Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac fibroblasts appear to be important in producing and maintaining the extracellular matrix (ECM) of the heart. The abnormal proliferation of cardiac fibroblasts and deposition of the ECM protein, collagen, associated with hypertension and myocardial infarction, may adversely affect the performance of the heart. Several groups of factors affect collagen gene expression and/or growth of cardiac fibroblasts. Angiotensin II, aldosterone and endothelins play a central role in the remodeling of the ECM in hypertension, and decrease collagenase activity and/or increase collagen synthesis in cultured cells. Regulatory peptides that are generally elevated at sites of injury, such as TGF-beta 1 and PDGF, increase collagen synthesis and/or stimulate mitogenesis. Mechanical stretch enhances collagen expression and cell proliferation, responses which could in part be due to integrin activation. Cytokines may stimulate or inhibit cell growth, the latter through prostaglandin formation. Angiotensin II is a principal determinant in vivo of cardiac fibroplasia and synthesis of the ECM proteins, collagen and fibronectin. Cardiac fibroblasts possess G-protein-coupled AT1 receptors for angiotensin II that couple to activation of multiple signalling pathways, including: phospholipase C-beta, with the subsequent release of Ca2+ from intracellular stores and activation of protein kinase C, mitogen-activated protein kinases, tyrosine kinases, phospholipase D, phosphatidic acid formation, and the STAT family of transcription factors. Cardiac fibroblasts respond to angiotensin II with hyperplastic/hypertrophic growth, and increased expression of collagen, fibronectin, and integrins. The mechanisms by which the AT1 receptor activates multiple signalling pathways are not known, although the receptor might interact at some level with both integrins and cytokine receptors. Different signalling pathways of the AT1 receptor may subserve different cellular responses, such as mitogenesis, ECM synthesis, or an inflammatory/stress response. Crosstalk among the signalling pathways of the AT1 receptor, and those of G-protein, cytokine, and growth-factor receptors, may determine the ultimate response of the cell.
Cardiovasc Res 1995 Oct
PMID:Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts. 857 2

To elucidate the molecular mechanism of the mitogenic effect of endothelin-1 (ET-1) on vascular smooth-muscle cells (VSMCs), we studied the effect of AG1478, a novel epidermal growth factor receptor (EGFR) kinase inhibitor, on p42/44 mitogen-activated protein (MAP) kinase activation, c-Fos expression, and DNA synthesis stimulated by ET-1. AG1478 dose-dependently (2.5 x 10(-8) M-2.5 x 10(-7) M) inhibited ET-1-induced MAP kinase activation. The ET-1-induced c-Fos protein expression was inhibited by AG1478 (2.5 x 10(-7) M). AG1478 also dose-dependently inhibited ET-1-stimulated [3H]thymidine incorporation. These data suggest that ET-1 induces MAP kinase activation, c-Fos expression, and promotes proliferation of VSMCs via transactivation of EGFR.
J Cardiovasc Pharmacol 1998
PMID:Endothelin-1 stimulates DNA synthesis of vascular smooth-muscle cells through transactivation of epidermal growth factor receptor. 959 33

Ischemic preconditioning is a phenomenon whereby exposure of the myocardium to a brief episode of ischemia and reperfusion markedly reduces tissue necrosis induced by a subsequent prolonged ischemia. Therefore, it is hoped that elucidation of the mechanism of preconditioning will yield therapeutic strategies capable of reducing myocardial infarction. In the rabbit, the brief period of preconditioning ischemia and reperfusion releases adenosine, bradykinin, opioids, and oxygen radicals that summate to induce the translocation and activation of protein kinase C (PKC). PKC appears to be the first element of a complex kinase cascade that is activated during the prolonged ischemia in preconditioned hearts. Current evidence indicates that PKC activates a tyrosine kinase that leads to the activation of p38 mitogen-activated protein (MAP) kinase or JNK, or possibly both. The stimulation of these stress-activated protein kinases ultimately induces the opening of mitochondrial K(ATP) channels that may be the final mediator of protection by ischemic preconditioning.
J Cardiovasc Electrophysiol 1999 May
PMID:Signal transduction in ischemic preconditioning: the role of kinases and mitochondrial K(ATP) channels. 1035 30

Apoptosis is a form of cell death that involves discrete genetic and molecular programs, de novo protein expression and a unique cellular phenotype. Evidence for the existence of apoptosis in the human heart has been reported in various cardiac diseases, including ischemic and non-ischemic heart failure, myocardial infarction and arrhythmias. Among the most potent stimuli that elicit cardiomyocyte apoptosis are: oxygen radicals (including NO), cytokines (FAS/TNF alpha-receptor signaling), stress conditions (chemical or physical, e.g., radiation), sphingolipid metabolites (ceramide) and autocoids, e.g., angiotensin II. Apoptosis of cardiac myocytes may contribute to progressive pump-failure, arrhythmias and cardiac remodeling. The recognition of numerous molecular targets associated with cardiomyocyte apoptosis may provide novel therapeutic strategies for diverse cardiac ailments, as recently suggested by pharmacologic studies in experimental animals. This review paper is aimed to highlight the role of protein kinase signaling pathways in apoptosis with special attention to the stress-activated protein kinases (SAPK) and mitogen-activated protein kinases (MAPK) systems.
Cardiovasc Res 2000 Feb
PMID:Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways. 1072 77

