Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homocysteine at abnormally high levels is an independent risk factor for atherosclerosis and may be a key factor in atherogenesis. Since homocysteine (Hcys) has been shown to promote cell proliferation and induction of the gene transcription factor c-fos in vascular smooth muscle cells (VSMCs), effects which can be mediated by MAP kinase, we hypothesized that homocysteine activates a MAP kinase-dependent signal transduction pathway. In this study, we find that homocysteine transiently activates MAP kinase (ERK2 isoform) in cultured VSMCs from chick embryos. Homocysteine activation of ERK2 is dose-dependent with an EC50 of approximately 500 nM and blocked by the MAP/Erk kinase (MEK) inhibitor PD98059. VSMC embryonic lineage is another determinant of homocysteine sensitivity. These findings demonstrate that homocysteine activates the MAP kinase signal transduction pathway and thus support the hypothesis that homocysteine may promote atherosclerosis by stimulation of growth promoting signal transduction pathways.
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PMID:ERK2 activation by homocysteine in vascular smooth muscle cells. 979 Sep 67

Monocyte infiltration into the vessel wall, a key initial step in the process of atherosclerosis, is mediated in part by monocyte chemoattractant protein-1 (MCP-1). Hypertension, particularly in the presence of an activated renin-angiotensin system, is a major risk factor for the development of atherosclerosis. To investigate a potential molecular basis for a link between hypertension and atherosclerosis, we studied the effects of angiotensin II (Ang II) on MCP-1 gene expression in rat aortic smooth muscle cells. Rat smooth muscle cells treated with Ang II exhibited a dose-dependent increase in MCP-1 mRNA accumulation that was prevented by the AT1 receptor antagonist losartan. Ang II also activated MCP-1 gene transcription. Inhibition of NADH/NADPH oxidase, which generates superoxide and H2O2, with diphenylene iodonium or apocynin decreased Ang II-induced MCP-1 mRNA accumulation. Induction of MCP-1 gene expression by Ang II was inhibited by catalase, suggesting a second messenger role for H2O2. The tyrosine kinase inhibitor genistein and the mitogen-activated protein kinase kinase inhibitor PD098059 inhibited Ang II-induced MCP-1 gene expression, consistent with a mitogen-activated protein kinase-dependent signaling mechanism. Ang II may thus promote atherogenesis by direct activation of MCP-1 gene expression in vascular smooth muscle cells.
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PMID:Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. 979 45

The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma
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PMID:Thiazolidinediones--tools for the research of metabolic syndrome X. 980 67

1. We have previously found that human chymase cleaves big endothelins (ETs) at the Tyr31-Gly32 bond and produces 31-amino acid ETs (1-31), without any further degradation products. In this study, we investigated the effect of synthetic ET-1 (1-31) on the proliferation of cultured human coronary artery smooth muscle cells (HCASMCs). 2. ET-1 (1-31) increased [3H]-thymidine incorporation and cell numbers to a similar extent as ET-1 at 100 nM. This ET-1 (1-31)-induced [3H]-thymidine uptake was not affected by phosphoramidon, an inhibitor of ET-converting enzyme. It was, however, inhibited by BQ123, an endothelin ET(A) receptor antagonist, but not by BQ788, an endothelin ET(B) receptor antagonist. 3. By using an in-gel kinase assay, we demonstrated that ET-1 (1-31) activated extracellular signal-regulated kinase 1/2 (ERK1/2) in a concentration-dependent manner (100 pM to 1 microM) in HCASMCs. ET-1 (1-31)-induced ERK1/2 activation was inhibited by BQ123, but not by BQ788 and phosphoramidon. Inhibition of protein kinase C (PKC) and ERK kinase also caused a reduction of ET-1 (1-31)-induced ERK1/2 activation, whereas tyrosine kinase inhibition had little effect. 4. Gel-mobility shift analysis revealed that the ERK1/2 activation was followed by an increase in transcription factor activator protein-1 DNA binding activity in HCASMCs. 5. Our results strongly suggest that ET-1 (1-31) itself stimulates HCASMC proliferation probably through endothelin ET(A) or ET(A)-like receptors. The underlining mechanism of cell growth by ET-1 (1-31) may be explained in part by PKC-dependent ERK1/2 activation. Since human chymase has been proposed to play a role in atherosclerosis, ET-1 (1-31) may be one of the mediators.
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PMID:Effect of endothelin-1 (1-31) on extracellular signal-regulated kinase and proliferation of human coronary artery smooth muscle cells. 984 40

