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)

Endothelial dysfunction by proinflammatory stimuli represents an important link between risk factors and the pathologic mechanisms underlying atherosclerosis. Thus, control of the inflammatory status of endothelial cells is crucial to limiting the disease. Tobacco smoking induces inflammatory reactions and promotes atherosclerosis; however, the mechanism that links cigarette smoking to an increased incidence of atherosclerosis is poorly understood. Our study demonstrates that acrolein, a known toxin in tobacco smoke, elevates oxidative stress via inactivation of thioredoxin reductase and stimulates expression of cyclooxygenase-2 through activation of the protein kinase C, p38 mitogen-activated protein kinase, and cAMP response element-binding protein pathway in endothelial cells. Our finding suggests that acrolein may play a role in the progression of atherosclerosis.
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PMID:Acrolein induces inflammatory response underlying endothelial dysfunction: a risk factor for atherosclerosis. 1844 14

C-reactive protein (CRP), the prototypic marker of inflammation, is a cardiovascular risk marker and recent in vitro studies suggest that it may promote atherogenesis. CRP promotes oxidative stress in vitro and induces tissue factor (TF) release. However, there is a paucity of data examining the effects of CRP on oxidative stress and tissue factor procoagulant activity (PCA) in vivo. Thus, we tested the effects of CRP administration on superoxide anion release and tissue factor activity and examined mechanistic pathways using a rat sterile air pouch model. Intraperitoneal administration of CRP (20mg/kg body weight) compared to human serum albumin (HuSA) increased superoxide anion release and tissue factor activity from peritoneal macrophages in vivo (p<0.01). This was confirmed using intrapouch administration of CRP (25mug/mL) compared to HuSA. Pretreatment with reactive oxygen species (ROS) scavengers or protein kinase C (PKC) inhibitor significantly abrogated CRP-induced superoxide anion release and tissue factor activity. Pretreatment with extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) inhibitors, but not p38 mitogen-activated protein kinase (p38MAPK) significantly decreased CRP-induced superoxide anion release from macrophages in vivo. CRP-induced tissue factor activity in vivo was abrogated by pretreatment with inhibitors to p38MAPK, JNK and NFkappab (nuclear factor-kappab), but not ERK. Antibodies to Fc gamma receptors, CD32 and CD64 resulted in significant reduction in CRP-induced superoxide and tissue factor activity in vivo. Thus, CRP appears to induce oxidative stress in vivo by stimulating NADPH oxidase via PKC, ERK and JNK phosphorylation, and induces tissue factor PCA in vivo via upregulation of PKC, p38MAPK, JNK, ROS and NFkappab. CRP-induced ROS appears to precede tissue factor release. These effects are abrogated by blocking Fc gamma receptors, CD32 and CD64. This in vivo demonstration provides further evidence for a role for CRP in atherothrombosis.
Atherosclerosis 2009 Mar
PMID:C-reactive protein stimulates superoxide anion release and tissue factor activity in vivo. 1862 73

Hypertriglyceridemia and associated high circulating free fatty acids are important risk factors for atherosclerosis. In contrast to omega-3 fatty acids, linoleic acid, the major omega-6 unsaturated fatty acid in the American diet, may be atherogenic by amplifying an endothelial inflammatory response. We hypothesize that omega-6 and omega-3 fatty acids can differentially modulate tumor necrosis factor alpha (TNF-alpha)-induced endothelial cell activation and that functional plasma membrane microdomains called caveolae are required for endothelial cell activation. Caveolae are particularly abundant in endothelial cells and play a major role in endothelial trafficking and the regulation of signaling pathways associated with the pathology of vascular diseases. To test our hypothesis, endothelial cells were preenriched with either linoleic acid or alpha-linolenic acid before TNF-alpha-induced endothelial activation. Measurements included oxidative stress and nuclear factor kappaB-dependent induction of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) under experimental conditions with intact caveolae and with cells in which caveolin-1 was silenced by small interfering RNA. Exposure to TNF-alpha induced oxidative stress and inflammatory mediators, such as p38 mitogen-activated protein kinase (MAPK), nuclear factor kappaB, COX-2, and PGE(2), which were all amplified by preenrichment with linoleic acid but blocked or reduced by alpha-linolenic acid. The p38 MAPK inhibitor SB203580 blocked TNF-alpha-mediated induction of COX-2 protein expression, suggesting a regulatory mechanism through p38 MAPK signaling. Image overlay demonstrated TNF-alpha-induced colocalization of TNF receptor type 1 with caveolin-1. Caveolin-1 was significantly induced by TNF-alpha, which was further amplified by linoleic acid and blocked by alpha-linolenic acid. Furthermore, silencing of the caveolin-1 gene completely blocked TNF-alpha-induced production of COX-2 and PGE(2) and significantly reduced the amplified response of linoleic acid plus TNF-alpha. These data suggest that omega-6 and omega-3 fatty acids can differentially modulate TNF-alpha-induced inflammatory stimuli and that caveolae and its fatty acid composition play a regulatory role during TNF-alpha-induced endothelial cell activation and inflammation.
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PMID:The role of fatty acids and caveolin-1 in tumor necrosis factor alpha-induced endothelial cell activation. 1880 34

