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)

Lipoprotein lipase (LPL), the major enzyme for hydrolysis of circulating triglyceride-rich lipoproteins, is bound to the luminal surface of capillary endothelial cells. Products of LPL-mediated lipolysis, such as free fatty acids (FFA) and lipoprotein-remnants, can affect endothelial function and gene expression, and hence vascular homeostasis. In this study we tried to identify lipolysis-induced mRNAs in porcine aortic endothelial cells (ECAP) using a cDNA subtraction method. cDNA obtained from ECAP incubated with LPL and VLDL was subtracted from cDNA from cells cultured under control conditions. Analysis of the identified sequences revealed an upregulation of several mRNAs with adenine and uracil-rich elements (ARE) in their 3'-untranslated regions, such as IL-8, ESM-1 and VCAM-1. HuR, a ubiquitously expressed RNA-binding protein, is known to stabilize ARE-harboring mRNAs. Therefore, we investigated whether HuR is involved in this process and found that lipolysis induced an increased polysomal localization of HuR, which is typical for its activation pathway. In addition, the mRNAs for GM-CSF and TNF-alpha - established ARE-containing targets for HuR-mediated regulation - were upregulated by LPL-mediated lipolysis in ECAP. Differential expression of AU-rich mRNAs in response to LPL-mediated lipolysis might have an impact on physiological processes regulating lipid metabolism or pathophysiological processes promoting endothelial dysfunction and atherogenesis.
Atherosclerosis 2006 Dec
PMID:LPL-mediated lipolysis of VLDL induces an upregulation of AU-rich mRNAs and an activation of HuR in endothelial cells. 1649 82

Recent experimental studies have shown that granulocyte-colony-stimulating factor (G-CSF) enhanced cardiac function after infarction. The concept of direct cytokine or cell-mediated effects on postischemic myocardial function was tested in the setting of human myocardial infarction subjected to percutaneous coronary intervention. In the FIRSTLINE-AMI study 50 consecutive patients with first ST-elevation myocardial infarction were randomly assigned to receive either 10 microg/kg G-CSF for 6 days after percutaneous coronary intervention in addition to standard medication, or standard care alone. G-CSF administration led to mobilization of CD34(+) mononuclear stem cells (MNC(CD34+)), with a 20-fold increase to 64 +/- 37 MNC(CD34+)/microl at day 6 without significant associated changes in rheology, blood viscosity or inflammatory reaction, or any major adverse effects. At 4 months the G-CSF group showed improved left ventricular ejection fraction of 54 +/- 8% versus 48 +/- 4% at baseline (P <0.001), and no evidence of left ventricular end-diastolic remodeling, with a diameter of 55 +/- 5 mm and improved segmental wall thickening (P <0.001); conversely, in control patients left ventricular ejection fraction was 43 +/- 5% at 4 months (P <0.001), with increased left ventricular end-diastolic dimension of 58 +/- 4 mm (P <0.001), and no segmental wall thickening. In conclusion, the FIRSTLINE-AMI study showed that G-CSF administration and mobilization of MNC(CD34+) after reperfusion of infarcted myocardium may offer a pragmatic strategy for preservation of human myocardium and prevention of remodeling without evidence of aggravated atherosclerosis.
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PMID:Effects of granulocyte-colony-stimulating factor on mobilization of bone-marrow-derived stem cells after myocardial infarction in humans. 1650 36

