Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 (ET-1) regulates contractility and growth of the mammalian heart by binding endothelin receptor type A (ET(A)) and endothelin receptor type B (ET(B)) G-protein-coupled receptors. To identify growth signaling pathways associated with ET-1 receptors in adult myocardium, a combined immunoprecipitation/proteomic analysis was performed. Signaling proteins believed to function downstream of ET(A) such as Galpha(q), phospholipase C-beta1, protein kinase C (PKC) epsilon, and PKCdelta were identified in immunoprecipitates of ET(A) by matrix-assisted laser desorption ionization/time of flight mass spectrometry. Also prominent were the growth factor receptor tyrosine kinases erbB2 and erbB4 and their downstream growth signaling effectors phosphoinositide-3 kinase (PI3 kinase), Akt, Raf-1, mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (Erk). Western blot analysis confirmed coimmunoprecipitation of erbB2/4, PI3 kinase, and Akt with ET(A), and confocal microscopy revealed their colocalization in cardiac transverse tubules (T-tubules). The erbB4 receptor ligand neuregulin-1beta (NRG1beta) promoted erbB2/4 tryosine phosphorylation and Akt serine phosphorylation in ventricular myocytes, whereas treatment with ET-1 did not. This observation argues against ET-1 growth signaling occurring via erbB2/4 transactivation in adult myocardium. ET-1 did, however, stimulate Erk1/2 phosphorylation and substantially blunted several NRG1beta-mediated actions, including erbB2/4 phosphorylation, serine phosphorylation of Akt, and negative inotropy. This inhibitory cross-talk between ET(A) and erbB2/4-Akt pathways was mimicked by a phorbol ester and blocked by pharmacological inhibition of PKC or MEK/Erk. The proteomic analysis and subsequent investigation of receptor cross-talk indicate that growth signaling between ET(A) and erbB pathways is fundamentally different in adult versus neonatal cardiac myocytes. The results may be relevant to cardiomyopathies associated with 1) prolonged exposure to ET-1; 2) degeneration of T-tubules; and 3) therapies targeted at erbB2 inhibition.
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PMID:Interaction and inhibitory cross-talk between endothelin and ErbB receptors in the adult heart. 1733 41

Given that vascular endothelial cells play an important role in the modulation of vascular structure and function, we hypothesized that endocardial endothelial cells (EECs) may have a modulator role in regulating the cardiac interstitial cells. Endocardial endothelial cells were isolated from freshly collected pig hearts and cardiac fibroblasts were isolated from 3- to 4-d-old Wistar rats. Fibroblasts were cultured in the presence or absence of conditioned medium from EECs. Proliferation of cardiac fibroblasts was measured by the incorporation of [3H]- Thymidine and collagen synthesis was assayed by the incorporation of [3H]-Proline. To determine the involvement of signaling mediators, in separate experiments, cardiac fibroblasts were incubated with BQ123 (selective ETA receptor antagonist), PD142893 (nonselective ETA/ETB receptor antagonist), Bis-indolylmaleimide (PKC inhibitor), PD 098059 (MEK inhibitor), or neutralizing anti-transforming growth factor (TGF)-beta-antibody. Endocardial endothelium-derived factors endothelin (ET)-1, TGF-beta, and Angiotensin (Ang)-II in the conditioned medium were assayed by enzyme-linked immunosorbent assay using commercially available kits. We report here evidence that suggest that endocardial endothelial cells stimulate both proliferation and collagen synthesis of cardiac fibroblasts. The response seems to be mediated by endothelin through its ETA receptor. Our results also indicate that protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathways are essential for the EEC-induced proliferation of cardiac fibroblasts.
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PMID:Endocardial endothelial cells stimulate proliferation and collagen synthesis of cardiac fibroblasts. 1740 60