High mobility group box 1 (HMGB1) is a non-histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis. The HMGB1 functions as a potent proinflammatory cytokine in the extracellular spaces. Recently, HMGB1 has been implicated in the progression of atherosclerosis. However, the association between HMGB1 and the development of atherosclerosis is poorly understood. Therefore, we examined whether serotonin (5-HT), a key factor involved in the development of atherosclerosis, induced HMGB1 release in human umbilical vein endothelial cells (HUVECs). We found that 5-HT induced the release of HMGB1 but not of ERK1/2 and JNK from HUVECs via the 5-HT receptor (5-HT1B)/p38 mitogen-activated protein kinase (MAPK) signaling pathway. The p38MAPK inhibitor SB203580 and the 5-HT1B antagonist GR55526 markedly inhibited HMGB1 release from 5-HT-stimulated HUVECs. The vascular endothelial growth factor (VEGF) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis. We found that HMGB1 induced VEGF production in macrophage-like RAW264.7 cells. HMGB1 induced the activation of p38MAPK, ERK1/2 and Akt. The PI3-kinase inhibitor LY294002 significantly inhibited VEGF production in HMGB1-stimulated macrophages, while other kinase inhibitors did not. These results suggest that HMGB1 release may contribute as a risk factor in the development and progression of atherosclerosis.
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PMID:Induction of high mobility group box 1 release from serotonin-stimulated human umbilical vein endothelial cells. 1894 84

Antiphospholipid syndrome is considered to be associated with a hypercoagulable state that leads to stroke and other ischemic events, and is currently diagnosed based on the modified Sapporo criteria that was proposed in 2006. Antiphospholipid antibodies (aPL) comprise a heterogeneous group of autoantibodies. Among them, the level of beta2-glycoprotein I-dependent anticardiolipin antibody, lupus anticoagulant (LA), and IgG anticardiolipin antibody are commonly measured. Recently, phosphatidylserine dependent anti-prothrombin antibody has been suggested to be closely related to LA. aPL is an independent risk factor for a first-ever ischemic stroke, especially in young female patients. It is still debatable whether aPL is a marker for recurrent stroke risk. The precipitating factors for the occurrence of stroke are beta2-GPI-dependent aCL, aGPL, and aCL levels of greater than 40, and the simultaneous presence of LA. Several mechanisms are considered to be involved in the thrombotic process in patients with antiphospholipid antibodies. Activation of protein C is impaired in patients with aPL. Beta2-GPI has simultaneous procoagulant and anticoagulant effects. Cardiac valvular involvement, which could be the cause of cardiogenic embolism, is prevalent in patients with aCL. In addition, the presence of aPL is associated with the development of atherosclerosis. Recently, it has been proposed that endothelial cells, monocytes, and platelets were reported to be activated by beta2-GPI: further, p38 mitogen-activated protein kinase has been reported to be phosphorylated. Several therapeutic options are available for the prevention of ischemic stroke in patients with aPL. For cases of cryptogenic ischemic stroke and positive aPL antibodies, antiplatelet therapy is reasonable. Oral anticoagulation with a target international normalized ratio (INR) of 2 to 3 is reasonable for patients with ischemic stroke who meet the criteria for antiphospholipid syndrome with venous and arterial occlusive disease in multiple organs.
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PMID:[Ischemic stroke with antiphospholipid antibody]. 1897 2

