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)

Reactive oxygen species have been implicated in the pathogenesis of atherosclerosis, hypertension, and restenosis, in part by promoting vascular smooth muscle cell (VSMC) growth. Many VSMC growth factors are secreted by VSMC and act in an autocrine manner. Here we demonstrate that cyclophilin A (CyPA), a member of the immunophilin family, is secreted by VSMCs in response to oxidative stress and mediates extracellular signal-regulated kinase (ERK1/2) activation and VSMC growth by reactive oxygen species. Human recombinant CyPA can mimic the effects of secreted CyPA to stimulate ERK1/2 and cell growth. The peptidyl-prolyl isomerase activity is required for ERK1/2 activation by CyPA. In vivo, CyPA expression and secretion are increased by oxidative stress and vascular injury. These findings are the first to identify CyPA as a secreted redox-sensitive mediator, establish CyPA as a VSMC growth factor, and suggest an important role for CyPA and enzymes with peptidyl-prolyl isomerase activity in the pathogenesis of vascular diseases.
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PMID:Cyclophilin A is a secreted growth factor induced by oxidative stress. 1105 83

Sphingosine 1-phosphate (S1P) is stored in and released from platelets in response to cell activation. However, recent studies show that it is also released from a number of cell types, where it can function as a paracrine/autocrine signal to regulate cell proliferation, differentiation, survival, and motility. This review discusses the role of S1P in cellular regulation, both at the molecular level and in terms of health and disease. The main biochemical routes for S1P synthesis (sphingosine kinase) and degradation (S1P lyase and S1P phosphatase) are described. The major focus is on the ability of S1P to bind to a novel family of G-protein-coupled receptors (endothelial differentiation gene [EDG]-1, -3, -5, -6, and -8) to elicit signal transduction (via G(q)-, G(i)-, G(12)-, G(13)-, and Rho-dependent routes). Effector pathways regulated by S1P are divergent, such as extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, phospholipases C and D, adenylyl cyclase, and focal adhesion kinase, and occur in multiple cell types, such as immune cells, neurones, smooth muscle, etc. This provides a molecular basis for the ability of S1P to act as a pleiotropic bioactive lipid with an important role in cellular regulation. We also give an account of the expanding role for S1P in health and disease; in particular, with regard to its role in atherosclerosis, angiogenesis, cancer, and inflammation. Finally, we describe future directions for S1P research and novel approaches whereby S1P signalling can be manipulated for therapeutic intervention in disease.
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PMID:Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors. 1115 May 92

Obese hypertensive patients with cardiovascular risk factor clustering and increased risk for atherosclerotic disease have increased plasma nonesterified fatty acid levels, including oleic acid (OA), and a more active renin-angiotensin-aldosterone system. Vascular smooth muscle cell (VSMC) migration and proliferation participate in the development of atherosclerotic plaque. OA and angiotensin (Ang) II induce synergistic mitogenic responses in VSMCs through sequential signaling pathways dependent on the activation of protein kinase C (PKC), oxidants (reactive oxygen species, ROS), and extracellular signal-regulated kinase (ERK) activation. We tested the hypotheses that (1) OA and Ang II have additive or synergistic effects on VSMC migration and (2) PKC, ROS, and mitogen-activated protein kinase are critical signaling molecules. OA at 100 micromol/L increases VSMC migration 60+/-10% over control (P:<0.001). Ang II (10(-)(9) mol/L) increases VSMC migration by 62+/-13% and 73% over control, respectively (P:<0.01). Coincubation of cells with OA and Ang II produces a nearly additive increase in VSMC cell migration at 107+/-20% (P:<0.01). Increases in VSMC migration induced by OA alone and combined with Ang II were reduced by PKC inhibition and downregulation. VSMC migration in response to OA alone and with Ang II was also inhibited by N:-acetyl-cysteine, MEK inhibition, and ERK antisense. VSMC migration in response to OA alone or combined with Ang II is dependent on activation of PKC, ROS, and ERK activation, further raising the possibility that increased plasma nonesterified fatty acids and an activated renin-angiotensin-aldosterone system in subjects with the risk factor cluster contribute to accelerated atherosclerosis through a PKC, ROS, and ERK-dependent signaling pathway.
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PMID:Signaling events mediating the additive effects of oleic acid and angiotensin II on vascular smooth muscle cell migration. 1123 Feb 90

