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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endostatin was suggested to be an antiangiogenic agent with the potential for clinical use in cancer therapy. Unfortunately, up to now no antiangiogenic effect was seen in clinical trials using this substance. The lack of response might be caused by an incomplete understanding of endostatin signaling. Endostatin is known to influence the vascular endothelial growth factor (VEGF) signaling pathway. It has been reported to bind to the VEGF receptor KDR directly and to decrease the phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 via the protein phosphatase 2A (PP2A). But so far no details of endostatin signaling with regard to NO downstream effectors have been revealed. In the present work the authors demonstrate that endostatin down-regulates the protein level of soluble guanylate cyclase (sGC) in endothelial cells of newly formed blood vessels in 5 day-old wounds (control: 62.5 +/- 33 vessels/mm2, endostatin: 9.2 +/- 3.2 vessels/mm2). This was confirmed in experiments with endothelial tubes of embryoid bodies and endothelial cells derived from embryonic stem cells (eESCs; control: 126 +/- 20, endostatin: 58 +/- 10). The decrease of sGC protein levels in response to endostatin was abolished after preincubation with the PP2A inhibitor okadaic acid. No alterations of sGC mRNA levels could be found under endostatin treatment in eESC. The authors conclude that endostatin affects VEGF signaling in endothelial cells by a post-transcriptional PP2A-dependent down-regulation of sGC protein levels.
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PMID:Endostatin down-regulates soluble guanylate cyclase (sGC) in endothelial cells in vivo: influence of endostatin on vascular endothelial growth factor (VEGF) signaling. 1641 Feb 24

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

Vascular endothelial growth factor-A (VEGF), which binds to both VEGF receptor-1 (Flt1) and VEGFR-2 (KDR/Flk-1), requires nitric oxide (NO) to induce angiogenesis in a cGMP-dependent manner. Here we show that VEGF-E, a VEGFR-2-selective ligand stimulates NO release and tube formation in human umbilical vein endothelial cells (HUVEC). Inhibition of phospholipase Cgamma (PLCgamma) with U73122 abrogated VEGF-E induced endothelial cell migration, tube formation and NO release. Inhibition of endothelial nitric oxide synthase (eNOS) using l-NNA blocked VEGF-E-induced NO release and angiogenesis. Pre-incubation of HUVEC with the soluble guanylate cyclase inhibitor, ODQ, or the protein kinase G (PKG) inhibitor, KT-5823, had no effect on angiogenesis suggesting that the action of VEGF-E is cGMP-independent. Our data provide the first demonstration that VEGFR-2-mediated NO signaling and subsequent angiogenesis is through a mechanism that is dependent on PLCgamma but independent of cGMP and PKG.
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PMID:VEGF-E activates endothelial nitric oxide synthase to induce angiogenesis via cGMP and PKG-independent pathways. 1672 9

Morphometric methodologies were developed and applied to investigate the patterns of vascular development in maternal (caruncular; CAR) and fetal (cotyledonary; COT) sheep placentas throughout the last two thirds of gestation. We also examined the expression levels of the major angiogenic factors and their receptors in CAR and COT sheep placentas. Although the vascularity of the CAR tissues increased continuously from Day 50 through Day 140 of pregnancy, those of the COT tissues increased at about twice the instantaneous rate (i.e., the proportionate increase/day) of the CAR. For CAR, vascularity increased 2-fold from Day 50 through Day 140 via relatively small increases in capillary number and 2- to 3-fold increases in capillary diameter. For COT, the increased vascularity resulted from a 12-fold increase in capillary number associated with a concomitant 2-fold decrease in capillary diameter. This large increase in fetal placental capillary number, which was due to increased branching, resulted in 6-fold increases in total capillary cross-sectional area and total capillary surface, per unit of COT tissue. Different patterns of expression of the mRNAs for angiogenic factors and their receptors were observed for CAR and COT. The dilation-like angiogenesis of CAR was correlated with the expression of vascular endothelial growth factor receptor-1 (FLT1), angiopoietin-2 (ANGPT2), and soluble guanylate cyclase (GUCY1B3) mRNAs. The branching-like angiogenesis of COT was correlated with the expression of vascular endothelial growth factor (VEGF), FLT1, angiopoietin-1 (ANGPT1), ANGPT2, and FGF2 mRNAs. Monitoring the expression of angiogenic factors and correlating the levels with quantitative measures of vascularity enable one to model angiogenesis in a spatiotemporal fashion.
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PMID:Placental growth throughout the last two thirds of pregnancy in sheep: vascular development and angiogenic factor expression. 1705 Aug 58