Monocyte chemotactic protein-1 and interleukin-6 are important inflammatory cytokines, which have close relationships with atherosclerosis. Visfatin is a novel adipokine involved in regulation of inflammatory cytokines, however, associations of visfatin with cytokines (MCP-1, IL-6) in human umbilical vein endothelial cells are unclear. The aim of this study was to determine whether visfatin has effects on the expression of MCP-1 and IL-6 in human umbilical vein endothelial cells. Enzyme-linked immunosorbent assay were used for measuring MCP-1 and IL-6 production in human umbilical vein endothelial cells. Real-time quantitative reverse-transcription polymerase chain reaction was used for determining MCP-1 and IL-6 mRNA expression. For the pathway determination following inhibitors were used: wortmannin [phosphatiylinositol 3-kinase (PI3K)], SB203580 [p38 mitogen-activated protein kinase (MAPK)], PD98059 [extracellular signal-regulated kinase (ERK) 1/2)], JNK inhibitor II [c-Jun NH 2-terminal kinase (JNK)]. We demonstrated that visfatin could obviously upregulate secretion of MCP-1and IL-6 in a dose- and time-dependent manner in human umbilical vein endothelial cells. Visfatin-induced effects were diminished by SB203580, wortmannin, and PD98059. In summary, these results suggest that visfatin-induced MCP-1 and IL-6 production involve p38 MAPK, PI3K, and ERK 1/2 pathways in human umbilical vein endothelial cells as determined by inhibition with specific inhibitors.
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PMID:Visfatin stimulates production of monocyte chemotactic protein-1 and interleukin-6 in human vein umbilical endothelial cells. 1900 99

Senescence of endothelial cells increases with systemic aging and is thought to contribute to the development of atherosclerosis. Cell therapy with highly proliferative endothelial progenitor cells (EPCs) is an emerging therapeutic option to promote endothelial regeneration, but little is known about their senescence and their vulnerability to inflammatory stressors. We therefore studied the senescence of proliferative human EPCs and investigated the effects of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) on their senescence. Human EPCs had a significantly lower rate of senescence at baseline, compared with that of mature endothelial cells. However, EPCs up-regulated the expression of the senescence-associated cell cycle arrest protein p16(INK4a) and markedly increased measured senescence levels when exposed to chronic TNF-alpha treatment. Analysis of telomere length showed that the increases in senescence were not related to changes in telomere length. Inhibition of the p38 mitogen-activated protein kinase pathway blocked the induction of p16(INK4a) and cellular senescence. In conclusion, highly proliferative EPCs have a low rate of intrinsic senescence but are vulnerable to premature senescence induction by chronic proinflammatory stimulation. These findings will lead to a better understanding of physiological endothelial regeneration as well as to targeted therapies with the aim of promoting endothelial regeneration through endothelial progenitor cells.
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PMID:Premature senescence of highly proliferative endothelial progenitor cells is induced by tumor necrosis factor-alpha via the p38 mitogen-activated protein kinase pathway. 1912 61