Proliferation of vascular smooth muscle cells (VSMC) contributes to the pathogenesis of atherosclerosis, and glycated serum albumin (GSA, Amadori adduct of albumin) might be a mitogen for VSMC proliferation, which may further be associated with diabetic vascular complications. In this study, we investigated the involvement of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and protein kinase C (PKC), in GSA-stimulated mitogenesis, as well as the functional relationship between these factors. VSMC stimulation with GSA resulted in a marked activation of ERK. The MAPK kinase (MEK) inhibitor, PD98059, blocked GSA-stimulated MAPK activation and resulted in an inhibition of GSA-stimulated VSMC proliferation. GSA also increased PKC activity in VSMC in a dose-dependent manner. The inhibition of PKC by the PKC inhibitors, GF109203X and Rottlerin (PKCdelta specific inhibitor), as well as PKC downregulation by phorbol 12-myristate 13-acetate (PMA), inhibited GSA-induced cell proliferation and blocked ERK activation. This indicates that phorbol ester-sensitive PKC isoforms including PKCdelta are involved in MAPK activation. Thus, we show that the MAPK cascade is required for GSA-induced proliferation, and that phorbol ester-sensitive PKC isoforms contribute to cell activation and proliferation in GSA-stimulated VSMC.
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PMID:Glycated serum albumin-induced vascular smooth muscle cell proliferation through activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by protein kinase C. 1123 43

Hyperinsulinemia in diabetes mellitus is a significant risk factor in the development of atherosclerosis and early restenosis after balloon angioplasty. These manifestations could be mediated by the ability of insulin to potentiate the cellular proliferative and reparative response of vascular cell types to local stimuli. Here we demonstrate that insulin stimulates DNA synthesis in aortic endothelial cells. Reverse transcription-polymerase chain reaction and Northern blotting revealed that insulin induces the expression and transcriptional activity of the immediate early gene and zinc finger transcription protein, early growth response factor-1 (Egr-1). Western immunoblot analysis revealed that insulin-inducible Egr-1 expression was inhibited using phosphorothioate-specific antisense oligonucleotides targeting Egr-1 mRNA. These agents blocked endothelial cell DNA synthesis stimulated by insulin in a dose-dependent manner and inhibited the capacity of insulin to potentiate the reparative response of endothelial cells to mechanical injury in vitro. These oligonucleotides also attenuated wound repair in smooth muscle cells. DNA synthesis induced by insulin was suppressed by inhibitors of two upstream activators of Egr-1, extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-phosphate (PI 3-K), whereas p38 kinase inhibitors had no effect. These present findings demonstrate that insulin-inducible DNA synthesis and repair after injury are processes critically dependent upon the activation of Egr-1. Additionally, they implicate this transcription factor as a potential target for the inhibition of restenosis in diabetics.
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PMID:Early growth response factor-1 mediates insulin-inducible vascular endothelial cell proliferation and regrowth after injury. 1125 35

