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)

Vascular endothelial cell growth factor (VEGF) was originally described as a potent vascular permeability factor (VPF) that importantly contributes to vascular pathobiology. The signaling pathways that underlie VEGF/VPF-induced permeability are not well defined. Furthermore, endogenous vascular peptides that regulate this important VPF function are currently unknown. We report here that VPF significantly enhances permeability in aortic endothelial cells via a linked signaling pathway, sequentially involving Src, ERK, JNK, and phosphatidylinositol 3-kinase/AKT. This leads to the serine/threonine phosphorylation and redistribution of actin and the tight junction (TJ) proteins, zona occludens-1 and occludin, and the loss of the endothelial cell barrier architecture. Atrial natriuretic peptide (ANP) inhibited VPF signaling, TJ protein phosphorylation and localization, and VPF-induced permeability. This involved both guanylate cyclase and natriuretic peptide clearance receptors. In vivo, transgenic mice that overexpress ANP showed significantly less VPF-induced kinase activation and vascular permeability compared with non-transgenic littermates. Thus, ANP acts as an anti-permeability factor by inhibiting the signaling functions of VPF that we define here and by preserving the endothelial cell TJ functional morphology.
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PMID:Deciphering vascular endothelial cell growth factor/vascular permeability factor signaling to vascular permeability. Inhibition by atrial natriuretic peptide. 1221 3

Brain natriuretic peptide (BNP) is a 32 amino acid cardiac natriuretic peptide hormone originally isolated from porcine brain tissue. The human BNP gene is located on chromosome 1 and encodes the prohormone proBNP. The biologically active BNP and the remaining part of the prohormone, NT-proBNP (76 amino acids) can be measured by immunoassay in human blood. Cardiac myocytes constitute the major source of BNP related peptides. The main stimulus for peptide synthesis and secretion is myocyte stretch. Recently, cardiac fibroblasts have also been shown to produce BNP. Other neurohormones may stimulate cardiac BNP production in different cardiac cell types. In contrast to atrial natriuretic peptides (ANP/NT-proANP), which originate mainly from atrial tissue, BNP related peptides are produced mainly from ventricular myocytes. Ventricular (NT-pro)BNP production is strongly upregulated in cardiac failure and locally in the area surrounding a myocardial infarction. In peripheral organs BNP binds to the natriuretic peptide receptor type A causing increased intracellular cGMP production. The biological effects include diuresis, vasodilatation, inhibition of renin and aldosterone production and of cardiac and vascular myocyte growth. In mice BNP gene knockout leads to cardiac fibrosis, gene over-expression to hypotension and bone malformations. BNP is cleared from plasma through binding to the natriuretic peptide clearance receptor type C, but it seems relatively resistant to proteolysis by neutral endopeptidase NEP 24.11. Clearance mechanisms for NT-proBNP await further study. While the plasma concentration of NT-proBNP and BNP is approximately equal in normal controls, NT-proBNP plasma concentration is 2-10 times higher than BNP in patients with heart failure. This relative change in peptide levels may be explained by shifts in cardiac secretion and/or clearance mechanisms.
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PMID:Essential biochemistry and physiology of (NT-pro)BNP. 1498 73

Brain natriuretic peptide (BNP) was isolated originally from porcine brain extracts but was soon defined as a cardiac natriuretic hormone. Together with the highly homologous atrial natriuretic peptide, it forms a dual natriuretic peptide system of the heart. The main stimulus for proBNP synthesis and secretion from cardiac myocytes is myocyte stretch. On secretion, the propeptide is split into the biologically active BNP and the remaining part of the prohormone N-terminal proBNP (NT-proBNP). In heart failure increased wall stretch, neurohormonal activation and hypoxia stimulate BNP secretion. The recently demonstrated production of BNP by stimulated cardiac fibroblasts is of uncertain pathophysiologic importance. In contrast to atrial natriuretic peptide, BNP is a constitutively secreted hormone with relatively little intracellular storage of mature peptide. In the normal state, the atrium is the main cardiac production site, but as heart failure develops, there is a profound activation of ventricular NT-proBNP synthesis. BNP acts on distant tissues and causes diuresis, vasodilatation, and decreased renin and aldosterone secretion. Known mechanisms of BNP clearance from plasma include binding to the natriuretic peptide clearance receptor type-C and proteolysis by peptidase NEP 24.11. NT-proBNP has a longer half-life and thus higher plasma concentration than BNP. It probably is cleared from plasma by renal excretion and possibly other unknown pathways.
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PMID:NT-ProBNP: the mechanism behind the marker. 1594 7