TGFbeta(1) deficiency has been attributed to the development of atherosclerosis. There is, however, little direct evidence for this concept. To examine this hypothesis, low-density lipoprotein receptor knockout (LDLR(-/-)) mice were injected via tail vein with recombinant adeno-associated virus type 2 (rAAV) carrying a bioactive TGFbeta(1) mutant (AAV/TGFbeta1ACT, n=10) or granulocyte-macrophage-colony stimulating factor (AAV/GM-CSF, n=10, a negative control) or saline (n=9, control), and then put on a high cholesterol diet. At 18 weeks, blood lipids were found to be similarly elevated in all LDLR(-/-) mice. TGFbeta1ACT and GM-CSF (DNA, mRNA, and protein) were highly expressed in the tissues of mice given TGFbeta1ACT or AAV/GM-CSF, respectively, showing sustained transfection following gene delivery by the systemic route. Saline-treated and AAV/GM-CSF-treated LDLR(-/-) mice showed extensive areas of atherosclerotic lesion formation. There was evidence of intense oxidative stress (nitrotyrosine staining), inflammation (CD68 staining), and expression of adhesion molecules and the ox-LDL receptor LOX-1 (gene array analysis) in the atherosclerotic tissues. Importantly, atherosclerotic lesion formation was markedly inhibited in the LDLR(-/-) mice given AAV/TGFbeta1ACT. Expression of adhesion molecules and LOX-1, oxidative stress, and inflammatory response all were inhibited in the mice given AAV/TGFbeta1ACT (P<0.05 vs. saline-treated or GM-CSF-treated LDLR(-/-) mice). These data for the first time demonstrate that systemic delivery of TGFbeta1ACT gene via AAV can inhibit formation of atherosclerotic lesions, possibly via anti-inflammatory and anti-oxidant mechanisms. These findings suggest a novel view of TGFbeta(1) in atherogenesis and a potential new gene therapy for treatment of atherosclerosis.
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PMID:Suppression of atherogenesis by delivery of TGFbeta1ACT using adeno-associated virus type 2 in LDLR knockout mice. 1663 3

Thiazolidinediones (TZDs), which were known as novel insulin-sensitizing antidiabetic agents, have been reported to inhibit the acceleration of atherosclerotic lesions. Macrophages play important roles in the development of atherosclerosis. We previously reported that oxidized low-density lipoprotein (Ox-LDL) induces macrophage proliferation through ERK1/2-dependent GM-CSF production. In the present study, we investigated the effects of two TZDs, troglitazone and ciglitazone on Ox-LDL-induced macrophage proliferation. Troglitazone significantly inhibited Ox-LDL-induced increases in [(3)H]thymidine incorporation into and proliferation of mouse peritoneal macrophages, whereas ciglitazone had no effects. Troglitazone and ciglitazone both significantly induced PPARgamma activity, suggesting that the inhibitory effect of troglitazone was not mediated by PPARgamma. Ox-LDL-induced production of GM-CSF was significantly inhibited by troglitazone, but not by ciglitazone. Troglitazone inhibited Ox-LDL-induced production of intracellular reactive oxygen species, whereas ciglitazone had no effect. The antioxidant reagents NAC and NMPG each inhibited phosphorylation of ERK1/2, whereas troglitazone and ciglitazone had no effects. However, troglitazone, NAC and NMPG all inhibited nuclear translocation of ERK1/2. In conclusion, troglitazone inhibited Ox-LDL-induced GM-CSF production by suppressing nuclear translocation of ERK1/2, thereby inhibiting macrophage proliferation. This suppression of macrophage proliferation by troglitazone may, at least in part, explain its antiatherogenic effects.
Atherosclerosis 2007 Mar
PMID:Troglitazone inhibits oxidized low-density lipoprotein-induced macrophage proliferation: impact of the suppression of nuclear translocation of ERK1/2. 1672 45

Lysophosphatidylcholine (LPC) is the major bioactive lipid component of oxidized LDL, thought to be responsible for many of the inflammatory effects of oxidized LDL described in both inflammatory and endothelial cells. Inflammation-induced transformation of vascular smooth muscle cells from a contractile phenotype to a proliferative/secretory phenotype is a hallmark of the vascular remodeling that is characteristic of atherogenesis; however, the role of LPC in this process has not been fully described. The present study tested the hypothesis that LPC is an inflammatory stimulus in coronary artery smooth muscle cells (CASMCs). In cultured human CASMCs, LPC stimulated time- and concentration-dependent release of arachidonic acid that was sensitive to phospholipase A2 and C inhibition. LPC stimulated the release of arachidonic acid metabolites leukotriene-B4 and 6-keto-prostaglandin F1alpha, within the same time course. LPC was also found to stimulate basic fibroblast growth factor release as well as stimulating the release of the cytokines GM-CSF, IL-6, and IL-8. Optimal stimulation of these signals was obtained via palmitic acid-substituted LPC species. Stimulation of arachidonic acid, inflammatory cytokines and growth factor release, implies that LPC might play a multifactorial role in the progression of atherosclerosis, by affecting inflammatory processes.
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PMID:Lysophosphatidylcholine induces inflammatory activation of human coronary artery smooth muscle cells. 1689 35