Abnormal vascular smooth muscle cell (VSMC) growth plays a key role in the pathogenesis of hypertension and atherosclerosis. Angiotensin II (Ang II) elicits a hypertrophic growth response characterized by an increase in protein synthesis in the absence of DNA synthesis and cell proliferation. Intracellular signaling mechanisms linking angiotensin type I receptor activation to protein synthesis in VSMC have not been fully characterized. The present study investigates the role of the nonreceptor proline-rich tyrosine kinase 2 (PYK2) in Ang II-induced VSMC protein synthesis and in the regulation of two signaling pathways that have been implicated in the control of protein synthesis, the extracellular signal-regulated kinase (ERK1/2) and the phosphatidylinositol 3-kinase/Akt pathways. PYK2 antisense oligonucleotides were used to down-regulate PYK2 expression in cultured VSMC. An 80% down-regulation in PYK2 expression resulted in an approximately 80% inhibition of ERK1/2 (3.8 +/- 1.3 versus 16.6 +/- 1.8), p70S6 kinase (1.03 +/- 0.03 versus 3.8 +/- 0.5), and Akt activation (3.0 +/- 0.8 versus 16.0 +/- 1.0) by Ang II. Furthermore, PYK2 down-regulation resulted in a complete inhibition of Ang II-induced VSMC protein synthesis. These data conclusively identify PYK2 as an upstream regulator of both the ERK1/2 and the phosphatidylinositol 3-kinase/Akt pathways that are involved in Ang II-induced VSMC protein synthesis.
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PMID:Down-regulation by antisense oligonucleotides establishes a role for the proline-rich tyrosine kinase PYK2 in angiotensin ii-induced signaling in vascular smooth muscle. 1126 15

Exposure to arsenical compounds enhances the risk of atherosclerosis. The reason is unknown but it might be because an effect of arsenite (As3+) on plaque smooth muscle cells (SMCs) activation of extracellular signal-regulated kinase (ERK), a crucial mediator of SMC function. We found that arsenite inhibits the activation of ERK by platelet-derived growth factor-BB (PDGF-BB). This inhibitory effect depends on the time of arsenite exposure, is reversible, and is attenuated by preincubation of SMCs with the antioxidant N-acetyl-cysteine. These observations are consistent with the assumption that oxidative stress is involved. The blockade of ERK by arsenite may be mediated by an inhibition of Ras as arsenite prevents GTP-loading of Ras in response to PDGF-BB. Moreover, the Ras blockade by arsenite is not specific for PDGF-BB because it was also observed following stimulation of SMCs with EGF. To address the role of Ras, we expressed constitutively active, GTP-bound Ha-Ras (V12Ras). Unexpectedly, in V12Ras expressing-SMCs, arsenite stimulates ERK, but still decreases ERK activity in the presence of PDGF-BB. Our data suggest that arsenite inhibits the Ras/ERK pathway in SMCs, and that arsenite may activate ERK in Ras-transformed cells by mechanisms different from those employed by growth factors.
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PMID:Arsenite inhibits Ras-dependent activation of ERK but activates ERK in the presence of oncogenic Ras in baboon vascular smooth muscle cells. 1126 57

Proliferation and subsequent dedifferentiation of vascular smooth muscle (VSM) cells contribute to the pathogenesis of atherosclerosis and postangioplastic restenosis. The dedifferentiation of VSM cells in vivo or in cell culture is characterized by a loss of contractile proteins such as smooth muscle-specific alpha-actin and myosin heavy chain (SM-MHC). Serum increased the expression of contractile proteins in neonatal rat VSM cells, indicating a redifferentiation process. RNase protection assays defined thrombin as a serum component that increases the abundance of SM-MHC transcripts. Additionally, serum and thrombin transiently elevated cytosolic Ca(2+) concentrations, led to a biphasic extracellular signal-regulated kinase (ERK) phosphorylation, up-regulated a transfected SM-MHC promoter construct, and induced expression of the contractile proteins SM-MHC and alpha-actin. Pertussis toxin, N17-Ras/Raf, and PD98059 prevented both the serum- and thrombin-induced second phase ERK phosphorylation and SM-MHC promoter activation. Constitutively active Galpha(q), Galpha(i), Galpha(12), and Galpha(13) failed to up-regulate SM-MHC transcription, whereas Gbetagamma concentration-dependently increased the SM-MHC promoter activity. Furthermore, the Gbetagamma scavenger beta-adrenergic receptor kinase 1 C-terminal peptide abolished the serum-mediated differentiation. We conclude that receptor-mediated differentiation of VSM cells requires Gbetagamma and an intact Ras/Raf/MEK/ERK signaling.
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PMID:Gbeta gamma mediate differentiation of vascular smooth muscle cells. 1127 22