Thrombomodulin (TM), a thrombin receptor protein found on the endothelial cell surface, contains 6 tandem epidermal growth factor (EGF)-like structures. Recombinant human TM peptide containing these 6 EGF-like domains (rTME1-6) exhibits mitogenic activity in Swiss 3T3 cells. We examined the localization of TM in atherosclerotic lesions and the effects of rTME1-6 on the growth of cultured rat vascular smooth muscle cells (SMCs). Immunohistochemical analysis demonstrated that TM antigen was localized on monocytes, macrophages, and vascular SMCs. In cultured vascular SMCs, rTME1-6 accelerated [3H]thymidine uptake into DNA in a dose-dependent manner up to 3.4 times the control level. This mitogenic activity was abolished by addition of polyclonal anti-human TM antibody. The rTME1-6-induced mitogenesis was enhanced by EGF. However, a neutralizing monoclonal antibody against the EGF receptor (monoclonal antibody 225) did not inhibit the mitogenic activity of rTME1-6. Calphostin C, a specific protein kinase C inhibitor, and lavendustin-A, an inhibitor of EGF receptor-specific protein tyrosine kinase, inhibited the mitogenic activities of both rTME1-6 and EGF. Finally, rTME1-6 treatment increased the level of phosphorylated mitogen-activated protein kinase in SMCs. Together, these results suggest that TM expression in atherosclerotic lesions may be associated with promotion of atherosclerosis through its mitogenic activity in vascular SMCs.
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PMID:Expression of thrombomodulin in atherosclerotic lesions and mitogenic activity of recombinant thrombomodulin in vascular smooth muscle cells. 984 77

Vascular smooth muscle cell (SMC) proliferation is a key event in the development of (spontaneous) atherosclerosis, hypertension-related arteriosclerosis, angioplasty-induced restenosis and venous bypass graft arteriosclerosis. Many factors or environmental stimuli are believed to be responsible for SMC growth or hypertrophy in the vessel wall. How these environmental stimuli or signals applied onto the surface of SMCs are transduced into the cell nucleus resulting in quantitative and qualitative changes in gene expression in SMCs of arterial walls is largely unknown. Mitogen-activated protein (MAP) kinases are rapidly activated in cells stimulated with various extracellular signals by dual phosphorylation of tyrosine and threonine residues. They are thought to play a pivotal role in transmitting transmembrane signals required for cell growth and differentiation. Recent studies have focused on the signalling events in vascular tissues in vivo and in cultured SMCs in vitro. It has been demonstrated that acute hypertension and angioplasty rapidly induced MAP kinase activation in the arterial wall. Kinase activation is followed by an increase in c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. A similar MAP kinase activation can be mimicked in in vitro cultured SMCs stimulated by either shear stress or cyclic strain stretch, suggesting direct effects of mechanical force. Interestingly, physical forces rapidly resulted in phosphorylation of platelet-derived growth factor (PDGF) receptor, an activated state, in cultured SMCs. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signalling pathways usually used by growth factors. These findings have significantly enhanced our knowledge concerning the pathogenesis of arteriosclerosis and provide a basis for therapeutic intervention on vascular diseases.
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PMID:Signal transduction in arteriosclerosis: mechanical stress-activated MAP kinases in vascular smooth muscle cells (review). 985 3

The mitogen-activated protein (MAP) kinase family members are ubiquitously expressed protein kinases activated in response to a variety of extracellular stimuli and shown to be involved in cell growth, transformation, differentiation and apoptosis. MAP kinases have been implicated in both growth and apoptosis of vascular smooth muscle cells (VSMC) which suggests that they play important roles in cardiovascular diseases such as essential hypertension, atherosclerosis, and restenosis followed angioplasty. The MAP kinases are themselves components of specific kinase cascades characterized by activation by specific stimuli, families of related serine and threonine kinases and downstream substrates that include other kinases, transcription factors, membrane receptors and other cell mediators. Cross-talk among the different MAP kinases results in direct modulation of signal transduction. In addition, increased expression and activation of MAP kinase phosphatases plays an important role in MAP kinase inactivation. Our laboratory has used angiotensin II (AngII), a potent activator of all MAP kinases in VSMC, to study mechanisms by which MAP kinases are regulated by vasoactive peptides. In this review, we describe the mechanisms by which AngII activates MAP kinases, and potential roles for MAP kinases in AngII-dependent effects on VSMC function.
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PMID:MAP kinases and vascular smooth muscle function. 988 83

