Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of vascular smooth muscle cells (SMCs) by platelet-derived growth factor (PDGF) is a seminal event in the initiation and progression of the atherosclerotic lesion and may contribute to atherosclerotic plaque instability with plaque rupture and thrombus formation. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play a major role in thrombus formation after plaque rupture. This study examined intracellular signaling pathways leading to TF expression and Egr-1 activation, a key element in tissue factor transcription, by PDGF-BB in rat SMCs. PDGF-BB induced TF mRNA and protein expression in a time-dependent manner. Early growth response factor-1 (Egr-1) binding activity was also induced by PDGF-BB, as well as phosphorylation of extracellular signal-regulated kinase. PDGF-BB-induced Egr-1 activation was suppressed by inhibitors of 2 upstream activators of Egr-1, extracellular signal-regulated kinase (ERK) and Src family kinases, whereas antioxidants, phosphatidylinositol 3-phosphate kinase, and p38 MAPK inhibitors had no effect. PDGF-BB-stimulated expression of the transcriptional co-repressor NAB2 was time-dependent. Furthermore, transient transfections of SMCs with wild-type and mutated TF promoter constructs showed that the Egr-1 binding region is an important transcriptional regulator of PDGF-BB-induced TF expression. Taken together, the results suggest that PDGF-BB induces TF expression and activity in SMC by a Src family kinases/ERK/Egr-1 signaling pathway and may therefore contribute to thrombus formation in advanced atherosclerosis and restenosis.
 ...
PMID:Platelet-derived growth factor induces tissue factor expression in vascular smooth muscle cells via activation of Egr-1. 1549 29

Hyperglycemia and hyperlipidemia are important risk factors for diabetes-accelerated atherosclerosis. Macrophage proliferation has been implicated in the progression of atherosclerosis. We therefore investigated the effects of hyperglycemia and hyperlipidemia on macrophage proliferation in murine atherosclerotic lesions and isolated primary macrophages. Hyperglycemic LDL receptor-deficient mice that were fed a cholesterol-free diet for 12 weeks did not have elevated cholesterol levels compared with nondiabetic mice, and there was no evidence of increased macrophage proliferation in atherosclerotic lesions. Moreover, elevated glucose levels did not increase proliferation of isolated mouse peritoneal macrophages. In contrast, hyperglycemic LDL receptor-deficient mice that were fed a cholesterol-rich diet showed increased cholesterol levels concomitant with macrophage proliferation in atherosclerotic lesions. Glucose promoted lipid and protein oxidation of LDL in vitro. Glucose-oxidized LDL resulted in phosphorylation of extracellular signal-regulated kinase and protein kinase B/Akt and stimulated proliferation of isolated macrophages. The mitogenic effect of glucose-oxidized LDL was mediated by CD36 and by extracellular signal-regulated kinase activation induced by protein kinase C-dependent and phosphatidylinositol 3-kinase-dependent pathways. Thus, hyperglycemia is not sufficient to stimulate macrophage proliferation in lesions of atherosclerosis or in isolated macrophages. A combination of hyperglycemia and hyperlipidemia, however, stimulates macrophage proliferation by a pathway that may involve the glucose-dependent oxidation of LDL.
 ...
PMID:Hyperlipidemia in concert with hyperglycemia stimulates the proliferation of macrophages in atherosclerotic lesions: potential role of glucose-oxidized LDL. 1556 53