Regulatory volume decrease (RVD) following hyposmotic stimulation was studied in isolated turbot, Scophthalmus maximus, hepatocytes. Exposed to a reduced osmolality (from 320 to 240 mosm kg(-1)), cells first swelled and then exhibited a RVD. Volume regulation was significantly inhibited in presence of NPPB, 9-AC, acetazolamide, DIDS and barium. Taken together, these results could suggest that RVD operated via separate K+ and Cl- channels and probably Cl-/HCO3(-) exchanger in turbot hepatocytes. The K+/Cl- cotransporter could also be involved as furosemide and DIOA strongly inhibited the process whereas NEM, a K+/Cl- cotransporter activator, added under isosmotic conditions, led to cell shrinkage. RVD in turbot hepatocytes appeared also to depend on proteins p38 MAP kinase and tyrosine kinase but not on proteins ERK 1/2. Arachidonic acid and leukotrienes could also be involved since inhibition of synthesis of both these compounds by quinacrine and NDGA, respectively, inhibited the volume regulation. Likewise, Ca2+ has been proved to be an essential messenger as RVD was prevented in absence of Ca2+. Finally, this work provides bases for novel studies on cell volume regulation in marine teleosteans.
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PMID:Volume regulation following hyposmotic shock in isolated turbot (Scophthalmus maximus) hepatocytes. 1639 90

The cardiac hormone atrial natriuretic peptide (ANP) signals via interaction with a plasma membrane receptor, which has guanylyl cyclase (GC) activity and is referred to as GC-A. Desensitization of GC-A is thought to represent a physiologically important regulatory mechanism, but the signaling pathways implicated and cell type-specific effects are still poorly understood. Here we demonstrate that sustained exposure to either ANP itself or the bioactive lipid lysophosphatidic acid (LPA) elicits GC-A desensitization in MA-10 Leydig cells. Both reactions show similar kinetics and evoke equal decreases (by 40%) in GC-A hormone responsiveness. Homologous (ANP induced) desensitization, in which cGMP is generated as second messenger, is blocked by distinct cAMP-dependent protein kinase [protein kinase A (PKA)] inhibitors, H 89, and Rp-8-CPT-cAMPs, providing evidence that PKA mediates the reaction. Accordingly, the ANP/cGMP-elicited effects are mimicked by a cAMP analog, 8-bromo-cAMP. The LPA-induced (heterologous) desensitization is not blocked by PKA inhibition, indicating a different signaling pathway. LPA, but not ANP, enhances ERK phosphorylation and induces cell rounding together with a dramatic reorganization of actin filaments. Consistent with the identification of LPA receptor (LPA2 and LPA3) gene expression, the findings are indicative of LPA receptor-mediated reactions. This study demonstrates for the first time coexistence of homologous and heterologous desensitization of GC-A in the same cell type, reveals that these reactions are mediated by different pathways, and identifies a novel cross talk between phospholipid and natriuretic peptide signaling. The morphoregulatory activities exerted by LPA suggest a crucial role for Leydig cell physiology.
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PMID:Homologous and lysophosphatidic acid-induced desensitization of the atrial natriuretic peptide receptor, guanylyl cyclase-A, in MA-10 leydig cells. 1652 39

