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)

Prolonged cardiac hypertrophy of pathologic etiology is associated with arrhythmia, sudden death, decompensation, and dilated cardiomyopathy. In an attempt to understand the mechanisms that underlie the hypertrophic response, extensive investigation has centered on a characterization of the molecular pathways that initiate or maintain the pathologic growth of individual cardiac myocytes. While a large number of signal transduction cascades have been identified as critical regulators of cardiac hypertrophy, here the scientific evidence implicating the protein phosphatase calcineurin (PP2B) and the mitogen-activated protein kinases (MAPK) as co-regulators of reactive hypertrophy will be discussed. Gain- and loss-of-function studies in genetically altered mice and in cultured cardiomyocytes have demonstrated the necessity and sufficiency of calcineurin to regulate pathologic cardiac hypertrophy. However, using similar approaches, the hypertrophic regulatory role attributed to various branches of the MAPK signaling pathway has been less conclusive, although a loose consensus suggests that the c-Jun N-terminal kinases (JNK) and p38 kinases function as mediators of dilated cardiomyopathy, while extracellular signal-regulated kinases (ERKs) function as regulators of hypertrophy. More recently, the actions of calcineurin and MAPK signaling pathways have been shown to be co-dependent such that unitary activation of calcineurin in myocytes leads to up-regulation in ERK and JNK signaling, but down-regulation in p38 signaling. Conversely, unitary activation of JNK or p38 in cardiac myocytes leads to down-regulation of calcineurin effectiveness by directly antagonizing nuclear factor of activated T cells (NFAT) nuclear occupancy. Thus, an emerging paradigm suggests that calcineurin-NFAT and MAPK signaling pathways are inter-dependent and together orchestrate the cardiac hypertrophic response.
Cardiovasc Res 2004 Aug 15
PMID:Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. 1527 72

We examined heart tissues of AIDS patients with or without HIV cardiomyopathy (HIVCM) by immunohistochemistry, in situ polymerase chain reaction, in situ riboprobe hybridization, and the TUNEL technique for apoptosis. In HIVCM tissues, only inflammatory cells, but not endothelial cells or cardiomyocytes, displayed HIV-1 DNA and RNA. However, macrophages, lymphocytes, and--in a patchy fashion--cardiomyocytes and endothelial cells exhibited virus envelope protein gp120. Macrophages infiltrated the myocardium in a perivascular fashion and expressed tumor necrosis factor family ligands; adjacent cardiomyocytes suffered apoptosis. In vitro HIV-1 strongly invaded neonatal rat ventricular myocytes (NRVMs) and coronary artery endothelial cells (CAECs) and induced microvilli but did not replicate. HIV-1, gp120, or Tat induced Erk 1/2 phosphorylation, activation of caspase-3, and apoptosis of NRVMs and CAECs; all of these were inhibited by a MAPK/ERK-kinase (MEK) inhibitor U0126. The pathogenesis of HIVCM involves HIV-1 replication in inflammatory cells and induction of cardiomyocyte apoptosis by (1) the extrinsic pathway through apoptotic ligands and (2) the intrinsic pathway through direct virus entry and gp120- and Tat-proapoptotic signaling.
Cardiovasc Toxicol 2004
PMID:HIV-1 induces cardiomyopathyby cardiomyocyte invasion and gp120, Tat, and cytokine apoptotic signaling. 1537 27

p38 mitogen-activated protein (MAP) kinase is activated during ischemic/hypoxic myocardial injury. However, the role of activated p38 MAP kinase on cardiac function after myocardial injury is not well understood. In the present study, we investigated the cardioprotective effects of p38 MAP kinase inhibition in a rat model of acute myocardial injury, induced by subcutaneous injection of isoproterenol (ISO, 20 mg/kg/d for 3 days). A synthetic p38 alpha MAP kinase inhibitor, SD-282 (40 mg/kg) or vehicle (0.25% Tween 80 in saline) was given intraperitoneally twice a day for 3 days, concomitant with ISO treatment. Cardiac function, systolic blood pressure, gene expression including collagen I and III, fibronectin and COX-2, and the myocardial injury were analyzed. Results showed that administration of SD-282 remarkably improved ISO-induced reduction of cardiac function with increases in ejection fraction (P < 0.001), cardiac output (P < 0.05), stroke volume (P < 0.001), and cardiac index (P < 0.01). SD-282 abolished ISO-induced reduction of systolic blood pressure (106.7 +/- 2.2 versus 123.1 +/- 5.3 mm Hg, P < 0.05). The ISO-induced expression of COX-2, collagen I and III, and fibronectin genes was reduced significantly (P < 0.05 in all cases) by administration of SD-282. The myocardial injury induced by ISO was significantly reduced by the treatment of SD-282 as judged by the reduction of myocardial necrosis. Data suggest that p38 alpha MAP kinase may be involved in the pathogenesis of cardiac dysfunction in ischemic myocardial injury. Inhibition of this enzyme may improve cardiac function and protect myocardium from ischemic/hypoxic injury that occurs during ischemic heart disease.
J Cardiovasc Pharmacol 2004 Oct
PMID:p38 alpha mitogen-activated protein kinase inhibition improves cardiac function and reduces myocardial damage in isoproterenol-induced acute myocardial injury in rats. 1545 58

