The Role of MAP Kinases in Trauma and Ischemia–Reperfusion
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Mitogen-activated protein kinases (MAPKs) have been the focus of a number of studies, as these compounds are involved in a number of important inflammatory cell signaling mechanisms. Recent studies have further elucidated the role of MAPKs in the inflammatory response, as a result of trauma and/or ischemia–reperfusion (I/R) injury. There are three major classes of MAPKs that may be involved in the inflammatory response: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs)/c-Jun NH2-terminal kinases (JNKs), and p38 MAPKs (p38). This is clinically relevant, because these pathways may be a possible target for anti-inflammatory drug intervention. This review studies the role of MAPKs in trauma and/or I/R.Keywords:
Inflammatory response
Objective: We investigated whether angiotensin (Ang) III induces ERK1/2 and p38 mitogen activated protein (MAP) kinases protein phosphorylation in isolated rat vascular smooth muscle cells (VSMCs). Background The molecular mechanisms by which Ang III induces various biological effects have not been fully investigated. Most studies have shown that MAP kinases mediate Ang II apoptosis and growth promoting effects in VSMCs.Moreover, Ang II induces vascular remodeling in these cells leading to increases in blood pressure. MAP kinases regulate or induce two crucial actions in VSMCs, proliferation and migration, which are associated with atherosclerosis and restenosis. Methods: Primary cultures of VSMCs were isolated from the thoracic aorta of adult Wistar rats by the explant technique. VSMCs were treated with Ang III ranging in concentration from 0.1 nM to 1000 nM for 10 minutes or with 100 nM Ang III for 1 minute to 30 minutes. Western blotting technique was used to determine whether Ang III induces ERK1/2 and p38 MAP kinases protein phosphorylation. Results: Concentration studies showed that Ang III caused a dose-dependent increase in ERK1/2 and p38 MAP kinases protein phosphorylation. The effects of Ang III on both MAP kinases phosphorylation were maximal between 10 nM and 100 nM concentrations. The peptide effects were rapid and significant, occurring within minutes of treatment and the maximal effects on MAP kinases phosphorylation was observed by 10 min. Conclusion These findings provide insight into the molecular nature of the actions of Ang III and offer possible mechanism by which Ang III physiological and possibly pathological actions occur in VSMCs.
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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant, exposure to it eliciting a broad spectrum of deleterious pathophysiological effects. Since mitogen-activated protein kinase (MAPK) pathways appear to play an important role in both cell survival and the apoptotic process, we assessed the effects of TCDD on the activation of extracellular signal-regulated kinase (ERK), Jun-N-terminal kinase (JNK), p38 MAPKs and caspase-3 in RAW 264.7 cells. TCDD treatment induced a transient upshift in ERK activity, followed by a decline, but a concomitant dramatic activation of p38. However, TCDD did not cause any apparent change in the activity of JNK, though it induced an up-regulation in caspase-3 activity. These results demonstrate that the equilibrium between the ERK and p38 pathways is critical to the fate of the cells, and that the activation of p38, upstream of caspase, plays an important role in the apoptotic process. The data obtained in this study also suggests that TCDD activates the MAPK pathway via an arylhydrocarbon receptor (AhR)-independent mechanism in RAW 264.7 murine macrophages.
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Mitogen-activated protein kinases (MAPKs) are protein-serine/threonine kinases activated by signaling pathways triggered by developmental stages, cell-surface receptors, cell stresses and other environmental cues. The MAPK family includes the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and a splice variant of each, at least two ERK3 isoforms, ERK5, ERK7, four p38 MAP kinases (p38α, β, γ, and δ), and three c-Jun-N-terminal kinases/stress-activated protein kinases (JNK1–3/SAPKα, β, and γ), each with multiple splice variants (1,2). These kinases are often categorized based on their most efficacious activators, although all are regulated by numerous overlapping stimuli. ERK1/2 are major targets of Ras-dependent signals and are usually most strongly activated by growth factors and proliferative stimuli. The p38 MAPKs and the JNK/SAPKs are recognized as stress sensors and, in some cases, promote apoptosis. ERK5 is significantly activated by growth factors and stresses and does not fits easily into either of these categories. Signals that activate ERK3 and ERK7 have not been determined.
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Mitogen-activated protein kinases (MAPKs) have been the focus of a number of studies, as these compounds are involved in a number of important inflammatory cell signaling mechanisms. Recent studies have further elucidated the role of MAPKs in the inflammatory response, as a result of trauma and/or ischemia-reperfusion (I/R) injury. There are three major classes of MAPKs that may be involved in the inflammatory response: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs)/c-Jun NH(2)-terminal kinases (JNKs), and p38 MAPKs (p38). This is clinically relevant, because these pathways may be a possible target for anti-inflammatory drug intervention. This review studies the role of MAPKs in trauma and/or I/R.
Inflammatory response
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Background Although many teratogens are known to activate apoptotic pathways culminating in abnormal development, little is known about how the embryo transduces a teratogenic exposure into specific responses. Signal reception and transduction are regulated by a number of signal transduction pathways, including the extracellular signal-regulated protein kinases (ERKs), c-Jun N-terminal kinases (JNKs) and the stress-activated protein kinase, p38. Methods To analyze the effects of teratogens on MAP kinases, we used whole embryo culture, Western blot analyses, and antibodies recognizing inactive or active MAP kinases, or both. Results We show that heat shock (HS) induces a rapid, strong, but transient activation of ERK, JNK, and p38 with maximal activation occurring within 30 min of the heat shock. By contrast, cyclophosphamide (CP) and staurosporine (ST) failed to activate ERK or JNK during the time period studied (7.5 hr). ST and CP did induce a low but reproducible activation of p38 beginning at around 3 hr and 5 hr, respectively, after the initiation of exposure. Previous work has shown that heat shock induces elevated cell death in the embryo, primarily in the developing neuroepithelium, but not in the embryonic heart. Thus, we also compared the activation of these three MAP kinase pathways in heads, hearts, and trunks isolated from day 9 embryos exposed to 43°C for 15 min. The results show that ERK, JNK, and p38 are activated in heads, hearts, and trunks. Conclusions Our results show that day 9 embryos do activate MAP kinase signaling pathways in response to teratogenic exposures; however, activation of a particular pathway does not appear to be required for teratogen-induced apoptosis. Teratology 62:14–25, 2000. © 2000 Wiley-Liss, Inc.
