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)

A hallmark of hyperlipidemia-induced atherosclerosis is altered gene expression that initiates cell proliferation and (de)differentiation in the intima of the arterial wall. The molecular signaling that mediates this process in vivo has yet to be identified. Extracellular signal-regulated kinases (ERKs) are thought to play a pivotal role in transmitting transmembrane signals required for cell proliferation in vitro. The present studies were designed to investigate the activity, abundance, and localization of ERK1/2 in atherosclerotic lesions of cholesterol-fed rabbits. Immunofluorescence analysis revealed abundant and heterogeneous distribution of ERK1/2, mainly localized in the cap and basal regions of atheromas. A population of ERK-enriched cells was identified as alpha-actin-positive smooth muscle cells (SMCs). ERK1 and 2 were heavily phosphorylated on tyrosyl residues and coexpressed with proliferating cell nuclear antigen in atherosclerotic lesions. ERK1/2 protein levels in protein extracts from atherosclerotic lesions were 2- to 3-fold higher than the vessels of chow-fed rabbits, and their activities were elevated 3- to 5-fold over those of the normal vessel. SMCs derived from atherosclerotic lesions had increased migratory/proliferative ability and higher ERK activity in response to LDL stimulation compared with cells from the normal vessel. Inhibition of ERK activation by PD98059, a specific inhibitor of mitogen-activated protein kinase kinases (MEK1/2), abrogated LDL-induced SMC proliferation in vitro. Taken together, our findings support the proposition that persistent activation and hyperexpression of ERK1/2 may be a critical element to initiate and perpetuate cell proliferation during the development of atherosclerosis.
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PMID:Hyperexpression and activation of extracellular signal-regulated kinases (ERK1/2) in atherosclerotic lesions of cholesterol-fed rabbits. 1063 96

The atherogenic effect of the renin-angiotensin system can be explained, in part, by the influence of its effector, angiotensin II (Ang II), on vascular smooth muscle cell (VSMC) growth. There is evidence that reactive oxygen species (ROS) play a role in the atherogenesis and activation of mitogen-activating protein (MAP) kinases, which are involved in proliferation and differentiation. The study was performed to further characterize the role of ROS in Ang II-mediated MAP kinase activation and the regulation of the transcription factor activator protein-1 (AP-1). Rat VSMCs were stimulated with Ang II. The activities of MAP kinases were assessed by Western blot analysis or by immunocomplex kinase assay. AP-1 binding was determined by using an electrophoretic mobility shift assay. Rat VSMCs were treated with Ang II-activated MAP kinases, extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase (JNK), p38 MAP kinase (p38 MAPK), and their downstream effector, AP-1. Interestingly, only the activation of ERK1/2, but not JNK or p38 MAPK, was tyrosine kinase, protein kinase C, and MEK1/2 dependent. Ang II also induced the rapid formation of ROS, which could be inhibited by a specific antibody as well as by antisense against the p22phox subunit of the NAD(P)H oxidase. JNK and p38 MAPK, but not ERK, activation was inhibited by an inhibitor of NAD(P)H oxidase. Antisense against p22phox also solely inhibited p38 MAPK but did not affect ERK. The results indicate that in VSMCs, Ang II activates MAP kinases and AP-1 through different pathways; the results further suggest that ROS, generated by p22phox, mediate Ang II-induced JNK and p38 MAPK activation, which may contribute to the pathogenesis of atherosclerosis.
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PMID:Differential activation of mitogen-activated protein kinases in smooth muscle cells by angiotensin II: involvement of p22phox and reactive oxygen species. 1076 57