Angiotensin II (Ang II) promotes vascular smooth muscle cell (VSMC) growth and migration, but the signaling pathways mediating these VSMC behaviors critical to restenosis and atherosclerosis are not completely known. The purpose of the present investigation was to define the role of mitogen-activated protein kinase (MAPK) in Ang II-induced DNA synthesis, migration, and c-fos induction in VSMCs. PD 98059, a synthetic inhibitor of MAPK kinase, or antisense oligodeoxynucleotides (ODNs) to deplete extracellular signal-regulated kinase (ERK)1 and ERK2 MAPKs, were used to inhibit MAPK signaling. PD 98059 at 30 micromol/L reduced Ang II-induced MAPK activity by 69% (P<0.01). Under these conditions, Ang II-induced DNA synthesis was completely inhibited (P<0.01), and Ang II-directed migration was attenuated by 76% (P<0.05). In contrast, induction of c-fos by Ang II was only partially suppressed (58% inhibition, P<0.01). Antisense ODNs against the initiation site of rat ERK1 and ERK2 MAPK mRNAs reduced corresponding protein levels by 63% (P<0.01) and completely inhibited MAPK activation by either Ang II (1 micromol/L) or 10% serum. Antisense ODNs (0.4 micromol/L) completely inhibited Ang II-induced DNA synthesis (P<0.01), decreased migration by 47% (P<0.01), and reduced c-fos induction by 40% (P<0.01 versus control ODN-transfected VSMCs). The Ang II type 1 (AT1)-receptor blocker irbesartan completely blocked DNA synthesis, migration, MAPK activation, and c-fos induction by Ang II in VSMCs. These results demonstrate that activation of MAPK plays a crucial role in Ang II-directed migration and DNA synthesis through the AT1 receptor. In contrast, Ang II-mediated c-fos induction and migration were only partially inhibited by either antisense ODNs or PD 98059, suggesting that other pathways in addition to the MAPK pathway may be involved in these actions of Ang II. We conclude that MAPK is a critical regulatory factor for Ang II-mediated migration and growth in VSMCs. Ang II-induced DNA synthesis showed a stronger MAPK dependence than did Ang II-directed migration or c-fos induction.
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PMID:Central role of the MAPK pathway in ang II-mediated DNA synthesis and migration in rat vascular smooth muscle cells. 988 69

Proliferation of vascular smooth muscle cells contributes to initimal hyperplasia during atherogenesis, but the factors regulating their proliferation are not well known. In the present study we report that sublytic C5b-9 assembly induced proliferation of differentiated human aortic smooth muscle cells (ASMC) in culture. Cell cycle re-entry occurred through activation of cdk4, cdk2 kinase and the reduction of p21 cell cycle inhibitor. We also investigated if C5b-9 cell cycle induction is mediated through activation of mitogen activated protein kinase (MAPK) pathways. Extracellular signal regulated kinase (ERK) 1 activity was significantly increased, while c-jun NH2-terminal kinase (JNK) 1 and p38 MAPK activity were only transiently increased. Pretreatment with wortmannin inhibits ERK1 activation by C5b-9, suggesting the involvement of phosphatidylinositol 3-kinase (PI 3-kinase). Both PI 3-kinase and p70 S6 kinase were activated by C5b-9 but not by C5b6. C5b-9 induced DNA synthesis was abolished by pretreatment with inhibitors of ERK1 and PI 3-kinase, but not by p38 MAPK. These data indicated that ERK1 and PI 3-kinase play a major role in C5b-9 induced ASMC proliferation.
Atherosclerosis 1999 Jan
PMID:Sublytic C5b-9 induces proliferation of human aortic smooth muscle cells: role of mitogen activated protein kinase and phosphatidylinositol 3-kinase. 992 May 5

Angiotensin-II (ANG-II) is a potent endocrine and paracrine hormone that functions in humans through two distinct G-protein-coupled transmembrane receptor subtypes (AT-1 and AT-2). ANG-II is found in nearly all tissues of the body including the brain, heart, kidneys, gonads, and gastrointestinal tract. Just as it is found in nearly every organ system of the body, so is it involved in an array of physiologic processes from fetal development to blood pressure control. ANG-II regulates blood pressure by controlling sodium reabsorption in the proximal tubule, altering the glomerular filtration rate and renal blood flow, and by modifying the production and release of aldosterone in the adrenal gland. Additionally, ANG-II is involved in several pathologic processes including the development of hypertension, cardiomyopathy, atherosclerosis, and diabetic nephropathy. It is able to exert influences in these widely varying processes by working together with multiple different second messenger systems including the MAP kinase pathway, nitric oxide production, and phospholipase C and D, and several arachidonic acid metabolites. This paper is a review of the current knowledge of ANG-II and its receptors in health and disease.
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PMID:Action of angiotensin receptor subtypes on the renal tubules and vasculature: implications for volume homeostasis and atherosclerosis. 993 Mar 75


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