Cardiac hypertrophy is a well known response to increased hemodynamic load. Mechanical stress is considered to be the trigger inducing a growth response in the overloaded myocardium. Furthermore, mechanical stress induces the release of growth-promoting factors, such as angiotensin II, endothelin-1, and transforming growth factor-beta, which provide a second line of growth induction. In this review, we will focus on the primary effects of mechanical stress: how mechanical stress may be sensed, and which signal transduction pathways may couple mechanical stress to modulation of gene expression, and to increased protein synthesis. Mechanical stress may be coupled to intracellular signals that are responsible for the hypertrophic response via integrins and the cytoskeleton or via sarcolemmal proteins, such as phospholipases, ion channels and ion exchangers. The signal transduction pathways that may be involved belong to two groups: (1) the mitogen-activated protein kinases (MAPK) pathway; and (2) the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. The MAPK pathway can be subdivided into the extracellular-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and the 38-kDa MAPK (p38 MAPK) pathway. Alternatively, the stress signal may be directly submitted to the nucleus via the cytoskeleton without the involvement of signal transduction pathways. Finally, by promoting an increase in intracellular Ca2+ concentration stretch may stimulate the calcium/calmodulin-dependent phosphatase calcineurin, a novel hypertrophic signalling pathway.
Cardiovasc Res 2000 Jul
PMID:Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. 1086 27

We have investigated the roles of protein kinase C (PKC) and mitogen-activated protein kinases (MAPK) in the phosphorylation and activation of cytosolic phospholipase A2 (cPLA2) in endothelin-1- (ET-1) stimulated cat iris sphincter smooth muscle (CISM) cells. We found that in these cells both PKC and p38 MAP kinases play a critical role in ET-1-induced cPLA, phosphorylation and arachidonic acid (AA) release. Our findings indicate that stimulation of the endothelin-A- (ET(A)) receptor leads to: (1) activation of Gq protein which stimulates phospholipase C to hydrolyze the polyphosphoinositide PIP, into diacylglycerol (DAG) and inositol trisphosphate (IP3), the DAG may then activate PKC to phosphorylate and activate cPLA2; and (2) activation of Gi protein, which, through a series of kinases, leads to the stimulation of p38 MAPK and subsequently to phosphorylation and activation of cPLA2. The ability of the activated ET(A)-receptor, which is coupled to both Gq and Gi proteins, to recruit and activate this complex signal transduction mechanism remains to be clarified.
J Cardiovasc Pharmacol 2000 Nov
PMID:Role of protein kinase C alpha and mitogen-activated protein kinases in endothelin-1-stimulation of cytosolic phospholipase A2 in iris sphincter smooth muscle. 1107 53

The vascular wall is an integrated functional component of the circulatory system that is continually remodeling or develops arteriosclerosis in response to hemodynamic or biomechanical stress. How vascular cells sense and transduce the extracellular mechanical signals into the cell nucleus resulting in quantitative and qualitative changes in gene expression is an interesting and challenging question. Based on recent progress in this field, this article attempts to formulate a biomechanical-stress hypothesis-that physical force initiates signal pathways, especially mitogen-activated protein kinases (MAPKs), leading to vascular cell death and inflammatory response followed by smooth muscle cell proliferation. Thus, mechanical stress, akin to cytokines or growth factors, can effectively activate signal transduction pathways, resulting in morphological and functional changes in vascular cells, which contribute to the development of arteriosclerosis.
Trends Cardiovasc Med 2000 Jan
PMID:Biomechanical-stress-induced signaling and gene expression in the development of arteriosclerosis. 1115 Jul 27

