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)

Platelet-derived growth factor (PDGF) stimulates expression of matrix metalloproteinases (MMPs), including stromelysin-1 (MMP-3). Induction of these expressions is known to occur during the course of atherosclerosis, tumor invasion, and metastasis. We investigated PDGF-alpha receptor (alphaR)- and beta receptor (betaR)-mediated signaling pathways for the expression of MMP-3 and invasion activity using porcine aortic endothelial (PAE) cells with stable expression of normal or mutated PDGF receptors. RT-PCR and Western blot analyses revealed that PDGF-BB induces MMP-3 expression in PAE cells that exclusively express either the PDGF-alphaR or the -betaR, but not in non-transfected control cells. To identify the signals necessary for PDGF receptor-mediated induction of MMP-3 expression, several lines of PAE cells expressing mutant PDGF receptors were further analyzed. Cells expressing mutant PDGF receptors unable to associate with Src or PLCgamma, retained the ability to induce MMP-3 expression as a result of PDGF-BB stimulation. However, incubation with PDGF-BB did not induce MMP-3 expression in cells expressing a mutant PDGF-betaR unable to associate with phosphatidylinositol 3(')-kinase (PI3K). LY294002, a PI3K inhibitor, reduced PDGF-BB-stimulated MMP-3 expression in PAE cells expressing wild-type PDGF receptors. In contrast, PDGF-BB induced MMP-3 expression in the presence of U-73122, a PLCgamma inhibitor. Moreover, PDGF-BB enhanced the invasiveness of cells expressing wild type PDGF-beta receptors, but not of cells expressing mutant PDGF-betaRs impaired in their ability to associate with PI3K. In light of these results, it appears that PDGF-BB is capable of inducing MMP-3 expression through both the PDGF-alphaR and the -betaR, and the effects are contributed by the PI3K-mediated transduction pathways.
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PMID:Functional analysis of aortic endothelial cells expressing mutant PDGF receptors with respect to expression of matrix metalloproteinase-3. 1205 99

The mortality rate from coronary artery disease (CAD) in France is approximately 50% compared to other European countries and the United States ("French paradox"). Epidemiological studies indicate an inverse relationship between moderate wine consumption and CAD mortality. Here, we demonstrate that preincubation of vascular smooth muscle cells (VSMCs) with red wine, but not white wine, inhibits ligand binding and the subsequent tyrosine phosphorylation of the platelet-derived growth factor beta receptor (betaPDGFR), which plays a critical role in the pathogenesis of atherosclerosis. As a consequence, red wine abrogates the ligand-induced recruitment of betaPDGFR-associated signaling molecules (RasGAP, SHP-2, PI3K, PLCgamma), PDGF-dependent downstream events such as Erk activation and induction of immediate early genes, and VSMC proliferation and migration. Wine analysis revealed flavonoids of the catechin family as major constituents of red wine, and these were identified as potent inhibitors of betaPDGFR signaling. Importantly, the concentrations of red wine/catechins shown to inhibit the PDGFR in vitro correlate with the serum levels after red wine consumption in humans. We conclude that nonalcoholic constituents of red wine, which accumulate during the "mash fermentation," inhibit betaPDGFR activation and PDGF-dependent cellular responses in VSMCs. Therefore, catechin-mediated inhibition of betaPDGFR signaling offers a molecular explanation for the "French paradox."
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PMID:Inhibition of the PDGF receptor by red wine flavonoids provides a molecular explanation for the "French paradox". 1239 93

Accelerated atherosclerosis is a major cause of morbidity and death in insulin-resistant states such as obesity and the metabolic syndrome, but the underlying mechanisms are poorly understood. We show that macrophages from obese (ob/ob) mice have increased binding and uptake of oxidized LDL, in part due to a post-transcriptional increase in CD36 protein. Macrophages from ob/ob mice are also insulin resistant, as shown by reduced expression and signaling of insulin receptors. Three lines of evidence indicate that the increase in CD36 is caused by defective insulin signaling: (a) Treatment of wild-type macrophages with LY294002, an inhibitor of insulin signaling via PI3K, results in an increase in CD36; (b) insulin receptor knockout macrophages show a post-transcriptional increase in CD36 protein; and (c) administration of thiazolidinediones to intact ob/ob mice and ob/ob, LDL receptor-deficient mice results in a reversal of macrophage insulin receptor defects and decreases CD36 protein. The last finding contrasts with the increase in CD36 that results from treatment of macrophages with these drugs ex vivo. The results suggest that defective macrophage insulin signaling predisposes to foam cell formation and atherosclerosis in insulin-resistant states and that this is reversed in vivo by treatment with PPAR-gamma activators.
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PMID:Increased CD36 protein as a response to defective insulin signaling in macrophages. 1499 Oct 75

