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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Na+/K+-ATPase functions as both an ion pump and a signal transducer. Cardiac glycosides partially inhibit Na+/K+-ATPase, causing activation of multiple interrelated growth pathways via the Na+/K+-ATPase/c-Src/epidermal growth factor receptor complex. Such pathways include Ras/MEK/ERK and Ral/RalGDS cascades, which can lead to cardiac hypertrophy. In search of novel Ral-GTPase binding proteins, we used RalB as the bait to screen a human testes cDNA expression library using the yeast 2-hybrid system. The results demonstrated that 1 of the RalB interacting clones represented the C-terminal region of the beta1 subunit of Na+/K+-ATPase. Further analysis using the yeast 2-hybrid system and full-length beta1 subunit of Na+/K+-ATPase confirmed the interaction with RalA and RalB. In vitro binding and pull-down assays demonstrated that the beta1 subunit of Na+/K+-ATPase interacts directly with RalA and RalB. Ral-GTP pull-down assays demonstrated that short-term ouabain treatment of A7r5 cells, a rat aorta smooth muscle cell line, caused activation of Ral GTPase. Maximal activation was observed 10 min after ouabain treatment. Ouabain-mediated Ral activation was inhibited upon the stimulation of Na+/K+-ATPase activity by Ang II. We propose that Ral GTPase is involved in the signal transducing function of Na+/K+-ATPase and provides a possible molecular mechanism connecting Ral to cardiac hypertrophy during diseased conditions.
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PMID:Ral-GTPase interacts with the beta1 subunit of Na+/K+-ATPase and is activated upon inhibition of the Na+/K+ pump. 1761 54

Vascular endothelial growth factor receptors (VEGFRs) are previously considered to exist exclusively in endothelial cells. However, little is known if the receptors are expressed in other non-endothelial cells. In this study, we measured activation of two VEGFRs, Flk-1 and Flt-1, and their biological functions in cultured adventitial fibroblasts and injured rat carotid injury arteries induced by balloon angioplasty. Our results indicated that Flt-1, but not Flk-1, existed in adventitial fibroblasts. Angiotensin II increased Flt-1 protein expression in a time- and concentration-dependent manner. Adventitial fibroblast migration stimulated by vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) required Flt-1 expression. The Flt-1-induced adventitial fibroblast migration was blocked by anti-Flt-1 neutralizing antibody and soluble VEGFR1 protein (sFlt-1). However, Flt-1 activation did not enhance cell proliferation. In addition, Flt-1 expression was significantly increased in the neointima and adventitia in injured rat carotid arteries. We concluded that functional expression of Flt-1 in adventitial fibroblasts might be an important mediator in the pathogenesis of vascular remodeling after arterial injury.
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PMID:Expression and function of vascular endothelial growth factor receptors (Flt-1 and Flk-1) in vascular adventitial fibroblasts. 1765 52

In this study, we clarified the intracellular mechanism of angiotensin II (Ang II) in promoting migration in rat aortic smooth muscle cells (RASMCs). RASMC migration was measured with the Boyden chamber assay, and the result was confirmed with an aortic sprout assay. The activities of kinases were investigated by western blot analysis. Ang II enhanced RASMC migration, which was chemotaxis directed, and induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK1/2), and heat shock protein 27 (Hsp27). Ang II-enhanced cell migration was inhibited by SB203580 (a p38 MAPK inhibitor) and piceatannol (a spleen tyrosine kinase inhibitor), but only partially by PD98059 (an ERK inhibitor) and PP2 (a Src inhibitor). The Ang II-stimulated phosphorylation of p38 MAPK and Hsp27 in RASMCs was inhibited by piceatannol and SB203580. The phosphorylation of ERK1/2 stimulated by Ang II was suppressed by PD98059, piceatannol, and PP2. Ang II increased the sprout outgrowth from aortic rings and this response was attenuated by pretreatment with SB203580, PD98059, PP2, or piceatannol. These results suggest that p38 MAPK contributes to the regulation of the Ang II-induced chemotactic migration of vascular smooth muscle cells, which is mediated by Hsp27 phosphorylation.
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PMID:p38 mitogen-activated protein kinase contributes to angiotensin II-stimulated migration of rat aortic smooth muscle cells. 1789 90