Vascular smooth muscle cell (VSMC) migration involves adhesion, locomotion, and invasion regulated by various signaling molecules, among which the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) play a critical role. We have shown that the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands troglitazone and rosiglitazone inhibit VSMC migration downstream of ERK MAPK. The purpose of the current study was to more specifically determine which step(s) in VSMC migration are targeted by inhibition of the ERK MAPK pathway or activation of PPAR-gamma. VSMC adhesion was not affected by the ERK MAPK pathway inhibitor PD98059 or PPAR-gamma ligands. Phosphorylation and activation of myosin light chain kinase (MLCK) play important roles in cell locomotion. Platelet-derived growth factor (PDGF)-induced MLCK phosphorylation (1.7-fold) was completely blocked by PD98059 at 30 microM (p < 0.05), but not by troglitazone or rosiglitazone. PDGF-directed migration (5.8-fold) was inhibited by PD98059 (-88% at 30 microM) and the MLCK inhibitor ML9 (0.1-1 microM, -84% at 1 microM) (all p < 0.05). The transcription factor Ets-1 mediates matrix metalloproteinase induction required for tissue invasion by VSMC. PDGF (20 ng/ml) stimulated an Ets-1 protein expression (14-fold at 60 min) in VSMC, which was inhibited by PD98059 (-72% at 30 microM), troglitazone (-69% at 20 microM), and rosiglitazone (-54% at 10 microM) (all p < 0.05). Immunohistochemistry of rat aortae 2 h after balloon injury showed a dramatic upregulation of Ets-1, which was markedly inhibited in animals that had received troglitazone treatment. In contrast, phosphorylated ERK MAPK was not affected by troglitazone. These data are consistent with PPAR-gamma ligands exerting their anti-migratory effects downstream of ERK MAPK activation by blocking nuclear events, such as Ets-1 expression, required for cell invasion in response to arterial injury.
J Cardiovasc Pharmacol 2001 Dec
PMID:Peroxisome proliferator-activated receptor-gamma ligands inhibit nuclear but not cytosolic extracellular signal-regulated kinase/mitogen-activated protein kinase-regulated steps in vascular smooth muscle cell migration. 1170 95

Although the understanding of how toxicants alter cardiac ion-channel function has matured rapidly over the past 20-30 yr, little is known about how xenobiotics may alter the signaling pathways of cardiac myocyte growth and death. Signaling molecules and pathways responsible for the growth of cardiac myocytes include the mitogen-activated protein kinases (MAPKs), janus kinase-signal transducer and activator of transcription (JAK-STATs), nuclear receptor signaling, calcineurin, and the mobilization of free calcium. Signaling molecules and pathways responsible for programmed cardiac myocyte death include the death receptors, mitochondrial proteins, p53 tumor suppressor protein, ceramide signaling, and caspases. Overlap or "crosstalk" between the various growth and death pathways in the myocardium is evident, and these pathways likely exist in a delicate balance where, for example, slight reductions in growth signaling may favor pathways leading to cardiac myocyte apoptosis. Several classical cardiotoxicants are now known to alter signaling pathways in cardiac myocytes; however, the significance of these effects is not entirely clear. Furthermore, xenobiotics that alter the interstitium or extracellular matrix, or both, may significantly alter signaling pathways in cardiac myocytes. The goal of this review is to summarize current findings regarding the interaction of xenobiotics with myocardial signal transduction pathways in the hope of stimulating new insights and highlighting important areas for future research.
Cardiovasc Toxicol 2002
PMID:Interaction of xenobiotics with myocardial signal transduction pathways. 1218 77

The aim of this study was to evaluate the effects of 9-cis retinoid acid (9-cis RA) and all-trans RA (ATRA) on proliferation, migratory ability, synthesis of extracellular matrix, intracellular signal transduction, and differentiation of human aortic smooth muscle cells (haSMCs) in vitro. Changes of cell proliferation following incubation with RAs in different doses (10-6 M, 10-7 M, and 10-8 M) were determined directly by proliferation kinetics and indirectly by bromodeoxyuridine enzyme-linked immuno sorbant assays and colony-formation assays. The migratory ability of haSMCs was examined with the help of migration assays. The production of the extracellular matrix protein tenascin was explored by immunostaining. The amounts of total p44/p42 mitogen-activated protein kinases (MAPKs) and their phosphorylated forms were detected with the help of Western blots. To judge the state of differentiation of haSMCs, cell cycle distribution and the pattern of alpha-actin were analyzed. Both RAs clearly inhibited the proliferation of haSMCs in a dose-dependent manner. 9-cis RA had a tendency to be more effective than ATRA. After treatment with RAs, the migratory ability was especially reduced during stimulation with platelet-derived growth factor (PDGF) and the synthesis of tenascin decreased. Although the total p44/p42 MAPKs were downregulated, the amounts of activated forms increased markedly in the cells incubated with RAs and particularly stimulated with PDGF. The cell-cycle analysis demonstrated an increased G1-phase, complemented by a stronger expression of alpha-actin after treatment. 9-cis RA especially has the potential to inhibit the proliferation, migration, and synthesis of extracellular matrix of haSMCs by inducing differentiation in vitro.
J Cardiovasc Pharmacol 2003 Apr
PMID:All-trans and 9-cis retinoid acids inhibit proliferation, migration, and synthesis of extracellular matrix of human vascular smooth muscle cells by inducing differentiation in vitro. 1265 53


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