Tenascin-C, an extracellular matrix molecule of the tumor-specific microenvironment, counteracts the tumor cell proliferation-suppressing effect of fibronectin by blocking the integrin alpha(5)beta(1)/syndecan-4 complex. This causes cell rounding and stimulates tumor cell proliferation. Tenascin-C also stimulates endothelin receptor type A (EDNRA) expression. Here, we investigated whether signaling through endothelin receptors affects tenascin-C-induced cell rounding. We observed that endothelin receptor type B (EDNRB) activation inhibited cell rounding by tenascin-C and induced spreading by restoring expression and function of focal adhesion kinase (FAK), paxillin, RhoA, and tropomyosin-1 (TM1) via activation of epidermal growth factor receptor, phospholipase C, c-Jun NH(2)-terminal kinase, and the phosphatidylinositol 3-kinase pathway. In contrast to EDNRB, signaling through EDNRA induced cell rounding, which correlated with FAK inhibition and TM1 and RhoA protein destabilization in the presence of tenascin-C. This occurred in a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-dependent manner. Thus, tumorigenesis might be enhanced by tenascin-C involving EDNRA signaling. Inhibition of tenascin-C in combination with blocking both endothelin receptors could present a strategy for sensitization of cancer and endothelial cells toward anoikis.
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PMID:Endothelin receptor type B counteracts tenascin-C-induced endothelin receptor type A-dependent focal adhesion and actin stress fiber disorganization. 1761 73

The pathological constriction of cerebral arteries known as cerebral vasospasm (CVS) is with a delay of 4 to 10 days linked to subarachnoid hemorrhage. Several agents have been suggested as being responsible; amongst these perhaps 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) are the most prominent given their ability to elicit powerful constriction of cerebral arteries. Investigating both 5-HT and ET receptors we have observed that there are distinct changes in receptor phenotype after experimental SAH, namely upregulation of the ETB and 5-HT1B receptors, and that this upregulation is linked to a higher sensitivity to the endogenous agonists. It has also been shown that reduction in regional cerebral blood flow (CBF) is associated with receptor upregulation and interventional animal experiments have shown a benefit from inhibiting the PKC and MAP kinase pathways on receptor upregulation, CBF and neurological outcome.
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PMID:Cerebral vasoconstriction after subarachnoid hemorrhage--role of changes in vascular receptor phenotype. 1798 99

The penis is kept in the flaccid state mainly via a tonic activity of norepinephrine and endothelins (ETs). ET-1 is important in salt-sensitive forms of hypertension. We hypothesized that cavernosal responses to ET-1 are enhanced in deoxycorticosterone acetate (DOCA)-salt mice and that blockade of ETA receptors prevents abnormal responses of the corpus cavernosum in DOCA-salt hypertension. Male C57BL/6 mice were unilaterally nephrectomized and treated for 5 weeks with both DOCA and water containing 1% NaCl and 0.2% KCl. Control mice were uninephrectomized and received tap water with no added salt. Animals received either the ETA antagonist atrasentan (5 mg x day(-1) x kg(-1) body weight) or vehicle. DOCA-salt mice displayed increased systolic blood pressure (SBP), and treatment with atrasentan decreased SBP in DOCA-salt mice. Contractile responses in cavernosal strips from DOCA-salt mice were enhanced by ET-1, phenylephrine, and electrical field stimulation (EFS) of adrenergic nerves, whereas relaxations were not altered by IRL-1620 (an ETB agonist), acetylcholine, sodium nitroprusside, and EFS of nonadrenergic noncholinergic nerves. PD59089 (an ERK1/2 inhibitor), but not Y-27632 (a Rho-kinase inhibitor), abolished enhanced contractions to ET-1 in cavernosum from DOCA-salt mice. Treatment of DOCA-salt mice with atrasentan did not normalize cavernosal responses. In summary, DOCA-salt treatment in mice enhances cavernosal reactivity to contractile, but not to relaxant, stimuli, via ET-1/ETA receptor-independent mechanisms.
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PMID:DOCA-salt treatment enhances responses to endothelin-1 in murine corpus cavernosum. 1851 94