Epigallocatechin-3-O-gallate (EGCG) is the main catechin, which is derived from Camellia sinensis plant. Vascular cell adhesion molecules (VCAMs) and intercellular adhesion molecules (ICAMs) mediate the binding of inflammatory cells onto the vascular wall-promoting the early phase of atherosclerosis. In the present study, we investigated the mechanism(s) by which EGCG inhibits angiotensin II (Ang II)-induced elevation of the membrane associated VCAM-1 and ICAM-1 in human umbilical vein endothelial cells (HUVEC). Ang II induced a 40% increase of VCAM-1 and ICAM-1 in the plasma membrane. EGCG (10 to 50 microM) inhibited the effect of Ang II in a concentration-dependent manner. In parallel, the Ang II-induced elevation of the mRNA expressions of VCAM-1 and ICAM-1 in HUVEC were completely inhibited by 50 microM EGCG. Since mitogen-activated protein kinase (MAPK) families are involved in vascular inflammation in response to stressful stimuli, we investigated the effects of EGCG on the MAPK signal transduction pathway stimulated by Ang II. EGCG (30 to 50 microM) completely inhibited the Ang II-induced phosphorylation of ERK (extracellular signal-regulated kinase) 1/2 and p38 MAPK. PD98059, an inhibitor of ERK1/2 inhibited the Ang II-induced increase of VCAM-1 but not of ICAM-1 in the plasma membranes. In contrast, SB203580, an inhibitor of p38 MAPK inhibited both the Ang II-induced enrichment of ICAM-1 and VCAM-1. From these results, it may be concluded that EGCG inhibits the Ang II-induced elevation of VCAM-1 and ICAM-1 in the HUVEC plasma membranes via inhibition of the p38 MAPK and the ERK1/2 signalling pathways resulting in an inhibition of the VCAM-1 and ICAM-1 transcription.
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PMID:Epigallocatechin-3-O-gallate inhibits the angiotensin II-induced adhesion molecule expression in human umbilical vein endothelial cell via inhibition of MAPK pathways. 1798 68

Connective tissue growth factor (CTGF) is overexpressed in kidney diseases associated with extracellular matrix accumulation. Angiotensin II (ANG II) participates in renal fibrosis by the upregulation of growth factors, including CTGF, and extracellular matrix proteins, such as type IV collagen. During renal injury, ANG II and the macrophage-produced cytokine interleukin-1beta (IL-1beta) may be present simultaneously in the glomerular environment. However, there are no studies about the interaction between ANG II and IL-1beta in renal fibrosis. For this reason, in cultured mesangial cells (MC), we investigated whether IL-1beta could regulate ANG II-mediated collagen accumulation and the mechanisms underlying this process. In MC, CTGF is a downstream mediator of type IV collagen production induced by ANG II. IL-1beta did not increase the production of CTGF and type IV collagen but significantly inhibited ANG II-induced CTGF and type IV collagen overexpression. Moreover, IL-1beta also inhibited type IV collagen upregulation caused by exogenous recombinant CTGF. Matrix metalloproteinase-9 (MMP-9) is the main enzyme involved in type IV collagen degradation. In MC, coincubation of IL-1beta and ANG II caused a synergistic increase in MMP-9 gene expression and activity, associated with type IV collagen inhibition. The described IL-1beta effects were dependent on activation of ERK/MAPK but independent p38-MAPK, JNK, phosphatidylinositol 3-kinase/Akt, and Rho-associated kinase pathways. In summary, these data indicate that IL-1beta inhibited ANG II-mediated type IV collagen production, via CTGF downregulation, and increased type IV collagen degradation, through MMP-9 upregulation. Our in vitro data show that the proinflammatory cytokine IL-1beta abrogates ANG II-induced CTGF production, describing antagonistic activities of proinflammatory cytokines on ANG II actions.
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PMID:Inhibitory effect of interleukin-1beta on angiotensin II-induced connective tissue growth factor and type IV collagen production in cultured mesangial cells. 1798 12