Oxidized low-density lipoprotein (OX-LDL) contributes significantly to the development of atherosclerosis. However, the mechanisms of OX-LDL-induced vascular smooth muscle cell (VSMC) proliferation are not completely understood. Therefore, we investigated the effect of OX-LDL on cell proliferation associated with a specific pattern of mitogen-activated protein kinase (MAPK) by [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in canine cultured VSMCs. OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in a time- and concentration-dependent manner in VSMCs. Pretreatment of these cells with pertussis toxin (PTX) for 24 hours attenuated the OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation, indicating that these responses were mediated through a receptor coupled to a PTX-sensitive G protein. In cells pretreated with PMA for 24 h and with either the PKC inhibitor staurosporine or the tyrosine kinase inhibitor genistein for 1h, substantially reduced the [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in response to OX-LDL. Removal of Ca(2+) by addition of BAPTA/AM plus EGTA significantly inhibited OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation, indicating the requirement of Ca(2+) for these responses. OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation was completely inhibited by PD98059 (an inhibitor of MEK1/2) and SB203580 (an inhibitor of p38 MAPK). Furthermore, we also showed that overexpression of dominant negative mutants of Ras (RasN17) and Raf (Raf-301) completely suppressed MEK1/2 and p42/p44 MAPK activation induced by OX-LDL and PDGF-BB, indicating that Ras and Raf may be required for activation of these kinases. Taken together, these results suggest that the mitogenic effect of OX-LDL is mediated through a PTX-sensitive G-protein-coupled receptor that involves the activation o Ras/Raf/MEK/MAPK pathway similar to those of PDGF-BB in canine cultured VSMCs.
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PMID:Activation of mitogen-activated protein kinase by oxidized low-density lipoprotein in canine cultured vascular smooth muscle cells. 1078 27

Hypercholesterolemia (HC) is associated with coronary endothelial dysfunction and increased circulating levels of endothelin-1. We show that pre-treatment of intact rat aortic rings with cholesterol synergistically enhances the vasoconstriction induced by endothelin-1 suggesting that elevated levels of cholesterol may predispose to hypertension by modulating the vascular reactivity to endogenous vasoconstrictors. Moreover, we report that SB202190, a selective inhibitor of p38 MAPK, and PD98059 an inhibitor of MEK1/2 are able to abolish the vasoactive properties of cholesterol. MK-886, an inhibitor of 5-lipoxygenase is inefficient at blocking the vasoactive properties of cholesterol whereas NS-398, a selective inhibitor of cyclooxygenase-2 (COX-2) completely abolishes cholesterol-induced vasoconstriction. In intact rat aortae, cholesterol stimulates prostaglandin E(2) and prostaglandin F(2 alpha) production, an effect that can be completely prevented by inhibiting p38 MAPK, or COX-2. In vitro, cholesterol appears to stimulate a similar pro-inflammatory pathway in human cerebrovascular smooth muscle cells. Disruption of the MAPK/COX-2 pathway may represent a valuable therapy to block the hypertension associated with HC, as well as the development of atherosclerosis.
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PMID:Cholesterol modulates vascular reactivity to endothelin-1 by stimulating a pro-inflammatory pathway. 1091 76

Cytokine activation of vascular endothelial cells renders the hyperadhesiveness for neutrophils. During the processes of inflammation and atherosclerosis, the production of reactive oxygen species by neutrophils contributes to endothelial cell (EC) damage and injury. However, the precise mechanisms for neutrophil activation by ECs remain unknown. Thus, we investigated what kinds of pathophysiological factors synthesized by inflammatory cytokine-activated ECs potentiated the activity of neutrophil functions. The magnitude of O(2)(-) release from neutrophils, which is one of pivotal neutrophil functions, was measured as an indicator potentiated by activated ECs. Neutrophils release massive amounts of O(2)(-) on coculture with activated ECs. Anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody (Ab) or specific platelet-activating factor (PAF)-receptor antagonist suppressed the O(2)(-) release from neutrophils on coculture with the activated ECs by 50% to 70%. The supernatants from activated ECs also induced O(2)(-) release by neutrophils. This stimulatory effect of activated EC supernatants on O(2)(-) release by neutrophils was abolished by anti-GM-CSF Ab or by PAF-receptor antagonist. As we previously reported, we demonstrated the expression of GM-CSF mRNA by Northern blotting and protein synthesis of GM-CSF by ELISA on tumor necrosis factor as well as interleukin-1-activated ECs. Although phosphorylation of mitogen-activated protein kinases was observed in ECs stimulated by tumor necrosis factor and interleukin-1, treatment of ECs with PD98059 (MEK1 inhibitor) and SB203580 (p38 mitogen-activated protein kinase inhibitor) in the presence of the cytokine failed to attenuate the stimulatory effect of activated ECs on neutrophil activation. We found that activated ECs regulated neutrophil function on coculture. We show here for the first time, to our knowledge, that the collaboration between GM-CSF and PAF synthesized by activated ECs markedly potentiated neutrophil activation.
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PMID:Activation of human neutrophil by cytokine-activated endothelial cells. 1123 Jan 10

