Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The renin-angiotensin system contributes to atherogenesis. Matrix metalloproteinases (MMP) are thought to participate in plaque destabilization through degradation of extracellular matrix. This study tested whether angiotensin II (ANG II) induces MMP in human vascular smooth muscle cells (SMC). ANG II induced expression of MMP-1, -3, and -9, but not of MMP-2 in SMC. The expression of MMP-1, a key enzyme for collagen degradation, was studied in detail. SMC stimulated with ANG II concentration-dependently released enzymatically active MMP-1. The ANG II type 1 receptor antagonists losartan and candesartan blocked ANG-II-induced MMP-1 release. Inhibition experiments with actinomycin D suggest ANG-II-induced MMP-1 mRNA regulation at the transcriptional level. Decoy oligodeoxynucleotides against nuclear factor-kappaB and activator protein 1 inhibited MMP-1 secretion, demonstrating participation of these transcription factors in MMP-1 transcription. Stimulation of MMP-1 by ANG II depended on cyclooxygenase 2. The antioxidants pyrrolidine dithiocarbamate and N-acetylcysteine, the flavin protein inhibitor diphenylene iodonium, and the NADP(H) oxidase inhibitor apocynin blocked MMP-1 release, suggesting a redox-sensitive mechanism involving NADP(H) oxidase. The reactive oxygen species (ROS) donor 2,3-dimethoxy-1,4-naphthoquinone induced MMP-1 secretion and enhanced ANG-II-stimulated MMP-1 expression. These findings indicate that ROS may increase their own production by activation of NADP(H) oxidase. The capability of ANG II to induce functionally active MMP in human SMC may contribute to the altered plaque composition seen in complicated stages of atherosclerosis.
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PMID:Angiotensin II stimulates matrix metalloproteinase secretion in human vascular smooth muscle cells via nuclear factor-kappaB and activator protein 1 in a redox-sensitive manner. 1610 92

The glycosaminoglycan hyaluronan is not merely the simple space filling substance it was long thought to be but is instead being increasingly recognized as a key player in numerous biological processes ranging from embryogenesis to the process of aging. Alterations in hyaluronan syntheses play an important role in ailments associated with aging such as rheumatoid arthritis, atherosclerosis and many forms of cancers, e.g. prostate cancers that mostly affect the elderly. Despite the increasing recognition of hyaluronan as a critical player in many disorders, little is known about the intracellular mechanisms involved in the regulation of the genes encoding hyaluronan synthases (HAS). Herein, evidence is provided that in type-B synoviocytes (TBS) HAS1 is a gene that depends on the transcription factor nuclear factor kappa B (NF-kappaB) for its activation. Stimulating such cells with IL-1beta results in a dose and time dependent activation of HAS1. Pyrrolidine dithiocarbamate (PDTC) blocks IL-1beta induced HAS1 activation entirely. Furthermore, PDTC treatment also prevents the degradation of the IkappaBalpha in TBS as shown by Western blot experiments. EMSA data confirm that PDCT, at concentrations sufficient to completely block IL-1beta induced HAS1 transcription, also entirely blocks IL-1beta induced NF-kappaB translocation. The reported findings stress important differences among the genes encoding hyaluronan and point at a role of HAS1 in inflammatory processes.
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PMID:The NF-kappaB inhibitor pyrrolidine dithiocarbamate blocks IL-1beta induced hyaluronan synthase 1 (HAS1) mRNA transcription, pointing at NF-kappaB dependence of the gene HAS1. 1672 3