The effects of monocarboxylic acid-derived Cl(-) channel blockers on cardiac depolarization-activated K(+) currents were investigated. Membrane currents in rat ventricular myocytes were recorded using the whole-cell configuration of the patch-clamp technique. 5-Nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and niflumic acid (NFA) induced an outward current at 0 mV. Both NPPB and NFA failed to induce any current when used intracellularly or after K(+) in the bath and pipette solutions was replaced by equimolar Cs(+). Voltage pulse protocols revealed that NPPB and NFA enhanced the steady-state K(+) current but inhibited the transient outward K(+) current. Genistein, a tyrosine kinase (PTK) inhibitor, inhibited NPPB- and NFA-induced outward current. Another PTK inhibitor, lavendustin A, produced a comparable effect. In contrast, the inactive analogue of genistein, daidzein, was ineffective. Orthovanadate, a tyrosine phosphatase inhibitor, markedly slowed the deactivation of the outward current induced by NPPB and NFA. The protein kinase A (PKA) inhibitor H-89 inhibited NPPB-induced outward current at 0 mV. In contrast, the protein kinase C (PKC) inhibitor H-7 was without significant effect on the action of NPPB. Pretreatment of the myocytes with genistein or H-89 prevented the enhancing effect of NPPB. Increasing intracellular Cl(-) from 22 to 132 mm slightly reduced NPPB-induced outward current at 0 mV. These results demonstrate that the monocarboxylic acid-derived Cl(-) channel blockers NPPB and NFA enhance cardiac steady-state K(+) current, and suggest that the enhancing effect of the Cl(-) channel blockers is mediated by stimulation of PKA and PTK signalling pathways.
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PMID:Effects of monocarboxylic acid-derived Cl- channel blockers on depolarization-activated potassium currents in rat ventricular myocytes. 1730 47

Estrogen has been reported to prevent development of cardiac hypertrophy in female rodent models and in humans. However, the mechanisms of sex steroid action are incompletely understood. We determined the cellular effects by which 17beta-estradiol (E2) inhibits angiotensin II (AngII)-induced cardiac hypertrophy in vivo. Two weeks of angiotensin infusion in female mice resulted in marked hypertrophy of the left ventricle, exacerbated by the loss of ovarian steroid hormones from oophorectomy. Hypertrophy was 51% reversed by the administration of E2 (insertion of 0.1 mg/21-d-release tablets). The effects of E2 were mainly mediated by the estrogen receptor (ER) beta-isoform, because E2 had little effect in ERbeta-null mice but comparably inhibited AngII-induced hypertrophy in wild-type or ERalpha-null mice. AngII induced a switch of myosin heavy chain production from alpha to beta, but this was inhibited by E2 via ERbeta. AngII-induced ERK activation was also inhibited by E2 through the beta-receptor. E2 stimulated brain natriuretic peptide protein expression and substantially prevented ventricular interstitial cardiac fibrosis (collagen deposition) as induced by AngII. Importantly, E2 inhibited calcineurin activity that was stimulated by AngII, related to E2 stimulating the modulatory calcineurin-interacting protein (MCIP) 1 gene and protein expression. E2 acting mainly through ERbeta mitigates the important signaling by AngII that produces cardiac hypertrophy and fibrosis in female mice.
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PMID:Estrogen inhibits cardiac hypertrophy: role of estrogen receptor-beta to inhibit calcineurin. 1837 23

Although deoxycorticosterone acetate (DOCA)-salt hypertension is a volume dependent model of hypertension, it shows polyuria and natriuresis. It is expected that dysregulation of aquaporin water channels (AQPs) and sodium transporters associated with natriuretic peptide (NP) system may play an escape role in sodium retaining state. One week after left unilateral nephrectomy, rats were subcutaneously implanted with silastic DOCA (200 mg/kg) strips. Physiologic saline was supplied as a drinking water to all animals. 4 weeks after operation, the protein expression of AQPs, sodium transporters, and endopeptidase (NEP) was determined in the kidneys by semiquantitative immunoblotting and immunohistochemistry. The mRNA expression of NP system was determined by real-time polymerase chain reaction. The amount of urinary ANP excretion was measured by radioimmunoassay. In DOCA-salt rats, urine osmolality was decreased while urinary excretion of sodium was increased. The expression of AQP1-3 as well as that of alpha-1 subunit of Na,K-ATPase, NHE3, NKCC2 and NCC was decreased in the kidney. The mRNA expression of ANP, brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) was increased in the kidney. The expression of NEP was decreased, and urinary ANP excretion was increased. Downregulation of AQPs and sodium transporters may contribute to mineralocorticoid escape in DOCA-salt hypertension. Increased expression of natriuretic peptides associated with downregulation of NEP may play a role in natriuresis.
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PMID:Altered regulation of renal sodium transporters and natriuretic peptide system in DOCA-salt hypertensive rats. 1942 59