Lysophosphatidylcholine, a component of oxidized low density lipoprotein, is critical for pathological conditions including atherosclerosis. However, the signaling mechanism of lysophosphatidylcholine remains poorly understood. Here we reported that lysophosphatidylcholine induces phosphorylation of p38 and the transcription factors, CREB and ATF-1 with concomitant up-regulation of cyclooxygenase-2 expression in cultured vascular endothelial cells. Lysophosphatidylcholine induced p38 phosphorylation in a time- and concentration-dependent manner partly via pathway depending on protein tyrosine kinase. Both lysophosphatidylcholine-stimulated phosphorylation of CREB and ATF-1 and lysophosphatidylcholine-increased expression of cyclooxygenase-2 mRNA and protein were effectively inhibited by a combination of SB203580 and PD98059, specific inhibitors of p38 and MEK1, respectively, as well as Ro31-8220 and H89, potent inhibitors of MSK1. These results suggest that both p38 and ERK may function as upstream signaling pathways capable of activating CREB and ATF-1 with subsequent induction of cyclooxygenase-2 expression by lysophosphatidylcholine.
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PMID:Signaling mechanism underlying COX-2 induction by lysophosphatidylcholine. 1124 76

1. It has been demonstrated that oxidized low-density lipoprotein (OX-LDL) is a risk factor in atherosclerosis by stimulating vascular smooth muscle cell (VSMC) proliferation. However, the mechanisms of OX-LDL-induced cell proliferation are not completely understood. Therefore, we investigated the effect of OX-LDL on cell proliferation associated with mitogen-activated protein kinase (MAPK) activation in rat cultured VSMCs. 2. Both native-LDL (N-LDL) and OX-LDL induced a time- and concentration-dependent incorporation of [(3)H]-thymidine in VSMCs. 3. OX-LDL induced time- and concentration-dependent phosphorylation of p42/p44 MAPK. Pretreatment of these cells with pertussis toxin or U73122 attenuated the OX-LDL-induced responses. 4. Pretreatment with PMA for 24 h, preincubation with a PKC inhibitor staurosporine or the tyrosine kinase inhibitors, genistein and herbimycin A for 1 h, substantially reduced [(3)H]-thymidine incorporation and p42/p44 MAPK phosphorylation induced by OX-LDL. 5. Removal of Ca(2+) by BAPTA/AM or depletion of the internal Ca(2+) pool by thapsigargin significantly inhibited OX-LDL-induced [(3)H]-thymidine incorporation and p42/p44 MAPK phosphorylation. 6. OX-LDL-induced [(3)H]-thymidine incorporation and p42/p44 MAPK phosphorylation was inhibited by PD98059 (an inhibitor of MEK1/2) and SB203580 (an inhibitor of p38 MAPK) in a concentration-dependent manner. 7. Overexpression of dominant negative mutants of Ras (H-Ras-15A) and Raf (Raf-N4) significantly suppressed MEK1/2 and p42/p44 MAPK activation induced by OX-LDL and PDGF-BB, indicating that Ras and Raf may be required for activation of these kinases. 8. These results suggest that the mitogenic effect of OX-LDL is mediated through a PTX-sensitive G protein-coupled receptor that involves the activation of the Ras/Raf/MEK/MAPK pathway similar to that of PDGF-BB in rat cultured VSMCs.
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PMID:Mitogenic effect of oxidized low-density lipoprotein on vascular smooth muscle cells mediated by activation of Ras/Raf/MEK/MAPK pathway. 1126 47

