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)

Heat-shock protein (hsp) expression can be induced by high temperature, exposure to cytokines or oxygen radicals, ischemia, hemodynamic overload, or viral infections. To determine whether surface expression of hsp60 occurs in aortic endothelial cells stressed by high temperature or cytokines, cells from rat aortas were cultivated and stained with several types of monoclonal antibodies against hsp60. Other antibodies, eg, those against intercellular adhesion molecule-1 (ICAM-1), or immune response-associated antigens were also used as controls. Positive staining of endothelial cells on the surface and in the cytoplasm was observed after pretreatment of the cells with cytokine-containing medium, tumor necrosis factor-alpha (TNF-alpha), or interleukin-1 alpha and labeling with a specific monoclonal antibody against hsp60 (II-13). Fluorescence-activated cell sorter analyses showed that over 80% of living endothelial cells stressed by cytokine-containing medium, by TNF-alpha, or at 42 degrees C, but not by interleukin-1 alpha, were positively surface stained with this antibody. Increased intensity of immunostaining with antibodies to ICAM-1 and immune response-associated antigen was also seen on the cytokine-stressed endothelial cells. Furthermore, when TNF-alpha stimulated endothelial cells labeled with 51Cr were incubated with antibody II-13 in the presence of complement, significant lysis occurred. In summary, endothelial cells stressed by high temperature or certain cytokines, eg, TNF-alpha, express hsp60 in the cytoplasm and on their surfaces, and these cells were susceptible to complement-dependent lysis by hsp60-specific antibody. These observations may be significant for elucidating the mechanisms of the involvement of immune reactions to hsp65/60 in initiating atherosclerosis.
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PMID:Surface staining and cytotoxic activity of heat-shock protein 60 antibody in stressed aortic endothelial cells. 752 2

Sphingomyelin and its metabolic products are now known to have second messenger functions in a variety of cellular signaling pathways. At the epicenter of the sphingomyelin--cell signaling pathway is a family of phospholipases called sphingomyelinases. These enzymes cleave sphingomyelin to produce ceramide and phosphocholine. Ceramide in turn serves as a lipid second messenger that induces a variety of cell regulatory phenomenon such as programmed cell death (apoptosis), cell differentiation, cell proliferation, and sterol homeostasis. Neutral sphingomyelinase (N-SMase) is a Mg2+ sensitive enzyme that can be activated by a host of physiologically relevant and structurally diverse molecules like tumor necrosis factor-alpha (TNF-alpha), oxidized human low density lipoproteins (Ox-LDL), and several growth factors. Large amounts of ceramide accumulate in human fatty streaks and plaques along with Ox-LDL, growth factors, and proinflammatory cytokines in human atherosclerosis. A further role of ceramide and N-SMase in atherosclerosis was uncovered by the finding that Ox-LDL and TNF-alpha stimulated N-SMase activity. In turn, ceramide and/or a homolog serves as an important stress signaling molecule in signal transduction, which leads to apoptosis. Interestingly, an antibody against N-SMase can abrogate Ox-LDL and TNF-alpha induced apoptosis, and therefore may be useful for additional studies of apoptosis in experimental animals. Overexpression of recombinant human N-SMase in human aortic smooth muscle cells markedly stimulate apoptosis, presumably via the multioligomerization of the 'death domain'. Since plaque stability is an integral aspect of atherosclerosis management, activation of N-SMase and subsequent apoptosis may be vital events in the onset of plaque rupture, stroke and heart failure. In contrast to these observations in human hepatocytes, TNF-alpha mediated N-SMase activation did not induce apoptosis. Rather it stimulated the maturation of sterol regulatory element (SRE) binding protein (SREBP-1). Moreover, a cell permeable ceramide was found to reconstitute the phenomenon above in a sterol-independent fashion. These findings provide alternate avenues for therapy of patients with hypercholesterolemia and atherosclerosis. The findings reported here suggests that N-SMase plays important cell regulatory roles and provide an exciting opportunity to further these findings to understand the pathophysiology of human disease states.
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PMID:Neutral sphingomyelinase: past, present and future. 1100 63