The objective of the present work was to study the effects of erythrocyte proteins phosphorylation in erythrocyte aggregation and deformability. Human whole blood samples were incubated in vitro in absent and in presence of the phosphorylation/dephosphorilation band 3 inhibitors and also with adenylyl cyclase, guanylate cyclase and PI3K inhibitors and the erythrocyte aggregation index (AIE) and deformability were assayed. The results show that when band 3 is phosphorylated in presence of a PTP inhibitor an increase in erythrocyte aggregation index is observed (p<0.0001). A partial dephosphorylation band 3 state, induced by PTK inhibitors, show a decrease in the erythrocyte aggregation index (p<0.002). However both manipulated states induced lower EAI values than blood samples aliquots controls. The guanylate cyclase and PI3-K inhibitors significantly decrease the erythrocyte aggregation index in relation with the control blood samples. Erythrocyte deformability in presence of all the inhibitors did not showed significant changes. PTP and PI3-K inhibitors showed a significantly increase in the plasma potassium concentrations not associated with EAI values. Methehemoglobin levels were increased significantly when guanylate cyclase inhibitor is present in the blood samples. In conclusion, the results suggest that erythrocyte aggregation index is dependent of the phosphorylated/dephosphorylated state of band 3.
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PMID:Modulation of erythrocyte hemorheological properties by band 3 phosphorylation and dephosphorylation. 1736 Oct 21

Ischemic preconditioning renders the heart resistant to infarction from ischemia/reperfusion. Over the past two decades a great deal has been learned about preconditioning's mechanism. Adenosine, bradykinin, and opioids act in parallel to trigger the preconditioned state and do so by activating PKC. While adenosine couples directly to PKC through the phospholipases, bradykinin and opioids do so through a complex pathway that includes in order: phosphatidylinositol 3-kinase (PI3-kinase), Akt, nitric oxide synthase, guanylyl cyclase, PKG, opening of mitochondrial K(ATP) channels, and activation of PKC by redox signaling. There are even differences between the opioid and bradykinin coupling as the former activates PI3-kinase through transactivation of the epidermal growth factor receptor while the latter has an unknown coupling mechanism. Protection stems from inhibition of formation of mitochondrial permeability transition pores early in reperfusion through activation of the survival kinases, Akt and ERK. These kinases are activated as a result of PKC somehow promoting signaling from adenosine A(2) receptors early in reperfusion. The survival kinases are thought to inhibit pore formation by phosphorylating GSK-3beta. The reperfused heart requires the support of the protective signals for only about an hour after which the ischemic injury is repaired and the signals are no longer needed.
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PMID:Signaling pathways in ischemic preconditioning. 1751 69

We have previously established an ovariectomized (OVX) ewe model to study how steroid removal and replacement affects uterine blood vessel and tissue growth. Using this model, endometrial expression of mRNA for 14 angiogenic factors (7 genes and their respective receptors) in caruncular (CAR) and intercaruncular (ICAR) endometrium were evaluated by quantitative real time RT-PCR at 0 (control), 2, 4, 8, 16, or 24 h after treating OVX ewes with an estradiol-17beta (E2) implant. In CAR and ICAR, compared to 0 h, the mRNA expression of vascular endothelial growth factor (VEGF), VEGF receptor (R)1, soluble guanylate cyclase (GUCY1B3; the R for nitric oxide [NO]), hypoxia inducible factor (HIF)1alpha, and placental growth factor (PlGF) increased by 4 h after E2-treatment, but basic fibroblast growth factor (FGF2), endothelial NO synthase (NOS3), angiopoietin (ANGPT)1, ANGPT2, ANGPT receptor Tie2 by 2 h after E2. Expression of mRNA for FGFR2 IIIc was increased at 2 h by E2-treatment in ICAR, but not in CAR. By contrast, expression of neuropilin (NP)1 mRNA was increased at 2 h in CAR, but not ICAR. The mRNA expression of VEGF, FGF2, HIF1 alpha, and PlGF was positively correlated with mRNA expression of NOS3, VEGFR1, and Tie2 suggesting some E2-stimulated interactions between these factors in promoting blood vessel growth. Thus, several major angiogenic factors and their receptors are increased within hours after E2-treatment, which indicates that E2 plays a role in regulation of angiogenesis in the uterus. By using the OVX ewe model, we may begin to understand the molecular basis of E2 effects on angiogenesis in the endometrium and, eventually, how angiogenesis is regulated in normal versus pathological conditions.
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PMID:Effects of estradiol-17beta on expression of mRNA for seven angiogenic factors and their receptors in the endometrium of ovariectomized (OVX) ewes. 1752 46

Ultrasonically induced effects of hematoporphyrin (HPD) on cell damage and membrane protein alteration of S180 isolated tumor cells in vitro were investigated, and the potential mechanisms of sonodynamic therapy (SDT) inhibiting tumor growth were discussed. Tumor cells suspended in air-saturated PBS (pH 7.2) were exposed to ultrasound at 1.8 MHz for up to 180s in the presence and absence of HPD. The viability of cells was determined by a trypan blue exclusion test. To estimate the damage effects of SDT on plasma membrane of tumor cells primarily, membrane integral proteins (EGFR, Ras, Fas, FasL) and cell proliferation associated enzymes (adenylate cyclase and guanylate cyclase) were checked with immunochemical methods. The results indicated that the intensity threshold for ultrasonically induced cell damage at 1.8 MHz was 3 W/cm2. At this condition, the expression of the integral proteins was obviously inhibited and the activity of the enzymes was decreased post ultrasound treatment in the presence of 20 microg/ml HPD. Loss of the membrane proteins and inactivity of AC and GC post SDT was time-dependent. This paper reveals SDT can cause the loss of tumor cell membrane integral proteins and inactivity of the enzymes associated with cell proliferation which might be attributed to a sonochemical activation mechanism. The mechanisms by that tumor growth is inhibited by SDT can be understood as that the growth signaling pathway is partially interdicted and the resistance of tumor cells to the specifically activated immune cells is weakened.
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PMID:Ultrasound exposure in the presence of hematoporphyrin induced loss of membrane integral proteins and inactivity of cell proliferation associated enzymes in sarcoma 180 cells in vitro. 1827 19