It has been reported that chronic inflammation of the vessel wall is a hallmark of atherosclerosis. Interleukin-6 (IL-6) is regarded as an important modulator of inflammatory events occurring during all stages of atherogenesis. Although many factors that induce IL-6 expression have been identified, the effect of homocysteine (Hcy) on the expression of IL-6 in atherogenesis and the underlying mechanisms are not entirely clear. The objective of the present study was to investigate the role of Hcy in IL-6 expression in rat aorta vascular smooth muscle cells (VSMCs). After VSMCs were incubated with Hcy for various time periods, enzyme-linked immunosorbent assay (ELISA) and semi-quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) were performed to measure the expression of IL-6. Electrophoretic mobility shift assay (EMSA) was used to examine nuclear factor kappaB (NF-kappaB) activity. Hcy (0.01-0.25 mmol/l) significantly increased the expression of IL-6 mRNA and protein in rat VSMCs. The increase in IL-6 expression was associated with the activation of NF-kappaB. Pyrrolidine dithiocarbamate (PDTC) suppressed Hcy-induced IL-6 release, a finding compatible with involvement of reactive oxygen species as second messengers in cytokine production mediated by Hcy. The present study has clearly demonstrated the ability of Hcy to elicit an inflammatory response in rat VSMCs by stimulation of IL-6 production and activation of NF-kappaB. Inflammation activation on vessel walls by elevation of Hcy may contribute to the pathogenesis of atherosclerosis.
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PMID:Homocysteine stimulates nuclear factor kappaB activity and interleukin-6 expression in rat vascular smooth muscle cells. 1681 50

Sialic acid containing glycosphingolipids (gangliosides) are thought to play important roles in the function of various biological phenomena such as atherosclerosis. We have previously shown that the overexpression of the disialoganglioside (GD3) synthase gene effectively suppresses cell proliferation, cell cycle progression, and MMP-9 expression in vascular smooth muscle cells (VSMC). However, the issue of how the overexpression of GD3 synthase gene results in the inhibition of cellular responses in VSMC remains unclear. The findings herein demonstrate that overexpression of the GD3 synthase gene suppresses VSMC responses through the generation of reactive oxygen species (ROS). Superoxide and hydrogen peroxide were generated at increased levels in GD3 synthase gene transfectants in comparison with empty vector (EV) -transfected VSMC. This phenomenon was blocked by antioxidants such as N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC). Increased ROS generation was associated with a decreased endogenous antioxidant activity, increased lipid peroxidation, and mitochondrial DNA damage. Further studies revealed that the blockade of ROS function with antioxidants reversed the effect of GD3 synthase gene overexpression on VSMC proliferation and cell cycle regulation in response to platelet-derived growth factor (PDGF). In addition, we found that treatment with antioxidants reversed the decreased matrix metalloproteinase-9 (MMP-9) expression in response to TNF-alpha as determined by zymography and immunoblot in GD3 synthase gene transfectants. This recovery effect was characterized by the up-regulation of MMP-9 promoter activity, which was transcriptionally regulated at NF-kappaB and activation protein-1 (activating protein (AP) -1) sites in the MMP-9 promoter. These findings suggest that ROS may play a role in GD3 synthase gene-mediated VSMC phenotypic changes that may contribute to plaque instability in atherosclerosis.
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PMID:Reactive oxygen species mediates disialoganglioside GD3-induced inhibition of ERK1/2 and matrix metalloproteinase-9 expression in vascular smooth muscle cells. 1681 14

Restenosis after balloon angioplasty and stenting is exacerbated by low flow. Flow-dependent restenosis after angioplasty but not stenting is prevented by the antioxidant pyrrolidine dithiocarbamate (PDTC). c-jun may play a role in these events as AP-1 activity is both flow and redox sensitive. Carotid arteries of cholesterol fed rabbits underwent stenting or balloon injury in the presence of low or normal flow. c-jun mRNA expression was enhanced by low flow and injury (stent>balloon) and inhibited by the antioxidant PDTC irrespective of the injury type. The effect of locally delivered DZ13 (a DNAzyme specific for c-jun) or scrambled DZ13 (inactive DNAzyme) was assessed by histomorphometry at 28 days. Low flow significantly increased intimal hyperplasia in B and S relative to normal flow (P<0.05). The active DNAzyme DZ13 markedly reduced intimal hyperplasia (P<0.001) and increased lumen size (P<0.05) in balloon-injured but not in stented segments, and abrogated the effect of low flow on restenosis after angioplasty, similar to the morphological effects of PDTC. We conclude that c-jun expression is enhanced by low flow and by injury (stent>balloon) and markedly attenuated by PDTC, and that c-jun is an important mediator of flow-dependent restenosis in balloon-injured but not stented vessels.
Atherosclerosis 2007 Oct
PMID:The role of c-jun in PDTC-sensitive flow-dependent restenosis after angioplasty and stenting. 2852 70

