1)/Edg1 receptor subtype. S1P stimulated the small GTPase Ras in a G(i)-dependent manner, and activated ERK and p38 MAPK in G(i)- and Ras-dependent manners. Pertussis toxin pretreatment, adenovirus-mediated Asn(17)Ras expression, the MEK inhibitor PD98059, or the p38 MAPK inhibitor SB203580 markedly suppressed PDGF mRNA and protein up-regulation, indicating the involvement of G(i)-Ras-ERK/p38 MAPK in S1P stimulation of PDGF expression. S1P stimulated expression of the transcription factor KLF5 in manners dependent on G(i), Ras, and ERK/p38 MAPK. Down-regulation of KLF5 by small interfering RNA duplexes abolished S1P-induced PDGF-A and -B chain expression. On the other hand, overexpression of KLF5 stimulated basal and S1P-induced PDGF expression. Either S1P stimulation or KLF5 overexpression increased the PDGF-B promoter activity in a cis-element-dependent manner. These results reveal the S1P(1)-triggered, G(i)-Ras-ERK/p38 MAPK-KLF5-dependent, stimulatory regulation of PDGF gene transcription in vascular smooth muscle cells.
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PMID:Blood lipid mediator sphingosine 1-phosphate potently stimulates platelet-derived growth factor-A and -B chain expression through S1P1-Gi-Ras-MAPK-dependent induction of Kruppel-like factor 5. 1471 26

High density lipoproteins (HDL) induce prostacyclin (PGI(2)) release in vascular smooth muscle cells (VSMC) by up-regulation of cyclooxygenase-2 (Cox-2). Our goal was to analyse the mechanisms underlying this effect, and its potential modulation by HMG-CoA reductase inhibition in human VSMC. The contribution of mitogen-activated protein kinase (MAPK) signalling pathways was assessed by Western blot analysis and using specific inhibitors [PD098059 for p42/44 MAPK kinase (MEK); SB203580 for p38 MAPK or L-JNKI1 for c-Jun N-terminal kinase-1 (JNK-1)]. HDL-induced PGI(2) release was inhibited by rofecoxib (a specific Cox-2 inhibitor, 5 microM). HDL induced the early activation of p42 MAPK, p38 MAPK and JNK-1. p42/44 MAPK was the major pathway involved in both Cox-2 up-regulation and PGI(2) synthesis; p38 MAPK was also involved in both processes while JNK inhibition only affected PGI(2) synthesis. Pertussis toxin (an inhibitor of Galphai/Galphao proteins) prevented MAPK activation and inhibited both Cox-2 up-regulation and PGI(2) release. Genistein (a tyrosine kinase inhibitor) inhibited PGI(2) release without affecting MAPK activation or Cox-2 up-regulation. Simvastatin (0.1-1 microM) increased HDL-induced PGI(2) release ( approximately 45% at 1 microM) but did not significantly modify early MAPK activation or Cox-2 expression. Simvastatin alone did not significantly affect PGI(2) release. Our results suggest that mechanisms associated with G protein-coupled receptor activation, trigger Cox-2 up-regulation and PGI(2) release via multiple MAPK signalling pathways in VSMC. The mechanism is independent of tyrosine kinase receptors, although cytosolic tyrosine kinases could activate Cox-2 post-translationally. The potential contribution of HDL to vascular homeostasis, via increases in PGI(2) synthesis, could be enhanced by HMG-CoA reductase inhibitors.
Atherosclerosis 2004 Jun
PMID:Simvastatin potenciates PGI(2) release induced by HDL in human VSMC: effect on Cox-2 up-regulation and MAPK signalling pathways activated by HDL. 1513 60


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