The oxidation of plasma LDLs (low-density lipoproteins) is a key event in the pathogenesis of atherosclerosis. LPC (lysophosphatidylcholine) and oxysterols are major lipid constitutents of oxidized LDLs. In particular, 7-oxocholesterol has been found in plasma from cardiac patients and atherosclerotic plaque. In the present study, we investigated the ability of 7-oxocholesterol and LPC to regulate the activation of eNOS (endothelial nitric oxide synthase) and cPLA2 (cytosolic phospholipase A2) that synthesize two essential factors for vascular wall integrity, NO (nitric oxide) and arachidonic acid. In endothelial cells from human umbilical vein cords, both 7-oxocholesterol (150 microM) and LPC (20 microM) decreased histamine-induced NO release, but not the release activated by thapsigargin. The two lipids decreased NO release through a PI3K (phosphoinositide 3-kinase)-dependent pathway, and decreased eNOS phosphorylation. Their mechanisms of action were, however, different. The NO release reduction was dependent on superoxide anions in LPC-treated cells and not in 7-oxocholesterol-treated ones. The Ca2+ signals induced by histamine were abolished by LPC, but not by 7-oxocholesterol. The oxysterol also inhibited (i) the histamine- and thapsigargin-induced arachidonic acid release, and (ii) the phosphorylation of both cPLA2 and ERK1/2 (extracellular-signal-regulated kinases 1/2). The results show that 7-oxocholesterol inhibits eNOS and cPLA2 activation by altering a Ca2+-independent upstream step of PI3K and ERK1/2 cascades, whereas LPC desensitizes eNOS by interfering with receptor-activated signalling pathways. This suggests that 7-oxocholesterol and LPC generate signals which cross-talk with heterologous receptors, effects which could appear at early stage of atherosclerosis.
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PMID:Lysophosphatidylcholine and 7-oxocholesterol modulate Ca2+ signals and inhibit the phosphorylation of endothelial NO synthase and cytosolic phospholipase A2. 1499 85

We used mesenteric arterial beds from normal rats and beef tallow-fed rats (hypercholesterolemic model) to study the interaction between the effects of viscosity-induced shear stress and agonists mesenteric vasoreactivity. Mesenteric arterial beds were perfused under constant-flow conditions (5 ml/min) via a peristaltic pump using warm oxygenated modified Krebs-Henseleit solution containing either 4% BSA to increase viscosity or 300 microM L-arginine, a NO synthase substrate. Whether beds were perfused with BSA alone or L-arginine alone as pretreatment, the methoxamine-induced contractile responses were similar to those in normal beds. However, methoxamine-induced contractile responses were significantly reduced following pretreatment with L-arginine plus BSA. These reduced responses underwent significant recovery when either tyrphostin A23 (30 microM, a tyrosine kinase inhibitor) or wortmannin (300 nM, a PI3K inhibitor) was present. The dose-response curve for methoxamine was shifted to the right and the maximum contractile response was reduced in mesenteric arterial beds from beef tallow-fed rats, but the modulation of this response induced by L-arginine plus BSA was preserved. In beef tallow-fed rats, the ACh-induced endothelium-dependent vasodilation was attenuated in both thoracic aortic strips and mesenteric arterial beds. These results suggest that in hypercholesterolemic rats, agonist-induced endothelial function is impaired, while shear stress-induced responses (tyrosine kinase- and PI3K-mediated NO production) are preserved. These abnormal vascular responses may contribute to hypertension in beef tallow-fed hypercholesterolemic model rats.
Atherosclerosis 2004 Jul
PMID:Modulations of shear stress-induced contractile responses and agonist-induced vasodilation in hypercholesterolemic rats. 1518 44