Although nuclear translocation of NF-kappaB and subsequent binding to promoters of ICAM-1 and VCAM-1 have been shown to be decisive for their expression, a number of discrepancies in the expression patterns of these adhesion molecules have been reported in both cell culture systems and disease settings, including atherosclerosis, asthma, and autoimmune diseases. Here we show that while p65 NF-kappaB nuclear translocation in TNF-treated smooth muscle cells (SMCs) was sufficient for the expression of VCAM-1, expression of ICAM-1 showed a critical requirement for PARP-1. I-kappaBalpha phosphorylation and subsequent degradation were virtually identical in both TNF-treated wild-type and PARP-1-/- SMCs. VCAM-1 expression in TNF-treated PARP-1-/- SMCs was completely inhibited by the NF-kappaB inhibitor, pyrrolidine dithiocarbamate, confirming that VCAM-1 expression was indeed NF-kappaB-dependent. The expression of both VCAM-1 and ICAM-1 was associated with a transient interaction between PARP-1 and p65 NF-kappaB when examined in the fibroblastic cell line, COS-7, and in the airway epithelial cell line, A549. Such interactions were confirmed using florescence resonance energy transfer analysis. Protein acetylation activity, mediated by p300/CBP, was required for both VCAM-1 and ICAM-1 expression in TNF-treated SMCs; however, the interaction of PARP-1 with p300/CBP was dispensable for VCAM-1 expression. These findings indicate that p65 NF-kappaB nuclear translocation may be sufficient for certain genes (e.g., VCAM-1) while insufficient for others (e.g., ICAM-1), thus providing a novel insight into the role of NF-kappaB in driving target gene expression. Furthermore, the data suggest a differential requirement for PARP-1 expression in inflammatory processes.
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PMID:Nuclear translocation of p65 NF-kappaB is sufficient for VCAM-1, but not ICAM-1, expression in TNF-stimulated smooth muscle cells: Differential requirement for PARP-1 expression and interaction. 1799 61

TRAIL/Apo2L (tumor necrosis factor-related apoptosis-inducing ligand) is a multifunctional protein regulating homeostasis of the immune system, infection, autoimmune diseases, and apoptosis. However, its function in normal, nontransformed tissues is not clear. Here we show that TRAIL increases vascular smooth muscle cell (VSMC) proliferation in vitro, effects that can be blocked with neutralizing antibodies to TRAIL receptors DR4 and DcR1. In aortocoronary saphenous vein bypass grafts in vivo, TRAIL co-localizes with VSMC, proliferating cell nuclear antigen, and insulin-like growth factor type 1 receptor (IGF1R) expression but not active caspase-3. TRAIL is required for serum-inducible IGF1R expression, and antisense IGF1R inhibits TRAIL-induced VSMC proliferation. At 1 ng/ml, TRAIL stimulates IGF1R mRNA expression greater than insulin-like growth factor-1 and also activates the IGF1R promoter 7-fold. TRAIL-inducible IGF1R expression requires NF-kappaB activation. Consistent with this, ammonium pyrrolidine dithiocarbamate, a pharmacological inhibitor of NF-kappaB, blocks TRAIL-induced IGF1R expression, and p65 overexpression increases IGF1R protein levels. In addition, NF-kappaB binds a novel TRAIL-responsive element on the IGF1R promoter. Our findings suggest that the biological functions of TRAIL in VSMC extend beyond its role in promoting apoptosis. Thus, TRAIL may play an important role in atherosclerosis by regulating IGF1R expression in VSMC in an NF-kappaB-dependent manner.
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PMID:TRAIL stimulates proliferation of vascular smooth muscle cells via activation of NF-kappaB and induction of insulin-like growth factor-1 receptor. 1817 61