Despite an improved understanding of the molecular mechanisms of insulin-like growth factor-I (IGF-I) signaling and the recognition that IGF-I mediates many effects in endothelial cells, some of which may be important for atherosclerosis, little is known about the signal transduction pathways that mediate the effects of IGF-I in endothelial cells. To that end, we examined the signaling pathways activated by IGF-I in endothelial cells and their contribution to IGF-I-stimulated endothelial cell migration and nuclear factor (NF)-kappaB-dependent transcription. Treatment of bovine pulmonary artery endothelial cells (PAEC) with IGF-I activated the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1/2 and ERK5. In contrast, IGF-I had no effect on either c-Jun amino-terminal kinase or p38 kinase activity. IGF-I also activated phosphatidylinositol (PI) 3-kinase, as reflected by increased phosphorylation of AKT: There was no evidence of cross-talk between the ERK and PI 3-kinase pathways in PAEC. In PAEC transiently transfected with pTK81-NFkappaB-Luc, which contained four copies of the NF-kappaB DNA binding site 5' to a minimal promoter and the luciferase gene, treatment with 50 ng/ml IGF-I increased luciferase activity 1.8-fold. Inhibition of ERK activity using PD98059 and PI 3-kinase activity with LY 294002 abrogated the induction of NF-kappaB-dependent transcription by IGF-I, suggesting that both pathways contribute to the effect of IGF-I on NF-kappaBdependent transcription. In contrast to the effect of tumor necrosis factor-alpha on NF-kappaB activation, Western blot analyses demonstrated that IGF-I had no effect on IkappaB phosphorylation and degradation or nuclear translocation and DNA binding of NF-kappaB. These data suggest a direct of effect of IGF-I on nuclear NF-kappaB. IGF-I also increased endothelial cell migration approximately 2-fold, as demonstrated using a Boyden chamber apparatus. IGF-I-induced endothelial cell migration was inhibited, in part, by LY 294002 but not PD98059. Together, these studies demonstrate that IGF-I activates multiple signaling pathways in endothelial cells with little evidence for cross-talk between the pathways. Moreover, these pathways appear to mediate both overlapping and distinct effects in that activation of both PI 3-kinase and the ERKs contributed to the stimulation of NF-kappaB-dependent transcription by IGF-I, whereas only PI 3-kinase mediated IGF-I-stimulated endothelial cell migration.
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PMID:The role of phosphatidylinositol 3-kinase and the mitogen-activated protein kinases in insulin-like growth factor-I-mediated effects in vascular endothelial cells. 1131 33

Plasminogen activator inhibitor type-1 (PAI-1) plays an integral role not only in the regulation of fibrinolytic activity but also in the pathogenesis of atherosclerosis and hypertension. We investigated the signaling pathways of angiotensin II (Ang II) leading to PAI-1 gene expression. Ang II increased the PAI-1 mRNA and protein levels in a time- and dose-dependent manner through the Ang II type 1 receptor in vascular smooth muscle cells. PAI-1 gene promoter activity measured by luciferase assay was significantly increased by Ang II. PAI-1 mRNA stability was also increased by Ang II. Ang II-induced PAI-1 mRNA upregulation was inhibited by BAPTA-AM, genistein, and AG1478, suggesting that intracellular calcium, tyrosine kinase, and epidermal growth factor receptor transactivation are involved. Furthermore, PD98059, an inhibitor of extracellular signal-regulated kinase (ERK) kinase (MEK), almost completely suppressed Ang II-induced PAI-1 upregulation. Adenovirus-mediated overexpression of the dominant-negative form of Rho-kinase or Y27632, a Rho-kinase inhibitor, also completely prevented PAI-1 induction by Ang II without affecting Ang II-induced ERK activation. These data suggest that activation of MEK/ERK and Rho-kinase pathways plays a pivotal role in PAI-1 gene upregulation by Ang II. The Rho-kinase pathway may be a novel target to inhibit Ang II signaling, and its inhibition may be useful in the treatment of hypertension as well as atherosclerosis.
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PMID:Critical role of Rho-kinase and MEK/ERK pathways for angiotensin II-induced plasminogen activator inhibitor type-1 gene expression. 1134 89


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