Diabetes confers an increased propensity to atherosclerosis. Inflammation is pivotal in atherogenesis, and diabetes is a proinflammatory state. Interleukin (IL)-6, in addition to inducing the acute-phase response, contributes to insulin resistance. Monocytes from type 2 diabetic patients secrete increased IL-6. The aim of this study was to examine molecular mechanisms for increased IL-6 release from monocytes under hyperglycemia. Monocytic cells (THP-1) were cultured in the presence of 5.5 mmol/l (normal) or 15 mmol/l (high) glucose and mannitol. Secreted IL-6, intracellular IL-6, and IL-6 mRNA were significantly increased with hyperglycemia (P < 0.001). Incubation of cells with inhibitors of reactive oxygen species failed to affect high-glucose-induced IL-6 release. Pan-protein kinase C (PKC) inhibitors significantly decreased high-glucose-induced IL-6 release. A specific inhibitor of p38 mitogen-activated protein kinase (MAPK; SB 202190), but not the extracellular signal-regulated kinase inhibitor PD98059, significantly decreased high-glucose-induced IL-6 release. Furthermore, the PKC-alpha/beta2 inhibitor decreased p38MAPK and the resulting high-glucose-induced IL-6 release. Both antisense oligos to PKC-beta and -alpha as well as small interfering RNA (siRNA) to PKC-alpha and -beta resulted in significantly decreased high-glucose-induced IL-6 release. Nuclear factor-kappaB (NF-kappaB) inhibitors significantly decreased IL-6 mRNA and protein. siRNA to PKC-beta and -alpha also significantly decreased NF-kappaB activity and IL-6 release. The combination was not additive to either siRNA alone, suggesting that they work through a common pathway. Thus, IL-6 release from monocytes under hyperglycemia appears to be mediated via upregulation of PKC, through p38MAPK and NF-kappaB, resulting in increased mRNA and protein for IL-6. Thus, inhibition of PKC-alpha and -beta can ameliorate the proinflammatory state of diabetes.
 ...
PMID:Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase c-{alpha} and -{beta}. 1561 14

Antidiabetic drug thiazolidinedione (TZD) also has anti-atherogenic effects. Among these effects, inhibition of smooth muscle cell (SMC) migration is considered to be essential. However, the mechanism whereby TZD inhibits SMC migration is not well understood. Since it is known that matrix metalloproteinases (MMPs) play a permissive role for SMC migration, we determined if TZD inhibits the upregulation of MMP-1 expression in SMCs by oxidized LDL (oxLDL), a potent stimulator for atherogenesis. Results showed that oxLDL markedly stimulated MMP-1 secretion, mRNA expression, and MMP-1 promoter activity, but pioglitazone significantly inhibited the oxLDL-upregulated MMP-1 expression. In an attempt to explore the signaling mechanism by which pioglitazone inhibits the oxLDL-upregulated MMP-1 expression, we found that extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK) pathways were required for the oxLDL-stimulated MMP-1 expression, but pioglitazone failed to antagonize the activation of ERK and JNK by oxLDL. Finally, our AP-1 activity assay showed that pioglitazone inhibited oxLDL-stimulated c-Jun activity. Taken together, the present study indicates that pioglitazone inhibits oxLDL-stimulated MMP-1 expression in VSMCs by inhibiting c-Jun transcriptional activity through a mitogen-activated protein kinase (MAPK)-independent mechanism.
Atherosclerosis 2005 Feb
PMID:Pioglitazone inhibits MMP-1 expression in vascular smooth muscle cells through a mitogen-activated protein kinase-independent mechanism. 1569 31

Low density lipoproteins (LDL) play important roles in the pathogenesis of atherosclerosis. Diabetes is associated with accelerated atherosclerosis leading to cardiovascular disease in diabetic patients. Although LDL stimulates the proliferation of arterial smooth muscle cells (SMC), the mechanisms are not fully understood. We examined the effects of native LDL and glycated LDL on the extracellular signal-regulated kinase (ERK) pathway. Addition of native and glycated LDL to rat aorta SMCs (RASMCs) stimulated ERK phosphorylation. ERK phosphorylation was not affected by exposure to the Ca2+ chelator BAPTA-AM but inhibition of protein kinase C (PKC) with GF109203X, inhibition of Src kinase with PP1 (5 microM) and inhibition of phospholipase C (PLC) with U73122/U73343 (5 microM) all reduced ERK phosphorylation in response to glycated LDL. In addition, pretreatment of the RASMCs with a cell-permeable mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059, 5 microM) markedly decreased ERK phosphorylation in response to native and glycated LDL. These findings indicate that ERK phosphorylation in response to glycated LDL involves the activation of PKC, PLC, and MEK, but is independent of intracellular Ca2+.
 ...
PMID:The Src/PLC/PKC/MEK/ERK signaling pathway is involved in aortic smooth muscle cell proliferation induced by glycated LDL. 1575 Mar 41