Inflammation and low oxygen diffusion are recognized characteristics of cardiovascular diseases such as atherosclerosis. Evodiamine, extracted from the traditional Chinese herb, Evodia rutaecarpa, is a bioactive anti-inflammatory alkaloid. The objective of this study was to investigate whether evodiamine could repress hypoxia-induced inflammatory response. We showed that evodiamine repressed not only COX-2 and iNOS expression but also prostaglandin E2 release in a concentration-dependent manner under hypoxic conditions. Furthermore, our studies indicated that COX-2 mRNA was inhibited by evodiamine, implying that transcriptional activity is involved in the mechanistic pathway. It is striking that hypoxia-inducible factor 1alpha (HIF-1alpha) inhibitor, camptothecin, suppressed hypoxia-induced COX-2 expression rather than pyrrolidine dithiocarbamate, a nuclear factor kappaB inhibitor. In addition, our studies have confirmed that evodiamine inhibited HIF-1alpha, which accounted for the transcriptional activity of COX-2, rather than nuclear factor kappaB in RAW264.7 cells. Finally, evodiamine did not affect either the level of HIF-1alpha mRNA or the degradation rate of HIF-1alpha protein, but it regulated the translational process of HIF-1alpha. We found that hypoxia-evoked phosphorylation of Akt and p70S6K was blocked after evodiamine treatment, in addition to the inhibition of phosphorylation of 4E-BP. These results suggest that the mechanism of repression of hypoxia-induced COX-2 expression by evodiamine is through the inhibition of HIF-1alpha at the translational level and is primarily mediated via dephosphorylation of Akt and p70S6K. Therefore, evodiamine could be an effective therapeutic agent against inflammatory diseases involving hypoxia.
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PMID:Evodiamine represses hypoxia-induced inflammatory proteins expression and hypoxia-inducible factor 1alpha accumulation in RAW264.7. 1910 18

Numerous studies have shown that both vasoconstrictive peptide endothelin-1 (ET-1) and inflammatory marker C-reactive protein (CRP) are implicated in the inflammatory process of atherosclerosis. The purpose of the present study was to observe effect of ET-1 on CRP production and the molecular mechanisms in rat vascular smooth muscle cells (VSMCs). The results showed that ET-1 was capable of stimulating VSMCs to produce CRP both in protein and in mRNA levels in vitro and in vivo. ET(A) receptor antagonist BQ123, but not ET(B) receptor antagonist BQ788, inhibited CRP production in VSMCs. In addition, ET-1 was able to elicit reactive oxygen species (ROS) generation and mitogen-activated protein kinase (MAPK) activation, and antioxidant pyrrolidine dithiocarbamate and p38MAPK inhibitor SB203580 inhibited ET-1-induced CRP expression. The results demonstrate that ET-1 induces CPR production in VSMCs via ET(A) receptor followed by ROS and MAPK signal pathway, which may contribute to better understanding of the role of ET-1 in inflammatory activation of the vessel wall during atherogenesis.
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PMID:Endothelin-1 induces the expression of C-reactive protein in rat vascular smooth muscle cells. 1974 88

There is evidence that reactive oxygen species (ROS) are related to the development of cardiovascular disease (CVD). Results from many studies support the hypothesis that ROS released from various sources or dysfunctional mitochondrial respiratory chain play a role in the development of atherosclerosis and its complications. This phenomenon is due to ROS-mediated signalling pathways that are involved in the modulation of several vascular mechanisms. Various animal models have demonstrated that ROS have a causal role in atherothrombosis and other vascular diseases. Oxidative stress is being proposed as the unifying mechanism for many CVD risk factors. In particular, ROS may be responsible for plaque rupture and subsequent thrombosis which lead to myocardial infarction and stroke. Many drugs or agents have been tested to prevent or block oxidation underlying atherothrombotic processes, often with discordant outcomes. We observed that pre-treatment with some antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine, as well as some vitamins with recognized antioxidant properties, namely ascorbic acid (vitamin C), all-trans Retinoic Acid (atRA) and alpha-tocopherol (vitamin E) can suppress oxidative stress (OS)-induced Tissue Factor (TF) expression in human coronary artery endothelial cells. The present review, starting from our experimental observations, focuses on the influence of redox balance on atherothrombotic processes and on the effects of antioxidant treatment. A better understanding of the complex regulation of cellular redox balance could facilitate the development of newer antioxidants aimed at specific cellular targets. Research could also help assess the role of combination pharmacological intervention for the treatment and prevention of vascular disease.
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PMID:Reactive oxygen species and antioxidants in the pathophysiology of cardiovascular disease: does the actual knowledge justify a clinical approach? 1975 11


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