Recent observations suggest that the vasoactive peptide endothelin-1 (ET-1) may be an important contributor to the etiology of glaucoma. ET-1 administration has been shown to produce optic nerve axonal loss and apoptosis of retinal ganglion cells. Ocular ET-1 levels are elevated in aqueous humor in response to elevated intraocular pressure both in glaucoma patients and in animal models of glaucoma; however, the precise mechanisms by which ET-1 mediates glaucomatous optic neuropathy are not clear. Presently we report that ET-1-mediated apoptosis was markedly attenuated in ETB receptor-deficient rats, suggesting a key role for ETB receptors in apoptosis of retinal ganglion cells by ET-1 treatment. Using virally transformed rat retinal ganglion cells (RGC-5 cells), we found that ET-1 (100 nmol/L) treatment produced apoptotic changes in these cells that was determined by flow cytometric analyses, release of mitochondrial cytochrome c to the cytosol, and increased phosphorylation of c-Jun N-terminal kinase. Pretreatment with the ETB-receptor antagonist BQ788 (1 micromol/L) was able to significantly attenuate ET-1-mediated apoptosis in RGC-5 cells. ET-1-mediated apoptotic changes in RGC-5 cells were associated with ETB-receptor activation and were accompanied by a significant upregulation of ETB-receptor expression. These studies suggest that ocular ET-1 acts through ETB receptors to mediate apoptosis of retinal ganglion cells, a key event in glaucoma and related optic neuropathies.
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PMID:Role of the ETB receptor in retinal ganglion cell death in glaucoma. 1851 2

Cells within the normal human colonic epithelium undergo a dynamic cycle of growth, differentiation, and death. The organotypic culture system of human fetal colonic epithelial cells seeded on top of collagen gels with embedded colonic fibroblasts allowed prolonged culture of the colonic epithelial cells (Kalabis J, Patterson MJ, Enders GM, Marian B, Iozzo RV, Rogler G, Gimotty PA, Herlyn M. FASEB J 17: 1115-1117, 2003). Herein, we have evaluated the role of endothelin-3 (ET3) and both cognate endothelin receptors (ETRA, ETRB) for human colonic epithelial cell growth and survival. ET3 was produced continuously by the fibroblasts as a result of adenovirus-mediated gene transfer. The presence and function of the endothelin receptors (ETRs) in epithelial cells was evaluated by [(3)H]thymidine incorporation using primary epithelial cells in monoculture and by immunohistochemistry on human fetal and adult paraffin-embedded tissues. In organotypic culture, ET3 increased the number of goblet cells but not of enteroendocrine cells. The increase in goblet cells was caused by prolonged cell survival and differentiation. The inhibition of both ETRA and ETRB significantly decreased the number of goblet cells and proliferation in epithelial cells, whereas the number of enteroendocrine cells remained unchanged. ET3 induced activation of IkappaB and MAPK in the epithelial cells, suggesting that these signaling pathways mediate its proproliferation and prosurvival activities. Our results demonstrate that ET3 is involved in regulating human colonic epithelial cell proliferation and survival, particularly for goblet cells, and may be an important component of colonic homeostasis.
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PMID:Endothelin-3 stimulates survival of goblet cells in organotypic cultures of fetal human colonic epithelium. 1883 50

Uterine leiomyoma are the most common benign tumors of the myometrium. We previously identified endothelin (ET)-1 as a proliferative and antiapoptotic factor in Eker rat-derived leiomyoma (ELT3) cells. A major role of ETB receptor in the prosurvival effect was revealed. Here we investigated, in ELT3 and myometrial cells, the respective contribution of ETA and ETB in the proliferative effect of ET-1. In myometrial cells, binding experiments show that ETA is almost exclusively expressed and stimulates phospholipase C (PLC) activity and ERK1/2 phosphorylation and proliferation. In ELT3 cells, ETB is expressed at about the same level as ETA, and the two receptors are differently coupled to Gi protein. The ETB agonist, sarafotoxin S6c, stimulates PLC activity 60% less than ET-1 but is as potent as ET-1 to increase ERK1/2 phosphorylation and induce proliferation. However, the ability of ETA to activate ERK1/2 is observed after ETB desensitization. Although ETA and ETB antagonists partially reduce ET-1 stimulated PLC activity, they are without effect on ET-1-induced ERK1/2 phosphorylation and proliferation. Only the simultaneous use of ETA and ETB antagonists reduces ET-1-triggered ERK1/2 activation. These unconventional properties of ETRs may reveal the existence of functional ETA-ETB heterodimers. Finally, treatment of ELT3 cells with ETB but not ETA-directed small interfering RNA reduces the proliferative effect of ET-1. All the data obtained in ELT3 cells strengthen the relation between ETB overexpression, which decreases the ETA to ETB ratio, and the ability of leiomyoma cells to highly proliferate and resist apoptosis.
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PMID:Differential endothelin receptor expression and function in rat myometrial cells and leiomyoma ELT3 cells. 1962 75