Vascular smooth muscle cells play a key role in the development of atherosclerosis. Culture of vascular smooth muscle A10 cells with high glucose for 4 weeks enhanced platelet-derived growth factor (PDGF)-induced BrdU incorporation. Since a long period of high glucose incubation was required for the effect, and it was inhibited by co-incubation with azaserine, the role of hexosamine biosynthesis in the development of atherosclerosis in diabetes was studied in A10 cells. Addition of glucosamine to the culture media enhanced PDGF-stimulated BrdU incorporation, and PDGF-induced tyrosine phosphorylation of the PDGF beta-receptor was increased by glucosamine treatment. Of the subsequent intracellular signaling pathways, PDGF-induced PDGF beta-receptor association with PLC gamma was not affected, whereas tyrosine phosphorylation of Shc, subsequent association of Shc with Grb2, and MAP kinase activation were relatively decreased. In contrast, PDGF-induced PDGF beta-receptor association with the p85 regulatory subunit of PI3-kinase and PI3-kinase activation were increased by 20% (P<0.01) and 36% (P<0.01), respectively. The intracellular signaling molecules responsible for the glucosamine effect were further examined using pharmacological inhibitors. Pretreatment with PLC inhibitor (U73122) had negligible effects, and MEK1 inhibitor (PD98059) showed only a slight inhibitory effect on the PDGF-induced BrdU incorporation. In contrast, pretreatment with PI3-kinase inhibitor (LY294002) significantly inhibited glucosamine enhancement of PDGF-induced BrdU incorporation. These findings suggest that glucosamine is involved in the development of atherosclerosis by enhancing PDGF-induced mitogenesis specifically via the PI3-kinase pathway.
Atherosclerosis 2001 Aug
PMID:Glucosamine enhances platelet-derived growth factor-induced DNA synthesis via phosphatidylinositol 3-kinase pathway in rat aortic smooth muscle cells. 1147 33

Previous work shows that osteopontin has a role during matrix reorganization after tissue injury including vascular conditions such as atherosclerosis and restenosis following angioplasty. In vitro, osteopontin promotes activities such as adhesion and migration but the mechanisms that regulate the expression of this matrix protein remain essentially unknown. This study examined if the ERK signaling pathway is involved in injury-induced osteopontin expression in cultured rat aortic smooth muscle cells. Northern and Western blotting demonstrated a marked activation of osteopontin expression in response to injury. Treating the cells with PD98059, a specific MEK1 inhibitor, prior to injury, blocked this upregulation. MEK1 phosphorylates ERK1/ERK2, which belong to the family of mitogen-activated protein kinases. We conclude that ERK1/ERK2 are involved in the regulation of osteopontin expression in cultured vascular smooth muscle cells.
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PMID:Injury-induced osteopontin gene expression in rat arterial smooth muscle cells is dependent on mitogen-activated protein kinases ERK1/ERK2. 1171 72

Vascular diseases such as atherosclerosis are characterized by abnormal accumulation of vascular smooth muscle cells (VSMCs) within the intimal lining. The intimal VSMCs exhibit an increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma), and the administration of pharmacological PPARgamma agonists attenuates vascular lesion formation. The factors that regulate PPARgamma expression in the vasculature are poorly defined. Here we report that platelet-derived growth factor (PDGF) upregulates PPARgamma by the phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling pathway. Using Northern-blotting and Western-blotting analyses, we observed that the levels of PPARgamma mRNA and protein were increased by 2- to 3.5-fold in human aortic smooth muscle cells (HASMCs) treated with PDGF (20 ng/mL). This was abolished by preincubation of HASMCs with a PI3-kinase inhibitor (LY294002, 50 micromol/L), and partially inhibited by a MEK1 inhibitor (U0126, 10 micromol/L), but not affected by a p38 kinase inhibitor (SB202190, 10 micromol/L). In addition, overexpression of the dominant-negative p85 subunit of PI3-kinase or Akt proteins blocked the PDGF-induced PPARgamma expression. Taken together, our results suggest that PDGF induces PPARgamma expression in VSMCs by a PI3-kinase/Akt signaling pathway. The characterization of factors and signaling pathways that modulate PPARgamma expression in VSMCs may have important implications for understanding the pathogenesis of vascular diseases.
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PMID:Platelet-derived growth factor promotes the expression of peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells by a phosphatidylinositol 3-kinase/Akt signaling pathway. 1171 47


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