The transcription factor NF-kappaB regulates cell cycle progression and proliferation in a number of cell types. An important unresolved issue is the potential role of NF-kappaB in the proliferation of vascular smooth muscle cells (VSMCs) as a basis for the development of vascular disease. To investigate the contribution of NF-kappaB to mitogen-induced proliferation of VSMCs, a knock-in mouse model expressing the NF-kappaB superrepressor IkappaBalphaDeltaN (c(IkappaBalphaDeltaN)) was used. Comparing wild-type and IkappaBalphaDeltaN-expressing VSMCs, we found that proliferation rates did not differ after mitogenic stimulation by platelet-derived growth-factor-BB (PDGF-BB) or serum. In line with this, NF-kappaB activation was not observed in VSMCs derived from transgenic mice expressing an NF-kappaB-dependent lacZ reporter (c((Igk)3conalacZ)). We further show, that classical mitogenic signaling pathways (namely mitogen-activated protein kinase [MAPK] and the phosphatidyl-inositol-3-OH-kinase [PI3K] pathways) control VSMC proliferation, but independently of NF-kappaB activation. In contrast to VSMCs, mouse embryonic fibroblasts (MEFs) derived from IkappaBalphaDeltaN-expressing mice showed significantly impaired proliferation rates after mitogenic stimulation. This was reflected by strongly impaired cyclin D1 expression in serum-stimulated MEFs derived from (c(IkappaBalphaDeltaN)) mice. These results implicate that essential pathogenetic functions of NF-kappaB in the development of atherosclerosis involve apoptotic and inflammatory signaling of VSMCs rather than proliferation. They further provide genetic evidence for a cell-type restricted requirement of NF-kappaB in the control of cellular proliferation.
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PMID:Regulation of vascular smooth muscle cell proliferation: role of NF-kappaB revisited. 1583 13

Vascular endothelial cells (EC) perform critical functions that require a balance of cell survival and cell death. EC death by apoptosis and EC activation and injury by the membrane attack complex of complement are important mechanisms in atherosclerosis and organ graft rejection. Although the effects of various cytokines on EC apoptosis have been studied, little is known about their effects on complement-mediated EC injury. Therefore, we studied the abilities of various cytokines to induce protection of porcine aortic EC against apoptosis and killing by human complement, a model of pig-to-human xenotransplantation. We found that porcine EC incubated with IL-4 or IL-13, but not with IL-10 or IL-11, became protected from killing by complement and apoptosis induced by TNF-alpha plus cycloheximide. Maximal protection required 10 ng/ml IL-4 or IL-13, developed progressively from 12 to 72 h of incubation, and lasted 48-72 h after cytokine removal. Protection from complement was not associated with reduced complement activation, C9 binding, or changes in CD59 expression. Inhibition of PI3K prevented development of protection; however, inhibition of p38 MAPK or p42/44 MAPK had no effect. IL-4 and IL-13 induced rapid phosphorylation of Akt. Although protection was inhibited by an Akt inhibitor and a dominant negative Akt mutant transduced into EC, it was induced by transduction of EC with the constitutively active Akt variant, myristylated Akt. We conclude that IL-4 and IL-13 can induce protection of porcine EC against killing by apoptosis and human complement through activation of the PI3K/Akt signaling pathway.
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PMID:IL-4 and IL-13 induce protection of porcine endothelial cells from killing by human complement and from apoptosis through activation of a phosphatidylinositide 3-kinase/Akt pathway. 1603 34

AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumour cells. These actions of AMPK appear to be mediated through multiple mechanisms including regulation of the cell cycle and inhibition of protein synthesis, de novo fatty acid synthesis, specifically the generation of mevalonate as well as other products downstream of mevalonate in the cholesterol synthesis pathway. Cell cycle regulation by AMPK is mediated by up-regulation of the p53-p21 axis as well as regulation of TSC2-mTOR (mammalian target of rapamycin) pathway. The AMPK signalling network contains a number of tumour suppressor genes including LKB1, p53, TSC1 and TSC2, and overcomes growth factor signalling from a variety of stimuli (via growth factors and by abnormal regulation of cellular proto-oncogenes including PI3K, Akt and ERK). These observations suggest that AMPK activation is a logical therapeutic target for diseases rooted in cellular proliferation, including atherosclerosis and cancer. In this review, we discuss about exciting recent advances indicating that AMPK functions as a suppressor of cell proliferation by controlling a variety of cellular events in normal cells as well as in tumour cells.
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PMID:AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer. 1661 76