We investigated the potential role of atorvastatin, given at reperfusion, to improve survival of the ischemic/reperfused myocardium by activation of p44/42 MAPK and p38 MAPK with its downstream effector, HSP27. We have previously shown that atorvastatin attenuates lethal reperfusion-induced injury via activation of the phosphatidyl inositol 3-kinase (PI3K) prosurvival signaling pathway. In this study we hypothesize that other prosurvival kinases may also be implicated in this protection. Langendorff-perfused mouse hearts were subjected to 35 minutes of global ischemia followed by 30 minutes of reperfusion, and either infarct size or the levels of phosphorylated AKT, p44/42 MAPK, p38 MAPK, and HSP27 were analyzed. Atorvastatin was administered during reperfusion only. We used wortmannin to block PI3K/AKT, U0126 to block p44/42 MAPK, and SB203580 to prevent the phosphorylation of p38 MAPK and HSP27. Atorvastatin significantly reduced infarct size (32.96 +/- 3.4% versus 51.27 +/- 2.79% in controls, P < 0.05). This protection was abrogated by wortmannin (48.38 +/- 4.28%), U0126 (52.58 +/- 7.58), and SB203580 (49.37 +/- 4.16%). Western blot analysis confirmed significant phosphorylation of AKT, p44/42 MAPK, p38 MAPK, and HSP27 following administration of atorvastatin during reperfusion and abrogation of the respective phosphorylation in the presence of their specific inhibitors. Atorvastatin given at reperfusion attenuates lethal reperfusion-induced injury by the phosphorylation of multiple prosurvival pathways involving not only PI3K/AKT but also p44/42 MAPK, p38 MAPK, and HSP27.
J Cardiovasc Pharmacol 2005 Mar
PMID:Atorvastatin and myocardial reperfusion injury: new pleiotropic effect implicating multiple prosurvival signaling. 1572 50

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases, although the mechanism leading to vascular dysfunction is not clear. The aim of this study was to examine the effect of homocysteine (Hcy) on oxi-dative stress and apoptosis in human umbilical vein endothelial cells (HUVECs). HUVECs were challenged for 24 h with Hcy (10 microM-3 mM) in the presence of various stress signaling inhibitors, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin (100 microM), the p38 mito-gen-activated protein kinase inhibitor SB203580 (2.5 microM), the extracellular signal-regulated kinase inhibitor U0126 (2.5 microM), the stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK) inhibitor JNK inhibitor II (10 microM), and antioxidants alpha-tocopherol (5 microg/mL) and N-acetyl cysteine (NAC, 2 mM). Reactive oxygen species (ROS) were detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride staining, annexin-V phosphatidyl- serine/propidium iodide, and caspase-3 assay. NADPH oxidase and SAPK/JNK signal were evaluated with immunoblotting. Hcy significantly enhanced ROS generation and apoptosis after 24-h incubation. Apocynin prevented Hcy-induced ROS generation but only partially restored Hcy-induced apoptosis. JNK inhibitor II, alpha-tocopherol, and NAC partially reduced Hcy-induced apoptosis, although SB203580 and U0126 had no effect. Immunoblotting analysis confirmed upregulation of NADPH oxidase and SAPK/JNK signaling. Collectively, our results suggested that Hcy may induce oxidative stress and apopto-sis through an NADPH oxidase and/or JNK-dependent mechanism(s).
Cardiovasc Toxicol 2005
PMID:Possible involvement of NADPH oxidase and JNK in homocysteine-induced oxidative stress and apoptosis in human umbilical vein endothelial cells. 1573 81