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BACKGROUND: The effects of aging on the cardiovascular system contribute to substantial alterations in cellular morphology and function. The variables regulating these changes are unknown; however, one set of signaling molecules which may be of particular importance in mediating numerous cellular responses including control of cell growth, differentiation and adaptation are the proteins associated with the mitogen activated protein kinase (MAPK) signaling systems. Further MAPKs have emerged as critical components for regulating numerous mechanotrasductive cellular responses. Previous reports have suggested that agng impairs biaxial-loading induced MAPK phosphorylation. How agigng may affect uniaxial mechanotrasductive processes is not clear. PURPOSE: Here we investigate the ability of a uniaxial stretch activate MAPK pathways in adult (6 mo old), aged (30 mo old) and very aged (36 mo old) Fischer 344 x Brown Norway rats. METHODS: Aortea of adult (6 month), aged (30 month), and very aged (36 month) Fischer 344/NNiaHSD X Brown Norway / BiNia rats were subjected to acute bout of a 20% uniaxial stretch. MAPK protein expression, basal phosphorylation and the uniaxial stretch induced changes in phosphorylation were evaluated by immunoblotting. RESULTS: Western blotting of the MAPK family proteins extracellular signal-regulated kinase (ERK) 1/2, p38-, and c-Jun NH2-terminal kinase (JNK)-MAPKs showed differential expression and basal activation between these proteins with age, with notably higher phosphorylation in ERK1/2 and JNK compared to the 6 month aniumals. However, an acute bout of a 20% uniaxial stretch using an ex vivo aortic preparation demonstrated similar regulation of ERK 1/2 MAPK, p38-, and JNK MAPK. CONCLUSIONS: These observations confirm previous data demonstrating MAPK proteins are mechanically regulated, and in addition, suggest that MAPK signaling following uniaxial stretch is not altered with aging. Taken together, these data may help explain the age related changes in vascular morphology, function and response to injury. (Supported by funds from NSF Grant #0314742)
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Mitogen-activated protein kinases (MAPKs) have been the focus of a number of studies, as these compounds are involved in a number of important inflammatory cell signaling mechanisms. Recent studies have further elucidated the role of MAPKs in the inflammatory response, as a result of trauma and/or ischemia–reperfusion (I/R) injury. There are three major classes of MAPKs that may be involved in the inflammatory response: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs)/c-Jun NH2-terminal kinases (JNKs), and p38 MAPKs (p38). This is clinically relevant, because these pathways may be a possible target for anti-inflammatory drug intervention. This review studies the role of MAPKs in trauma and/or I/R.
Inflammatory response
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AIM:To investigate the apoptotic effect of cepharanthine(CEP)on neonatal rat cardiomyocytes (NRCMs)and the underlying mechanisms.METHODS:MTT assay was used to detect the viability of the cells.CEP-induced apoptosis in NRCMs was evaluated by Hoechst 33342 staining and the expression of activated caspase-3.The phosphorylation levels of mitogen-activated protein kinases(MAPKs),such as extracellular signal-regulated kinase (ERK),c-jun N-terminal kinase(JNK)and p38 MAPK,were examined by Western blotting.The specific inhibitors of ERK and p38 MAPK were applied for identifying the roles of the corresponding signal pathways in CEP-induced apoptosis of cardiomyocytes.RESULTS:CEP inhibited the viability of NRCMs in a dose-and time-dependent manners.Positive nuclear fragmentation and activated caspase-3 were found in CEP-treated NRCMs.The phosphorylation levels of ERK and p38 MAPK were significantly elevated in CEP-treated NRCMs,but the change of JNK was not obvious.SB203580, an inhibitor of p38 MAPK,significantly alleviated the apoptotic effect induced by CEP.However,PD98059,an inhibitor of ERK1/2,did not significantly reduce the apoptotic effect.CONCLUSION:p38 MAPK is involved in CEP-induced apoptosis in NRCMs.
MTT assay
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Ionizing radiation is known to activate both the cytotoxic stress-activated kinases (SAPK/JNK, p38) and the cytoprotective mitogen-activated protein kinases (MAPKs, ERKs), which send divergent signals to the nucleus. However, all these kinases could not be activated simultaneously and at all the doses. An attempt has been made in this study to establish the dose and temporal response of these kinases with a view to establish the identity of the transcription factors that remain activated because only these will be translated into an effect. The study indicates that the stress-activated kinases (SAPK/JNK and p38) are activated by very low doses (0.1 Gy) of ionizing radiation. An induction of expression of MKK4, precursor to SAPK and p38, was found at lower doses (0.1#x2013;0.5 Gy). However, the cytoprotective ERK2 showed a progressive increase in expression with dose, except at 3 Gy where it shows a marginal decline. The stress-activated kinases show an increased expression or activation at early periods, unlike ERK2, which shows a prolonged response to stimuli. This study reveals that in the in vivo condition there is a chronological order of activation of the kinases and a dose-dependent activation. The activations of the cytoplasmic kinases and the transcription factors, Elk-1 and c-Jun, both show prolonged activation and maximum response at high doses.
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