Farnesyl pyrophosphate synthase (FPPS), an essential enzyme in the mevalonate pathway, was reported to be upregulated in young spontaneously hypertensive rats (SHR) when compared with Wistar-Kyoto (WKY) rats, and this was accompanied by development of left ventricular hypertrophy. Five-week-old rats were daily gavaged with vehicle or an FPPS inhibitor (alendronate, 1 or 10 mg/kg) and blood pressures was monitored by the tail-cuff method every other week. Twelve weeks of alendronate treatment attenuated the left ventricular weight to body weight ratio (LVW/BW), hydroxyproline content, collagen deposition in the interstitia, and gene expression of atrial natriuretic peptide, B-type natriuretic peptide, and procollagen type I/III in the SHR left ventricle, all of which were significantly higher in SHRs than in WKY rats. Furthermore, long-term treatment with an FPPS inhibitor significantly reduced RhoA activation, ERK phosphorylation, and TGF-beta1 expression in the SHR left ventricle, all of which were upregulated more in SHRs than in WKY rats. In conclusion, chronic treatment with an FPPS inhibitor attenuates the development of cardiac hypertrophy and fibrosis, and the suppression of ERK1/2 phosphorylation and TGF-beta1 expression with inhibition of RhoA activation may be an important mechanism.
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PMID:Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats. 1980 Aug 72

The adult differentiated insulin-secreting pancreatic islet beta-cell experiences slow growth. This study shows that atrial natriuretic peptide (ANP) stimulates cell proliferation and [(3)H]thymidine incorporation in INS-1E glucose-sensitive rat beta-cell line cells and isolated rat islet DNA. In addition, cGMP, the second messenger of natriuretic peptide receptors (NPR) A and B, stimulated islet DNA biosynthesis. The NPR-A receptor was expressed in INS-1E cells and islets. ANP-stimulated INS-1E cell DNA biosynthesis was blocked by preincubation with LY294002 (50 microM), an inhibitor of phosphatidylinositol 3'-kinase (PI3K). An indicator of cell cycle progression, cyclin D2 mRNA was increased by 2- to 3-fold in ANP- or 8-Br-cGMP-treated INS-1E cells and islets, and these responses were inhibited by LY294002. ANP and 8-Br-cGMP stimulated the phosphorylation of Akt and Foxo1a in INS-1E cells and islets, and LY294002 inhibited these responses. In contrast, ANP reduced the levels of phospho-ERK in INS-1E cells. Pancreas duodenum homeobox-1 (PDX-1) is essential for pancreas development, insulin production, and glucose homeostasis, and ANP increased PDX-1 mRNA levels by 2- to 3-fold in INS-1E cells and islets. The levels of glucokinase mRNA in islets and INS-1E cells were also increased in response to ANP. The evidence suggests that pancreatic beta-cell NPR-A stimulation results in activation of a growth-promoting signaling pathway that includes PI3K/Akt/Foxo1a/cyclin D2. These data support the conclusion that the activation of Akt by ANP or 8-Br-cGMP promotes cyclin D2, PDX-1, and glucokinase transcription by phosphorylating and restricting Foxo1a activity.
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PMID:Atrial natriuretic peptide promotes pancreatic islet beta-cell growth and Akt/Foxo1a/cyclin D2 signaling. 1983 76


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