Cardiovascular disease is accompanied by an impaired endothelium-dependent vasodilatory response. Loss of endothelial nitric oxide synthase (eNOS) expression may contribute to endothelial dysfunction. The aim of the present study was to analyze the effect of cerivastatin, a novel HMG CoA reductase inhibitor, on tumor necrosis factor-alpha (TNF-alpha)-induced downregulation of eNOS protein expression in bovine aortic endothelial cells (BAEC). TNF-alpha (10 ng/ml)- incubated BAEC showed a reduced expression of eNOS protein and decreased eNOS mRNA stabilization. This effect was associated with an increased binding activity of BAEC cytosolic proteins to the 3'-untranslated region (3'UTR) of eNOS mRNA. Cerivastatin prevented TNF-alpha-induced downregulation of eNOS protein expression in a concentration-dependent manner (10(-8) to 10(-5) M). Cerivastatin also prevented the binding of the cytosolic proteins to 3'-UTR of eNOS mRNA and was associated with eNOS mRNA stabilization. The reduced expression of eNOS protein by TNF-alpha was also prevented by coincubation with cycloheximide. In addition cycloheximide inhibited the binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA, suggesting the inducible character of the mentioned-cytosolic proteins. TNF-alpha stimulated the translocation of nuclear factor-kappaB (NF-kappaB), an effect that was not modified by cerivastatin. Furthermore, an inhibitor of NF-kappaB translocation, pyrrolidine dithiocarbamate failed to modify both the downregulation of eNOS expression and the increased binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA by TNF-alpha. The effect of cerivastatin on eNOS expression and the binding activity of the cytosolic proteins were reversed by coincubation with L-mevalonate. In conclusion, cerivastatin stabilized eNOS mRNA and upregulated eNOS expression in the endothelium, and this was associated with a decreased binding activity of cytosolic proteins to 3'-UTR of eNOS mRNA. The effect of cerivastatin on the regulation of eNOS expression was independent of NF-kappaB mobilization by TNF-alpha. These findings suggest that cerivastatin may have beneficial effects on the endothelial dysfunction associated with cardiovascular diseases beyond its effect on lowering cholesterol.
Atherosclerosis 2001 Mar
PMID:Cerivastatin prevents tumor necrosis factor-alpha-induced downregulation of endothelial nitric oxide synthase: role of endothelial cytosolic proteins. 1122 27

Inflammatory cytokines, such as interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, activate nuclear factor-kappa B (NF-kappaB) which transactivates inducible nitric oxide synthase (iNOS) gene in vascular smooth muscle cells (VSMCs). However, it remains obscure whether cytokine-mediated iNOS expression in VSMCs requires signaling pathway(s) other than NF-kappaB activation. The present study was designed to elucidate whether protein tyrosine kinases (PTKs) are involved in the cytokine-induced NF-kappaB activation and iNOS expression in cultured rat VSMCs. Both IL-1beta and TNF-alpha stimulated NF-kappaB activity, iNOS mRNA and protein expression with massive nitrite/nitrate (NOx) production in rat VSMCs. PTK inhibitors (genistein, herbimycin A) dose-dependently inhibited the cytokine-stimulated NOx production and iNOS mRNA expression. However, neither genistein nor herbimycin A affected the cytokine-stimulated phosphorylation and degradation of IkappaB-alpha, or NF-kappaB activation, whereas they completely blocked the cytokine-stimulated iNOS transcriptional activity. Tyrphostin B42 (AG490), a Jak-2 tyrosine kinase inhibitor, similarly blocked the cytokine-induced NOx production, iNOS expression and its promoter activity without affecting NF-kappaB-dependent transcription. Transfection of a dominant-negative Jak-2 mutant antagonized the cytokine-induced NOx production and iNOS expression, while wild-type Jak-2 expressing construct was without effect. These data indicate that the cytokine-induced iNOS expression involves activation of Jak-2 signaling pathway independent from NF-kappaB activation in rat VSMCs.
Atherosclerosis 2002 Jan
PMID:Cytokine-activated Jak-2 is involved in inducible nitric oxide synthase expression independent from NF-kappaB activation in vascular smooth muscle cells. 1175 29

Atherosclerosis and its complications such as stroke, myocardial infraction and peripheral vascular disease, remain the major causes of morbidity and mortality in the world. Studies have showed that chemokines and adhesion molecules are involved in causing atherosclerosis by promoting directed migration of inflammatory cells. Monocyte chemoattractant protein-1 (MCP-1) is one of the key factors critical for the initiating and developing of atherosclerotic lesions. IL-8, a CXC chemokine, stimulates neutrophil chemotaxis. Aspirin is the most common drug used to prevent the complications of atherosclerosis such as stroke and coronary heart disease. In this study, we found that aspirin inhibited TNF-alpha (10 ng/ml)-induced MCP-1 and IL-8 expression at the RNA and protein levels in human umbilical vein endothelial cells (HUVECs), monocyte adhesion and transmigration, and that its inhibitory effects were not due to decreased HUVEC viability as assessed by MTT test. Aspirin at the dose as low as 10 microg/ml significantly inhibited the release of TNF-stimulated MCP-1 by 29.1% (P = 0.008) and IL-8 by 26.9% (P = 0.0146) as compared to TNF-stimulated release. Antibodies pretreatment were likely to decrease the production of MCP-1 (P < 0.0001) and IL-8 (P < 0.0001). Furthermore, aspirin (10 microg/ml) inhibited U937 cell adhesion by a 13.4% (P = 0.0119) inhibition as compared to TNF-stimulated alone. Finally, at higher concentration, aspirin also inhibited U937 migration to HUVEC by 89.1% (P = 0.0475) as compared to TNF-stimulated alone. These results in our study suggest that aspirin inhibits TNF-alpha stimulated MCP-1 and IL-8 release in HUVECs, for its additional therapeutic effects of aspirin in causing atherosclerosis.
Atherosclerosis 2004 Jun
PMID:Aspirin inhibits monocyte chemoattractant protein-1 and interleukin-8 expression in TNF-alpha stimulated human umbilical vein endothelial cells. 1513 50