It has been established that syndecan-1 is an important modulator of events relevant to acute tissue repair and chronic injury responses. The current studies were designed to examine syndecan-1 expression during atherosclerotic lesion formation and whether angiotensin II influences syndecan-1 expression in macrophages. ApoE knockout mice maintained on an atherogenic diet were treated for 8 weeks with an infusion of angiotensin II to induce atherosclerosis. Immunohistochemistry was employed to characterize the expression of syndecan-1 in atherosclerotic lesions. Quantitative real-time PCR (QRTPCR) was used to define the role of angiotensin II and responsible signaling pathways involved syndecan-1 expression in RAW264.7 murine macrophages. Protein expression and shedding were characterized by fluorescence activated cell sorting (FACS) and slot blot analysis. Syndecan-1 was abundantly expressed in macrophages located within early atherosclerotic lesions. Accordingly, we hypothesized that angiotensin II regulates syndecan-1 expression in macrophages. A time- and dose-dependent study was performed in RAW264.7 macrophages. QRTPCR demonstrated maximum syndecan-1 mRNA up-regulation at 6 h after 500 nM AgII stimulation (threefold; P < 0.05). Through administration of specific inhibitors, we established that ERK/MAPK, PI3K and JNK signaling pathways mediated this effect. FACS and slot blot analyses demonstrated that cAMP induced posttranscriptional syndecan-1 protein expression in a dose-dependent manner with or without initial angiotensin II stimulation. In particular, angiotensin II induced an increase in cell surface syndecan-1 (mean fluorescence intensity: 147 +/- 5.7 vs. 176 +/- 4.8; P < 0.05; n = 3) and accelerated syndecan-1 shedding. Angiotensin II is a potent regulator of syndecan-1 expression in atherosclerotic lesions via a specific effect on macrophages that is mediated by ERK/MAPK, PI3K, and JNK signaling pathways.
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PMID:Decoupled syndecan 1 mRNA and protein expression is differentially regulated by angiotensin II in macrophages. 1807 60

Regulation of renal proximal transport by angiotensin II (Ang II) is biphasic: low concentrations (picomolar to nanomolar) stimulate reabsorption, but higher concentrations (nanomolar to micromolar) inhibit reabsorption. Traditionally, the stimulatory effect has been attributed to activation of protein kinase C and/or a decrease in intracellular cAMP, whereas the inhibitory action has been attributed to the activation of phospholipase A2 (PLA2) and the subsequent release of arachidonic acid. The Ang II receptor subtype responsible for these effects and the intracellular signaling pathways involved are not completely understood. We isolated proximal tubules from wild-type, Ang II type 1A receptor (AT1A)-deficient, and group IVA cytosolic phospholipase A2 (cPLA2alpha)-deficient mice, and compared their responses to Ang II. In wild-type mice, we found that the stimulatory and inhibitory effects of Ang II on Na+-HCO3(-) cotransporter activity are both AT1-mediated but that ERK activation only plays a role in the former. The stimulatory effect of Ang II was also observed in AT1A-deficient mice, suggesting that this occurs through AT1B. In contrast, the inhibitory effects of Ang II appeared to be mediated by cPLA2alpha activation because high-concentration Ang II stimulated Na+-HCO3(-) cotransporter activity when cPLA2alpha activity was abrogated by pharmacological means or genetic knockout. Consistent with this observation, we found that activation of the cPLA2alpha/P450 pathway suppressed ERK activation. We conclude that Ang II activates ERK and cPLA2alpha in a concentration-dependent manner via AT1, and that the balance between ERK and cPLA2alpha activities determines the ultimate response to Ang II in intact proximal tubules.
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PMID:Roles of ERK and cPLA2 in the angiotensin II-mediated biphasic regulation of Na+-HCO3(-) transport. 1809 67