There is considerable evidence implicating a key role for p38 mitogen-activated protein kinase (MAPK) in ischemic and pharmacological preconditioning against myocardial infarction. However, there have been few, if any, studies examining the role of p38 MAPK in the protection of stunned myocardium. The purpose of this study was to determine whether p38 MAPK plays a role in the adenosine A(1) receptor anti-stunning effect in in vivo porcine myocardium. Regional myocardial stunning in anesthetized, open-chest pigs was induced by 15 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion (RP). Animals were treated with either vehicle (n = 5), AMP579 (70 microg/kg i.v.; 25 microg/kg bolus + 1.5 microg/kg/min for 30 min prior to ischemia, n = 5), the p38 MAPK inhibitor SB203580 (0.25 mg/kg i.v. bolus, n = 4) or a combination of SB203580 plus AMP579 (n = 5). Regional ventricular function was monitored by measurements of segment shortening and load insensitive parameters including preload recruitable stroke work (PRSW) and PRSW area (PRSWA). The ischemic area at risk was similar in all groups and there was no necrosis in any heart. Treatment with AMP579 significantly improved reperfusion regional PRSW and PRSWA compared to vehicle controls. The p38 inhibitor SB203580 alone did not alter the extent of myocardial stunning, but it abolished the beneficial effect of AMP579 pretreatment. These results provide the first evidence that p38 MAPK activation may play an important role in the mechanism by which adenosine agonists attenuate myocardial stunning.
Cardiovasc Drugs Ther 2004 Nov
PMID:The p38 MAPK inhibitor SB203580 blocks adenosine A(1) receptor-induced attenuation of in vivo myocardial stunning. 1577 Apr 30

Expression of endothelin-B receptor gradually increases as melanocytic lesions progress to melanoma, suggesting that endothelin-B receptor and its ligands, endothelin-1 and endothelin- 3, play a role in the melanoma progression. The selective blockade of endothelin-B receptor results in inhibition of focal adhesion kinase and mitogen-activated protein kinase phosphorylation and cell proliferation induced by endothelins in human melanoma cell lines. In these cells, endothelins induce downregulation of E-cadherin expression and concomitant upregulation of transcriptional factor Snail. Activation of the endothelin-B receptor pathway by endothelins also upregulates N-cadherin, phosphorylates the gap junctional protein connexin 43, increases alphavbeta3 and alpha2beta1 integrin expression and tumor proteolytic activity, thus enhancing endothelin-B receptor-mediated cell adhesion, migration and invasiveness. In this study we demonstrated that activation of the endothelin-B receptor pathway by endothelin-1 and endothelin-3 contributes to disruption of normal host-tumor interactions by downregulating, at mRNA and protein levels, the expression of E-cadherin and associated alpha-catenin and beta-catenin adhesion proteins, which are critical for E-cadherin function. A-192621, an orally active non-peptide endothelin-B receptor antagonist, significantly inhibited melanoma growth in nude mice, suggesting that the pharmacological interruption of endothelin-B receptor signaling by endothelin-B receptor antagonist may represent a new therapeutic approach in the treatment of cutaneous melanoma.
J Cardiovasc Pharmacol 2004 Nov
PMID:Endothelin-B receptor blockade inhibits molecular effectors of melanoma cell progression. 1583 63

Ovarian carcinoma cells release high amounts of endothelin-1 and exhibit increased expression of endothelin-A receptor. Engagement of the endothelin-A receptor triggers tumor growth, survival, neoangiogenesis and invasion. Cyclooxygenase-1 and cyclooxygenase-2 are enzymes involved in the production of prostaglandins and play a role in the regulation of tumor progression in several malignancies, including ovarian carcinomas. Endothelin-1 significantly increases the expression of cyclooxygenase-1 and cyclooxygenase-2 mRNA and protein, the activity of the cyclooxygenase- 2 promoter, and the release of prostaglandin E2 from two ovarian carcinoma cell lines, HEY and OVCA 433. The cyclooxygenase- 2 inhibitor, NS-398 drastically decreased the endothelin- 1-induced prostaglandin E2 production and vascular endothelial growth factor upregulation, indicating a role for cyclooxygenase-2 in endothelin-1-induced vascular endothelial growth factor-mediated angiogenesis. In this study we demonstrated that endothelin-1-induced cyclooxygenase-2 and related prostaglandin E2 release were dependent upon the activation of endothelin-A receptor and of multiple mitogen-activated protein kinase signal pathways, including extracellular signal-regulated kinase 1/2 kinase, p38 mitogen-activated protein kinase and the transactivation of the epidermal growth factor receptor. In human ovarian xenografts, the levels of cyclooxygenase-2 protein expression were significantly reduced following treatment with the endothelin-A receptor selective antagonist, atrasentan, compared with untreated mice. These results suggest that the pharmacological blocking of endothelin-A receptor is an attractive strategy to control the cyclooxygenase-2 protein expression in ovarian carcinoma.
J Cardiovasc Pharmacol 2004 Nov
PMID:Endothelin-1 stimulates cyclooxygenase-2 expression in ovarian cancer cells through multiple signaling pathways: evidence for involvement of transactivation of the epidermal growth factor receptor. 1583 64