To evaluate the estrogenic potential of the phytoestrogen secoisolariciresinol diglycoside (SDG) found in linseed meal (LSM) on jejunal mass, cellular proliferation, vascularity, and expression of angiogenic factors and their receptors, 48 ovariectomized ewes (54.6 +/- 1.1 kg) were fed a diet containing 12.5% LSM for 0, 1, 7, or 14 d and implanted with estradiol-17beta (E(2)) for 0, 6, or 24 h before tissue collection. Angiogenic factors and receptors measured included vascular endothelial growth factor (VEGF), VEGF receptor-1 (FLT), VEGF receptor-2 (KDR), fibroblast growth factor (FGF), FGF receptor 2 IIIc (FGFR), angiopoietin (ANG)-1, ANG-2, ANG receptor (Tie-2), endothelial nitric oxide synthase (eNOS), and soluble guanylate cyclase (sGC). There was a LSM x E(2) interaction (P = 0.003) on the jejunal cellular proliferation index. Jejunal cellular proliferation increased (P < 0.002) in ewes not fed LSM and implanted with E(2) for 6 or 24 h compared with ewes implanted for 0 h but did not increase when LSM was fed for 1, 7, or 14 d. Neither feeding LSM nor implanting ewes with E(2) altered vascular area density (P > 0.75) or vascular surface area (P > 0.29) of the jejunal villi. Expression of mRNA for the angiogenic factors VEGF, FGF, FGFR, ANG-1, ANG-2, and Tie-2 were not altered (P > 0.33) by feeding LSM or implanting ewes with E(2). Implanting ewes with E(2) for 6 h increased (P = 0.04) eNOS expression compared with ewes implanted for 0 h. Feeding LSM and implanting ewes with E(2) interacted to alter mRNA expression of FLT (P = 0.04), KDR (P < 0.001), and sGC (P = 0.04). When LSM was fed for 1, but not 0, 7, or 14 d, expression of FLT mRNA decreased (P < 0.03) when ewes were implanted with E(2) for 24 h compared with ewes implanted for 0 or 6 h. Expression of KDR mRNA was suppressed in ewes fed LSM for 1 (P = 0.03) or 7 d (P = 0.0007) and implanted with E(2) for 24 h compared with ewes implanted for 0 h. When LSM was fed for 14 d, implanting ewes for 6 h increased (P = 0.04) KDR expression compared with ewes implanted for 0 h. Ewes fed LSM for 0 and 1 d experienced an increase in sGC mRNA expression when implanted for 6 h (P = 0.001) compared with ewes implanted for 0 h. When implanted for 24 h, levels were similar (P = 0.80) to those observed when ewes were implanted for 0 h. Expression of sGC was not altered by E(2) when LSM was fed for 1, 7, or 14 d (P > 0.11). The impacts of E(2) and LSM on nutrient uptake and growth during physiologically important time points are unknown.
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PMID:Impacts of linseed meal and estradiol-17beta on mass, cellularity, angiogenic factors, and vascularity of the jejunum. 1856 19

Although much has been learned about the role of the amygdala in Pavlovian fear conditioning, relatively little is known about the signaling pathway involved in the acquisition of an active avoidance reaction. The aim of this study is to investigate the potentiating effects of the NO-guanylate cyclase activator YC-1 on learning and memory of shuttle avoidance test in rats. YC-1 enhanced the induction of long-term potentiation (LTP) in amygdala through NO-cGMP-PKG-ERK pathway and the increase of BDNF expression. The Western blot and PCR methods were used to examine the signaling pathways involved in fear memory. It was found that YC-1 increased the avoidance responses during learning period and the memory retention lasted longer than one week. The enhancement of learning behavior by YC-1 was antagonized by intracerebroventricular injection of NOS inhibitor l-NAME, PKG inhibitor Rp-8-Br-PET-cGMPS and MEK inhibitor PD98059, indicating that NO-cGMP-PKG and ERK pathways are involved in the learning potentiating action of YC-1. In addition, YC-1 increased the activation of ERK and Akt 30 min after Day-1 training in amygdala. YC-1 also potentiated the expression of BDNF and CREB in response to fear memory test. Taken together, these findings suggest that NO-cGMP-PKG-ERK signaling pathway is involved in the action of YC-1 in enhancing the fear memory.
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PMID:Enhancement of active shuttle avoidance response by the NO-cGMP-PKG activator YC-1. 1859 Jul 24


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