Tetramethylpyrazine (TMP) is the major component extracted from the Chinese herb, Chuanxiong, which is widely used in China for the treatment of cardiovascular problems. The aims of this study were to examine whether TMP may alter angiotenisn II (Ang II)-induced proliferation and to identify the putative underlying signaling pathways in rat aortic smooth muscle cells. Cultured rat aortic smooth muscle cells were preincubated with TMP and then stimulated with Ang II, [3H]-thymidine incorporation and the ET-1 expression was examined. Ang II increased DNA synthesis which was inhibited by TMP (1-100 microM). TMP inhibited the Ang II-induced ET-1 mRNA levels and ET-1 secretion. TMP also inhibited Ang II-increased NAD(P)H oxidase activity, intracellular reactive oxygen species (ROS) levels, and the ERK phosphorylation. Furthermore, TMP and antioxidants such as Trolox and diphenylene iodonium decreased Ang II-induced ERK phosphorylation, and activator protein-1 reporter activity. In summary, we demonstrate for the first time that TMP inhibits Ang II-induced proliferation and ET-1, partially by interfering with the ERK pathway via attenuation of Ang II-increased NAD(P)H oxidase and ROS generation. Thus, this study delivers important new insight in the molecular pathways that may contribute to the proposed beneficial effects of TMP in cardiovascular disease.
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PMID:Tetramethylpyrazine inhibits angiotensin II-increased NAD(P)H oxidase activity and subsequent proliferation in rat aortic smooth muscle cells. 1818 88

Cardiomyocyte hypertrophy is formed in response to pressure or volume overload, injury, or neurohormonal activation. The most important vascular hormone that contributes to the development of hypertrophy is angiotensin II (Ang II). Accumulating studies have suggested that reactive oxygen species (ROS) may play an important role in cardiac hypertrophy. Propofol is a general anesthetic that possesses antioxidant action. We therefore examined whether propofol inhibited Ang II-induced cardiomyocyte hypertrophy. Our results showed that both ROS formation and hypertrophic responses induced by Ang II in cardiomyocytes were partially blocked by propofol. Further studies showed that propofol inhibited the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated protein kinase/ERK kinase 1/2 (MEK1/2) induced by Ang II via a decrease in ROS production. In addition, propofol also markedly attenuated Ang II-stimulated nuclear factor-kappaB (NF-kappaB) activation via a decrease in ROS production. In conclusion, propofol prevents cardiomyocyte hypertrophy by interfering with the generation of ROS and involves the inhibition of the MEK/ERK signaling transduction pathway and NF-kappaB activation.
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PMID:Propofol depresses angiotensin II-induced cardiomyocyte hypertrophy in vitro. 1822 75

The recent discovery of the angiotensin II (Ang II)-breakdown enzyme, angiotensin I converting enzyme (ACE) 2, suggests the importance of Ang II degradation in hypertension. The present study explored the signaling mechanism by which ACE2 is regulated under hypertensive conditions. Real-time PCR and immunohistochemistry showed that ACE2 mRNA and protein expression levels were high, whereas ACE expression levels were moderate in both normal kidney and heart. In contrast, patients with hypertension showed marked ACE up-regulation and ACE2 down-regulation in both hypertensive cardiopathy and, particularly, hypertensive nephropathy. The inhibition of ACE2 expression was shown to be associated with ACE up-regulation and activation of extracellular regulated (ERK)1/2 and p38 mitogen-activated protein (MAP) kinases. In vitro, Ang II was able to up-regulate ACE and down-regulate ACE2 in human kidney tubular cells, which were blocked by an angiotensin II (AT)1 receptor antagonist (losartan), but not by an AT2 receptor blocker (PD123319). Furthermore, blockade of ERK1/2 or p38 MAP kinases by either specific inhibitors or a dominant-negative adenovirus was able to abolish Ang II-induced ACE2 down-regulation in human kidney tubular cells. In conclusion, Ang II is able to up-regulate ACE and down-regulate ACE2 expression levels under hypertensive conditions both in vivo and in vitro. The AT1 receptor-mediated ERK/p38 MAP kinase signaling pathway may be a key mechanism by which Ang II down-regulates ACE2 expression, implicating an ACE/ACE2 imbalance in hypertensive cardiovascular and renal damage.
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PMID:Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. 1840 95


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