The tumor necrosis factor (TNF) superfamily member TNF-like weak inducer of apoptosis (TWEAK) was initially described in a 1997 publication co-authored by investigators from the biotechnology company Biogen (now Biogen-Idec) and the University of Geneva. Four years later, researchers at the biotechnology company Immunex (now part of Amgen) reported the cloning and characterization of the human TWEAK receptor. A sequence database search revealed that the predicted TWEAK receptor amino acid sequence was identical to that of fibroblast growth factor-inducible 14 (Fn14), a small transmembrane protein described one year earlier in a publication from investigators at the American Red Cross Holland Laboratory. Recent studies have revealed that the TWEAK-Fn14 ligand-receptor pair likely plays an important role in a variety of cellular processes and in the pathogenesis of several human diseases, including atherosclerosis, stroke, rheumatoid arthritis and cancer. In this paper, we first summarize the general properties of these two proteins and then review the available data implicating TWEAK and Fn14 in multiple aspects of tumor biology.
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PMID:Role of TWEAK and Fn14 in tumor biology. 1712 78

Liver X receptors (LXRs) are ligand-activated transcription factors involved in the control of lipid metabolism and inflammation. Several studies have recently shown that LXRs promote reverse cholesterol transport and inhibit atherosclerosis. Our study investigated whether LXRs affect macrophage uptake of LDL by human monocyte-derived macrophages. We have previously shown that human monocytes differentiated into macrophages with macrophage-colony-stimulating factor (M-CSF) constitutively take up large amounts of native LDL by receptor-independent, fluid-phase pinocytosis. In the research reported here, human monocytes were differentiated to macrophages in the presence of M-CSF with or without the LXR agonists T0901317 or 22(R)-hydroxycholesterol. Then, macrophages were incubated with native (125)I-LDL to determine LDL uptake. T0901317 and 22(R)-hydroxycholesterol inhibited (125)I-LDL uptake by 68 +/- 1% and 69 +/- 2%, respectively, and decreased pinocytotic vacuoles in the macrophages. (125)I-BSA uptake, a measure of fluid-phase pinocytosis, and (125)I-LDL uptake were the same, and T0901317 treatment inhibited uptake of both to the same degree. T0901317 did not affect receptor-mediated uptake of acetylated LDL, showing that the LXR effect is specific for fluid-phase pinocytosis of lipoproteins. Our results show that LXRs downregulate macrophage pinocytosis of LDL. The findings reveal an additional new mechanism by which LXR agonists may inhibit macrophage cholesterol accumulation and atherosclerosis, namely, by inhibiting macrophage uptake of LDL.
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PMID:Liver X receptors inhibit human monocyte-derived macrophage foam cell formation by inhibiting fluid-phase pinocytosis of LDL. 1769 24

An autopsy case of diffuse axonopathic leukoencephalopathy induced by drug treatment is reported. A 70-year-old woman with multiple myeloma developed encephalopathy several days after completing a course of intravenous human immunoglobulin (IVIg) and granulocyte-colony stimulating factor (G-CSF), and died within I month. T2-weighted MRI demonstrated multifocal high-signal areas in the bilateral cerebral white matter, especially in the right frontal lobe. Neuropathologically, multifocal hydropic axonal swelling with a poor glial reaction was recognized diffusely in the bilateral deep cerebral white matter, being especially marked in the frontal lobe. The cortex, subcortical U-fibers, corpus callosum, and anterior commissure were spared. The cerebellar white matter also showed similar changes, albeit less marked, but the brainstem was spared. Microscopically, the myeloma involvement of the CNS was limited to the dura, and the cerebral arteries showed slight atherosclerosis, but neither thrombi nor angitis. This case, although ultimately fatal, neurologically and neuroradiologically resembled reversible posterior leukoencephalopathy syndrome (RPLS) induced by IVIg and/or G-CSF, and the nature and selective distribution of the neuropathological changes suggested that the pathogenesis involved vasospasm of the bilateral internal carotid artery and the main trunks of the cerebral arteries, due to unknown cause, inducing ischemia in the deep white matter, which is supplied by long nutrient arteries.
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PMID:An autopsy case of drug-induced diffuse cerebral axonopathic leukoencephalopathy: the pathogenesis in relation to reversible posterior leukoencephalopathy syndrome. 1789 90