The signaling pathways of endothelin-1-induced contraction, including the role of protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), protein kinase C (PKC) and RhoA/Rho-kinase were studied using rabbit basilar arteries by isometric tension and Western blot. The following results were observed: (1) endothelin-1 produced phosphorylation of MAPK and RhoA and contraction by activation of endothelin-A but not endothelin-B receptors; (2) MAPK inhibitors, PD 98059 and U0126, PTK inhibitor, genistein, Src kinase inhibitor, damnacanthal, and Janus tyrosine kinase (JAK2) inhibitor, AG-490, abolished endothelin-1-induced contraction and MAPK immunoreactivity; (3) PTK inhibitor, staurosporine, and phosphatidylinositol 3-kinase (PI- 3K) inhibitor wortmannin abolished endothelin-1 induced contraction but not MAPK immunoreactivity; (4) Rho-kinase inhibitor, Y-27632, reduced endothelin-1-induced contraction; (5) PI-3K inhibitor, wortmannin, but not PKC and PTK inhibitors, reduced endothelin-1-induced RhoA activation; (6) endothelin-1 increased the level of myosin light chain (MLC) phosphorylation, and Rho-kinase inhibitor, Y-27632, reduced the effect of endothelin- 1 on MLC phosphorylation. This study demonstrated that three signaling pathways Src-JAK2-PTK-MAPK, PI-3K-RhoA-Rhokinase- MLC and PKC all contribute to endothelin-1-induced contraction in the rabbit basilar artery. MAPK is downstream of PTK, Src and JAK pathways. PI-3 kinase and MLC might be the upstream and downstream factors of RhoA activation.
J Cardiovasc Pharmacol 2004 Nov
PMID:Signal transduction of ET-1 in contraction of cerebral arteries. 1583 90

We have previously demonstrated that endothelin-1 (ET-1)-induced extracellular signal-regulated kinase (Erk) activity via the ETB receptor (EDNRB) is mediated through two independent pathways, a protein kinase C-dependent pathway and a pertussis toxin (PTX)-sensitive pathway, in astrocytes. In this study, we showed that the molar potency of ET-1 to induce Erk activation was two orders of magnitude higher in dibutyryl cAMP (DBcAMP)-treated astrocytes than in quiescent astrocytes. This DBcAMP-enhanced molar potency of ET-1 in Erk activation was selectively inhibited by pretreatment of astrocytes with PTX. The expression level of EDNRB in astrocytes was markedly upregulated by DBcAMP-induced cytodifferentiation. However, this up-regulation was simply attributed to the high expression of low-affinity sites. The molar potency of ET-1 to induce both stimulation of inositol trisphosphate production and activation of protein kinase C in DBcAMP-treated astrocytes was similar to that in quiescent astrocytes. On the contrary, the molar potency of ET-1 to induce accumulation of Ras-GTP was two orders of magnitude higher in DBcAMP-treated astrocytes than in quiescent astrocytes, which was consistent with the case of ET-1-induced Erk activation. Moreover, the ET-1-induced Ras activation was PTX sensitive. These results suggest that cytodifferentiation selectively enhances the PTXsensitive Ras/Erk pathway induced by ET-1 in astrocytes, and that cytodifferentiation-induced EDNRB up-regulation might not contribute to this selective potentiation of ET-1 signaling.
J Cardiovasc Pharmacol 2004 Nov
PMID:Cytodifferentiation enhances Erk activation induced by endothelin-1 in primary cultured astrocytes. 1583 8


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