Early growth response factor-1 (Egr-1) is a zinc-finger transcription factor that induces genes that promote atherosclerosis. The goal of the present study was to determine whether Egr-1 expression is modulated by atherogenic, triglyceride rich lipoproteins known as chylomicron remnants. Chylomicron remnants induced Egr-1 mRNA and protein expression in rat cultured vascular smooth muscle cells (VSMCs) and activated extracellular signal-regulated kinase (ERK) 1/2 in VSMCs. Further, chylomicron remnant-induced Egr-1 expression was inhibited by PD98059, a selective inhibitor of MAPK kinase (MEK), suggesting that the action of chylomicron remnants on Egr-1 was dependent on the ERK/MEK pathway. Chylomicron remnants also induced mRNA expression of the pro-inflammatory cytokines, IL-2 and IFN-gamma in VSMCs. We conclude that chylomicron remnants act as atherogenic lipoproteins via induction of Egr-1 expression and via cytokine-mediated inflammation.
 ...
PMID:Chylomicron remnants regulate early growth response factor-1 in vascular smooth muscle cells. 1592 98

Salvia miltiorrhiza Bunge, a traditional Chinese herbal medicine, is often used for prevention and treatment of cardiovascular disorders such as atherosclerosis. To understand its mechanism of pharmacological action, its effects on endothelial monolayer permeability are studied. The present study demonstrated that extract of S. miltiorrhiza (ESM) and its major ingredients, Danshensu (DSS) and salvianolic acid B (Sal B), inhibited tumor necrosis factor (TNF-alpha) induced endothelial permeability, whereas the other major ingredient, protocatechualdehyde, was ineffective. ESM, DSS and Sal B also repressed expression of vascular endothelial growth factor (VEGF) and extracellular signal-regulated kinase (ERK) activation in TNF-alpha induced HUVEC cells. Furthermore, it was found that ESM attenuated the disorganization of vascular endothelial (VE)-cadherin induced by TNF-alpha. The effect of ESM on TNF-alpha induced endothelial permeability and redistribution of VE-cadherin is likely due to a reduction of VEGF protein expression as a result of modulation of the ERK signaling pathway. Endothelial cell hyperpermeability is implicated in inflammation and subsequent ischemic reperfusion injury and atherosclerosis. Data from this study suggest that one of the mechanisms S. miltiorrhiza exerts its pharmacological effect is through its modulation of endothelial cell permeability.
 ...
PMID:Aqueous extract of Salvia miltiorrhiza attenuates increased endothelial permeability induced by tumor necrosis factor-alpha. 1603 54

Plasminogen activator inhibitor type 1 (PAI-1), which plays a role in the development of atherosclerosis, is produced by endothelial cells following stimulation with various inflammatory cytokines such as tumor necrosis factor (TNF-alpha). In the present study, we investigated the effects of a potent water-soluble antioxidant, salvianolic acid B (SalB; derived from the Chinese herb, Salvia miltiorrhiza), on the expression of PAI-1 in TNF-alpha-treated human umbilical vein endothelial cells (HUVECs). We found that SalB inhibited TNF-alpha-induced PAI-1 mRNA production and protein secretion in HUVECs. Treatment with SalB (0.05 and 0.15 microM) notably attenuated TNF-alpha induced expression of PAI-1 to 90.5% and 74.6%, respectively, after 12 h, and to 75.1% and 64.2%, respectively, after 18 h. We also observed a dose-dependent decrease in PAI-1 protein production in the presence of SalB. We then used pathway inhibitors to investigate which step of the TNF-alpha induced signaling pathway was targeted by SalB. We found that the c-Jun N-terminal kinase (JNK) inhibitor, SP600125, increased the inhibitory effects of SalB on TNF-alpha-induced PAI-1 secretion, whereas the nuclear factor-kappaB (NF-kappaB) inhibitor, emodin, and the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, did not. A gel shift assay further showed that SalB inhibited the TNF-alpha-activated NF-kappaB and AP-1 DNA binding activities in a dose-dependent manner. Collectively, these results indicate that the NF-kappaB and ERK-AP-1 pathways are possible targets of SalB in the regulation of TNF-alpha-stimulated PAI-1 production in HUVECs.
 ...
PMID:Salvianolic acid B attenuates plasminogen activator inhibitor type 1 production in TNF-alpha treated human umbilical vein endothelial cells. 1605 13