The role of glutathione (GSH) in inflammation is largely discussed from the context of providing reducing equivalents to detoxify reactive oxygen and nitrogen species. Inflammation is now recognized to be an underlying cause of many vascular diseases including atherosclerosis, a disease in which endothelial GSH concentrations are decreased. However, mechanisms that control GSH levels are poorly understood. Key players in the inflammatory process are endothelial adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1). This adhesion molecule is present constitutively and can be induced by a variety of inflammatory stimuli. In this study, using mouse aortic endothelial cells (MAEC) deficient in ICAM-1, we demonstrate a novel interplay between constitutive ICAM-1 and cellular GSH. Deficiency of ICAM-1 was associated with an approximately twofold increase in total GSH content. Inhibiting glutamate-cysteine ligase (GCL), the enzyme that catalyses the rate-limiting step in GSH biosynthesis, prevented the increase in GSH. In addition, the catalytic subunit of GCL was increased (approximately 1.6-fold) in ICAM-1 deficient relative to wild-type cells, suggesting that constitutive ICAM-1 represses GCL expression. Furthermore, the ratio of reduced (GSH) to oxidized (GSSG) glutathione was also increased suggesting a role for ICAM-1 in modulating cellular redox status. Interestingly, increasing cytosolic GSH in wild-type mouse endothelial cells decreased constitutive ICAM-1, suggesting the presence of an inverse and reciprocal pathway. To test the effects of inducible ICAM-1 on GSH, cells were stimulated with the proinflammatory cytokine TNF-alpha. TNF-alpha stimulated production of ICAM-1, which was however not associated with induction of GSH. In contrast, supplementation of endothelial cells with GSH before TNF-alpha addition, inhibited induction of ICAM-1. These data suggest a novel regulatory pathway between constitutive ICAM-1 and GSH synthesis in the endothelium and are discussed in the context of modulating the inflammatory response.
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PMID:Regulation of endothelial glutathione by ICAM-1: implications for inflammation. 1518 Sep 61

Plasminogen activator inhibitor 1 (PAI-1) is an important mediator of atherosclerosis and liver fibrosis in insulin resistance. Circulating levels of PAI-1 are elevated in obese individuals, and PAI-1 messenger RNA is significantly higher in the livers of obese type 2 diabetic individuals than in nonobese type 2 diabetic individuals. To address the mechanism underlying the up-regulation of hepatic PAI-1 in obesity, we tested the effects of tumor necrosis factor alpha (TNF-alpha), an important link between obesity and insulin resistance, on PAI-1 production in the nonmalignant human hepatocyte cell line, THLE-5b. Incubation of THLE-5b cells with TNF-alpha stimulated PAI-1 production via protein kinase C-, mitogen-activated protein kinase-, protein tyrosine kinase-, and nuclear factor-kappaB-dependent pathways. A thiazolidinedione, pioglitazone, reduced TNF-alpha-induced PAI-1 production by 32%, via protein kinase C- and nuclear factor-kappaB-dependent pathways. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin inhibited TNF-alpha-induced PAI-1 production by 59%, which was reversed by coincubation with mevalonic acid. In conclusion, obesity and TNF-alpha up-regulation of PAI-1 expression in human hepatocytes may contribute to the impairment of the fibrinolytic system, leading to the development of atherosclerosis and liver fibrosis in insulin-resistant individuals. A thiazolidinedione and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor may thus be candidate drugs to inhibit obesity-associated hepatic PAI-1 production.
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PMID:Tumor necrosis factor-alpha-induced production of plasminogen activator inhibitor 1 and its regulation by pioglitazone and cerivastatin in a nonmalignant human hepatocyte cell line. 1704 48