Vascular smooth muscle cell (VSMC) apoptosis occurs in advanced atherosclerotic plaques where it may contribute to plaque instability. VSMCs express the death receptor Fas but are relatively resistant to Fas-induced apoptosis due in part to the intracellular sequestration of Fas. Although inflammatory cytokines such as interferon (IFN)-gamma present in plaques can prime VSMCs to FasL-induced death, the mechanism of this effect is unclear. We examined Fas expression and FasL-induced apoptosis in human VSMCs in response to IFN-gamma. IFN-gamma induced Fas trafficking to the cell surface within 24 hours, an effect that required Jak2/Stat1 activity. IFN-gamma also stimulated Akt activity, and both Fas trafficking and Stat1 activation were inhibited by blocking PI3K, Akt, or Jak-2. IFN-gamma increased Fas-induced apoptosis in vitro by 46 +/- 8% (mean +/- SEM, P = 0.04), an event that could be abrogated by inhibition of PI3K, Akt, or Jak-2. IFN-gamma also increased Fas-induced apoptosis in vivo 7.5- to 15-fold (P < 0.05) in human arteries transplanted into immunodeficient mice, accompanied by increased Fas and phospho-Ser727-Stat1. We conclude that IFN-gamma primes VSMCs to Fas-induced apoptosis, in part by relocation of Fas to the cell surface, a process that involves PI3K, Akt, and Jak-2/Stat1. IFN-gamma present in plaques may co-operate with FasL to induce VSMC apoptosis in atherosclerosis.
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PMID:Interferon-gamma induces Fas trafficking and sensitization to apoptosis in vascular smooth muscle cells via a PI3K- and Akt-dependent mechanism. 1672 18

We present evidence for a novel TLR2 function in transmodulating the adhesive activities of human monocytes in response to the fimbriae of Porphyromonas gingivalis, a pathogen implicated in chronic periodontitis and atherosclerosis. Monocyte recruitment into the subendothelium is a crucial step in atherosclerosis, and we investigated the role of P. gingivalis fimbriae in stimulating monocyte adhesion to endothelial cells and transendothelial migration. Fimbriae induced CD11b/CD18-dependent adhesion of human monocytes or mouse macrophages to endothelial receptor ICAM-1; these activities were inhibited by TLR2 blockade or deficiency or by pharmacological inhibitors of PI3K. Moreover, this inducible adhesive activity was sensitive to the action of Clostridium difficile toxin B, but was not affected by Clostridium botulinum C3 exoenzyme, pertussis toxin, or cholera toxin. Accordingly, we subsequently showed through the use of dominant negative signaling mutants of small GTPases, that Rac1 mediates the ability of fimbria-stimulated monocytes to bind ICAM-1. A dominant negative mutant of Rac1 also inhibited the lipid kinase activity of PI3K suggesting that Rac1 acts upstream of PI3K in this proadhesive pathway. Furthermore, fimbriae stimulated monocyte adhesion to HUVEC and transmigration across HUVEC monolayers; both activities required TLR2 and Rac1 signaling and were dependent upon ICAM-1 and the high-affinity state of CD11b/CD18. P. gingivalis-stimulated monocytes displayed enhanced transendothelial migration compared with monocytes stimulated with nonfimbriated isogenic mutants. Thus, P. gingivalis fimbriae activate a novel proadhesive pathway in human monocytes, involving TLR2, Rac1, PI3K, and CD11b/CD18, which may constitute a mechanistic basis linking P. gingivalis to inflammatory atherosclerotic processes.
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PMID:TLR2 transmodulates monocyte adhesion and transmigration via Rac1- and PI3K-mediated inside-out signaling in response to Porphyromonas gingivalis fimbriae. 1675 12


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