In atherosclerosis, abnormal vascular smooth muscle cell (VSMC) proliferation plays an important role to form fibroproliferative lesions and platelet-derived growth factor (PDGF)-BB is one of the most potent chemoattractants and proliferative factors for VSMCs. Taurine, sulfur-containing beta-amino acid, has been considered to prevent the development of atherosclerosis, although the molecular mechanism remains obscure. Previously, we demonstrated that taurine significantly suppressed PDGF-BB-induced cell proliferation, DNA synthesis, immediate-early gene expressions and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in VSMCs. The present study was aimed at elucidating the precise molecular mechanism of taurine in PDGF-BB signaling pathway. We showed that taurine significantly suppressed PDGF-BB-induced phosphorylation of PDGF-beta receptor and activation of its downstream signaling molecules such as Ras, MAPK/ERK kinase (MEK)1/2 and Akt. Because taurine did not attenuate phorbol 12-myristate 13-acetate (PMA)-induced PDGF-beta receptor-independent ERK1/2 phosphorylation, we further investigated the suppressive mechanism of taurine in PDGF-beta receptor level. Although taurine did not directly affect PDGF receptor autophosphorylation in vitro, taurine promoted PDGF-beta receptor dephosphorylation and restored PDGF-BB-induced suppression of protein tyrosine phosphatase (PTPase) activity. Taken together, we propose that taurine could prevent or delay the progression of atherosclerosis by PTPase-mediated suppression of PDGF-beta receptor phosphorylation, and by decreasing the activation of its downstream signaling molecules in VSMCs.
 ...
PMID:Taurine suppresses platelet-derived growth factor (PDGF) BB-induced PDGF-beta receptor phosphorylation by protein tyrosine phosphatase-mediated dephosphorylation in vascular smooth muscle cells. 1611 11

CD40 is a 48kDa phosphorylated transmembrane glycoprotein that belongs to the tumor necrosis factor receptor superfamily and may play a role in formation of atherosclerotic plaques. Here, we investigated the effect of chylomicron remnants on CD40 expression in the human premonocytic cell line, THP-1 cells. Chylomicron remnants upregulated the expression of CD40 protein and mRNA in a dose- and time-dependent manner. Further, chylomicron remnants increased the generation of reactive oxygen species as determined by an increasing level of 2',7'-dichlorofluorescein. Pretreatment with the antioxidant, N-acetylcysteine, inhibited chylomicron remnant-induced CD40 protein expression by 60%. On the other hand, chylomicron remnants transiently increased the phosphorylation of extracellular signal-regulated kinase (ERK 1/2) and p38 mitogen-activated protein kinase (MAPK). Pretreatment with the MAPK kinase inhibitor, U0126, completely inhibited chylomicron remnants-induced CD40 protein expression, whereas the p38 MAPK inhibitor, SB203580, had no effect. Pretreatment with N-acetylcysteine had no effect on chylomicron remnant-induced ERK 1/2 phosphorylation. These data suggest that CD40 expression stimulated by chylomicron remnants in THP-1 cells is dependent on ERK 1/2-mediated pathway, which is followed by redox-sensitive mechanism-dependent and independent pathway. Thus, chylomicron remnants may contribute to the formation of atherosclerotic plaques via their immunological and proinflammatory effects.
Atherosclerosis 2006 Aug
PMID:Chylomicron remnants upregulate CD40 expression via the ERK pathway and a redox-sensitive mechanism in THP-1 cells. 1635 5


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>