Endothelin (ET) was first isolated and described by Yanagisawa et al. and has since been described as one of the most potent known vasoconstrictor compounds. ET-1 mediates its effects via two types of receptors, ETA and ETB, which are expressed in the vascular smooth muscle cells, endothelial cells, intestines and brain. Secretion of ET-1 results in long-lasting vasoconstriction, increased blood pressure and, in turn, overproduction of free radicals. As dysregulation of the endothelin system is an important factor in the pathogenesis of several diseases including atherosclerosis, hypertension and endotoxic shock, the ETA and ETB receptors are attractive therapeutic targets for treatment of these disorders. The biosynthesis and release of ET-1 are regulated at the transcriptional level. Studies have shown that p38MAP kinase, nuclear factor kappaB (NF-kappaB), PKC/ERK and JNK/c-Jun all take part in the ROS-activated production of ET-1. Furthermore, administration of ET(A) significantly reduces the generation of free radicals. However, treatment with ETB receptor blockers does not elicit the same effect. Therefore, the effects of endothelin receptor blockers on blood pressure and the generation of free radicals remain debatable. This review summarizes recent investigations into the role of endothelin receptor blockers with respect to the modulation of hemodynamic parameters and the generation of free radicals.
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PMID:Role of endothelin-1 receptor blockers on hemodynamic parameters and oxidative stress. 2036 Jun 13

Endothelin 1 (ET-1) is an endogenous peptide that promotes vasoconstriction, endothelial and smooth muscle cell (SMC) proliferation, and fibrosis. ET-1 receptor antagonists are an important treatment strategy for pulmonary arterial hypertension, but less effective in systemic vascular disease. This observation suggests a special role for ET-1 in the pulmonary circulation. We hypothesized that ET-1 contributes to the pathogenesis of pulmonary arterial hypertension, in part, by promoting pulmonary vascular SMC migration. ET-1 treatment promoted migration in 3 distinct types of cultured pulmonary SMC. Pulmonary SMC migration was blocked by an ETA receptor selective agonist and a combined ETA-ETB antagonist, but not by a selective ETB antagonist. In contrast to the effect on pulmonary SMCs, ET-1 had no effect on migration of aortic SMCs. Flow cytometry showed that the ETA receptor was expressed at comparable levels on pulmonary and aortic SMCs, excluding receptor density as an explanation for the divergent effect. ET-1-induced pulmonary SMC migration was blocked by the structurally distinct MEK inhibitors PD98059 and U0126, consistent with a role for ERK1/2 MAP kinase. By Western blot in cultured cells and immunohistochemistry in ex vivo vessels, ET-1 stimulated phosphorylation of ERK1/2 as efficaciously as platelet-derived growth factor in pulmonary, but not aortic, SMCs. In conclusion, ET-1 induces SMC migration, with the ETA receptor tightly coupled to ERK1/2 phosphorylation only in the pulmonary circulation. This finding may help explain the striking difference in the efficacy of endothelin receptor blockers for pulmonary hypertension as compared to that for systemic cardiovascular disease.
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PMID:Endothelin-1 induces pulmonary but not aortic smooth muscle cell migration by activating ERK1/2 MAP kinase. 2072 41


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