Monocyte chemoattractant protein-1 (MCP-1) is a 76-amino-acid chemokine that is considered to be an important chemotactic factor for monocytes. MCP-1 is expressed in the macrophage-rich areas of atherosclerotic lesions. A recent report indicated that MCP-1 expression in human umbilical vein endothelial cells (HUVECs) is induced by the stimulation of tumor necrosis factor (TNF)-alpha via the c-Jun N-terminal kinases (JNK) pathway. In this study, we examined the effects of JNK inhibitor (JNKI-1), on MCP-1 expression. The results of this study indicated that the expression of MCP-1 mRNA and protein were stimulated in the presence of TNF-alpha. TNF-alpha stimulated the phosphrylation of JNK, however, JNKI-1 inhibited the TNF-alpha stimulated MCP-1 secretion and gene expression. As expected, JNKI-1 blocked the stimulatory effect of TNF-alpha on the MCP-1 promoter activity. In conclusion, JNKI-1 partially inhibits the TNF-alpha-induced MCP-1 expression in HUVECs, and therefore JNKI-1 may be of therapeutic value in the treatment of diseases such as atherosclerosis.
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PMID:c-Jun N-terminal kinases inhibitor suppresses the TNF-alpha induced MCP-1 expression in human umbilical vein endothelial cells. 1910 3

Chios mastic gum (CMG) is a white, semitransparent, natural resin that is obtained as a trunk exudate from mastic trees. Triterpenic compounds and phytosterols like tirucallol are among its major components. CMG has been associated with cardiovascular protection, exerting its effect mainly through increasing the antioxidant defense system, and effectively lowering the levels of serum cholesterol in human subjects. However, data on its anti-inflammatory effect on endothelium are scarce. Attachment of leukocytes to the vascular endothelium and the subsequent migration of cells into the vessel wall are early events in atherogenesis, and this process requires the expression of endothelial adhesion molecules. In this study, we examined the effect of CMG neutral extract (25-200 microg/ml) and tirucallol (0.1-100 microM) on the following: 1) the expression of adhesion molecules (VCAM-1 and ICAM-1) by Cell ELISA and 2) the attachment of monocytes (U937 cells) in TNF-alpha stimulated Human Aortic Endothelial Cells (HAEC) by Adhesion assay. The impact of treatment with CMG neutral extract and tirucallol in NFkB phosphorylation was also examined by a cell-based ELISA kit. Both CMG extract and tirucallol inhibit significantly VCAM-1 and ICAM-1 expression in TNF-alpha-stimulated HAEC. They also inhibit significantly the binding of U937 cells to TNF-alpha-stimulated HAEC and attenuate the phosphorylation of NFkB p65. This study extends existing data regarding the cardioprotective effect of CMG, expands the spectrum of known phytosterols with potent antiatheromatic activity, provides new insight into the mechanisms underlying the beneficial effect of CMG on endothelial function, and may aid in design of new therapy for intervention in atherosclerosis.
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PMID:Chios mastic gum extract and isolated phytosterol tirucallol exhibit anti-inflammatory activity in human aortic endothelial cells. 1923 52

Tumor necrosis factor (TNF-alpha) is a pleiotropic cytokine exerting both inflammatory and cell death activity and is thought to play a role in the pathogenesis of atherosclerosis. The present study was designed to examine whether the raloxifene analogue, LY117018 could inhibit TNF-alpha-induced apoptosis in vascular endothelial cells and to clarify the involved mechanisms. Apoptosis of endothelial cells was determined by DNA fragmentation assay and the activation of caspase-3. LY117018 significantly inhibited TNF-alpha-induced caspase-3 activation and cell DNA fragmentation levels in bovine carotid artery endothelial cells. The inhibitory effect of LY117018 was abolished by an estrogen receptor antagonist ICI 182,780. p38 MAPK, JNK, ERK1/2 and Akt have been shown to act as apoptotic or anti-apoptotic signals. TNF-alpha stimulated the phosphorylation levels of p38 MAPK, JNK, ERK1/2 and Akt in vascular endothelial cells. TNF-alpha-induced apoptosis was significantly decreased by SB203580, a p38 MAPK inhibitor or SP600125, a JNK inhibitor, but was enhanced by an ERK1/2 pathway inhibitor, PD98059 or a PI3-kinase/Akt pathway inhibitor, wortmannin. The anti-apoptotic effect of LY117018 was abrogated only by PD98059 but was not affected by the inhibitors for p38 MAPK, JNK, or Akt. LY117018 stimulated the further increase in phosphorylation of ERK1/2 in TNF-alpha treated endothelial cells but it did not affect phosphorylation levels of p38 MAPK, JNK or Akt. These results suggest that LY 110718 prevents caspase-3 dependent apoptosis induced by TNF-alpha in vascular endothelial cells through activation of the estrogen receptors and the ERK1/2 signaling pathway.
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PMID:A selective estrogen receptor modulator inhibits TNF-alpha-induced apoptosis by activating ERK1/2 signaling pathway in vascular endothelial cells. 1927 68


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