Everolimus inhibits the mammalian target of rapamycin (mTOR) in proliferating cells. It is widely used in transplant patients and has also been exploited by drug-eluting stents for the treatment of cardiovascular disease. However, there is only limited data on the pathophysiological effects of mTOR-inhibitors on the vascular wall. We aimed to unravel the effects of everolimus on cholesterol-induced atherosclerosis and on circulating cell mediators in LDL-receptor-deficient (LDLR(-/-)) mice. Male hypercholesterolemic LDLR(-/-) mice received either solvent (group A; n=28) or everolimus at 0.05 mg/kg (group B, n=22) and 1.5 mg/kg (group C, n=29) per body weight per day by subcutaneously implanted osmotic minipumps for the study period of 12 weeks. Group B showed 44% reduction of atherosclerotic lesions at the brachiocephalic artery (BCA). In group C atherosclerotic lesions were reduced by 85% in the BCA and by 60% at the aortic root. This was associated with a significantly lower complexity of lesions in both treated groups (p<0.001) and despite a 40% increase of plasma cholesterol. Everolimus caused a significant reduction of circulating cell mediators such as interleukin-1alpha, interleukin-5, GM-CSF and interleukin-12p40. Everolimus increased the plasma levels of KC but had no effect on eighteen other circulating cell mediators studied. Everolimus strongly inhibits atherosclerosis development in LDL-receptor(-/-) mice despite severe hypercholesterolemia. Everolimus application had only small effects on circulating cell mediators. The significant reduction of atherosclerotic lesions was associated with a delayed transition from early macrophages enriched lesions to advanced atherosclerotic plaques.
Atherosclerosis 2008 May
PMID:Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR-/- mice despite severe hypercholesterolemia. 1798 Mar 69

Strong evidence suggests that neutrophils may play an active role in acute and chronic inflammatory disorders, such as rheumatoid arthritis and atherosclerosis. Given the role of pro-inflammatory cytokine TNF-alpha in these inflammatory processes, we planned the present study to investigate the effect of short term incubation with TNF-alpha on neutrophil migration to CCL3, a chemokine produced in inflammatory sites and normally devoid of neutrophil chemotactic properties. We found that TNF-alpha primed neutrophils for migration to CCL3 via CCR5. TNF-alpha-induced migration was a consequence of the TNF-alpha-induced up-regulation of integrin CD11b/CD18 (Mac-1) on neutrophil surface. Furthermore, TNF-alpha activity was found to be strictly dependent on the activation of ERK 1/2 p44, cooperating with the intracellular pathways involving Src kinases, PI3K/Akt, p38 MAPK, well known as activated in response to classical chemoattractants (CXCL8) or priming agents (GM-CSF). On the contrary, the effect of TNF-alpha on neutrophil migration to CCL3 was not dependent on JNK 1/2. In conclusion, the present report shows that TNF-alpha unveils a previously unknown capacity of neutrophils to migrate to CCL3 through the intervention of Mac-1. TNF-alpha regulates Mac-1 up-regulation through signalling pathways, involving various kinases, but not JNK 1/2. Although highly speculative, ERK 1/2 p44 may represent a selective target for the pharmacologic manipulation of neutrophil-mediated adverse activities in TNF-alpha-mediated inflammatory states.
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PMID:Tumor necrosis factor-alpha (TNF-alpha) induces integrin CD11b/CD18 (Mac-1) up-regulation and migration to the CC chemokine CCL3 (MIP-1alpha) on human neutrophils through defined signalling pathways. 1816 90


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