Increasing evidence demonstrates that interleukin (IL)-32 is a pro-inflammatory cytokine, inducing IL-1alpha, IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and chemokines via nuclear factor (NF)-kappaB, p38 mitogen-activated protein kinase (MAPK), and activating protein (AP)-1 activation. Here we report that IL-32 is expressed and is also functional in human vascular endothelial cells (EC) of various origins. Compared with primary blood monocytes, high levels of IL-32 are constitutively produced in human umbilical vein EC (HUVEC), aortic macrovascular EC, and cardiac as well as pulmonary microvascular EC. At concentrations as low as 0.1 ng/ml, IL-1beta stimulated IL-32 up to 15-fold over constitutive levels, whereas 10 ng/ml of TNFalpha or 100 ng/ml of lipopolysaccharide (LPS) were required to induce similar quantities of IL-32. IL-1beta-induced IL-32 was reduced by inhibition of the IkappaB kinase-beta/NF-kappaB and ERK pathways. In addition to IL-1beta, pro-coagulant concentrations of thrombin or fresh platelets increased IL-32 protein up to 6-fold. IL-1beta and thrombin induced an isoform-switch in steady-state mRNA levels from IL-32alpha/gamma to beta/epsilon. Adult EC responded in a similar fashion. To prove functionality, we silenced endogenous IL-32 with siRNA, decreasing intracellular IL-32 protein levels by 86%. The knockdown of IL-32 resulted in reduction of constitutive as well as IL-1beta-induced intercellular adhesion molecule-1 (ICAM-1) (of 55% and 54%, respectively), IL-1alpha (of 62% and 43%), IL-6 (of 53% and 43%), and IL-8 (of 46% and 42%). In contrast, the anti-inflammatory/anti-coagulant CD141/thrombomodulin increased markedly when IL-32 was silenced. This study introduces IL-32 as a critical regulator of endothelial function, expanding the properties of this cytokine relevant to coagulation, endothelial inflammation, and atherosclerosis.
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PMID:IL-32-dependent effects of IL-1beta on endothelial cell functions. 1922 41

Oxidative stress has been strongly implicated in pathological processes. Isoketals are highly reactive gamma-ketoaldehydes of the isoprostanes pathway of free radical-induced peroxidation of arachidonic acid that are analogous to cyclooxygenase-derived levuglandins. Because aldehydes, that are much less reactive than isoketals, have been shown to trigger platelet activation, we investigated the effect of one isoketal (E(2)-IsoK) on platelet aggregation. Isoketal potentiated aggregation and the formation of thromboxane B(2) in platelets challenged with collagen at a concentration as low as 1 nM. Moreover, the potentiating effect of 1 nM isoketal on collagen-induced platelet aggregation was prevented by pyridoxamine, an effective scavenger of gamma-ketoaldehydes. Furthermore, we provide evidence for the involvement of p38 mitogen-activated protein kinase in isoketal-mediated platelet priming, suggesting that isoketals may act upstream the activation of collagen-induced cytosolic phospholipase A(2). Additionally, the incubation of platelets with 1 nM isoketal led to the phosphorylation of cytosolic phospholipase A(2). The cytosolic phopholipase A(2) inhibitors AACOCF3 and MAFP both fully prevented the increase in isoketal-mediated platelet aggregation challenged with collagen. These results indicate that isoketals could play an important role in platelet hyperfunction observed in pathological states such as atherosclerosis and thrombosis through the activation of the endogenous arachidonic acid cascade.
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PMID:Low concentrations of reactive gamma-ketoaldehydes prime thromboxane-dependent human platelet aggregation via p38-MAPK activation. 1923 11

Endothelial dysfunction is thought to be a major cause of vascular injury in smokers. Ghrelin is a recently discovered peptide that plays a modulatory role in atherosclerosis. However, it is unknown how ghrelin regulates nicotine-induced vascular cell adhesion molecule-1 (VCAM-1) expression. We examined nicotine-induced VCAM-1 expression in human umbilical vein endothelial cells pretreated with ghrelin and detected the activity of protein kinase C (PKC), p38 mitogen-activated protein kinase (p38 MAPK), and nuclear factor (NF)-kappaB. Our study showed that ghrelin inhibited nicotine-induced VCAM-1 expression in human umbilical vein endothelial cells in a concentration-dependent and time-dependent way. We also found that ghrelin inhibited nicotine-induced PKC, p38 MAPK, and NF-kappaB activation. The results suggest that ghrelin inhibits nicotine-induced VCAM-1 expression, and PKC, p38 MAPK, and NF-kappaB play active roles in that process. Exogenous ghrelin may provide a possible approach for preventing or reversing atherosclerosis in smokers.
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PMID:Inhibitory effect of ghrelin on nicotine-induced VCAM-1 expression in human umbilical vein endothelial cells. 1924 91


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