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)

In the vicinity of an acute inflammatory response both cellular and non-cellular elements may interact to modify the overall response. Evidence suggests that leukocytes may play an active role in the modulation of platelet function and vice-versa. This interaction may be abnormal in certain pathological states. Neutrophils have been found to alter platelet behaviour by several mechanisms. These include transcellular metabolism of eicosanoids. Neutrophils utilize platelet-derived arachidonate to increase leukotriene synthesis. Other arachidonate metabolites result from platelet-neutrophil interaction and these differ quantitatively and qualitatively from those arising from either cell-type alone. Another mechanism is the release of a nitric oxide-like factor by neutrophils. Nitric oxide inhibits platelet adhesion and aggregation via guanylate cyclase stimulation. Neutrophils, under different conditions, are potent inducers of platelet calcium flux, aggregation and secretion. This activity is mediated by a neutrophil-derived protease, most likely to be cathepsin G. The interaction of platelets with neutrophils may help to explain some of the pathophysiological events associated with different clinical states.
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PMID:Platelet-neutrophil interactions: their significance. 163 10

This study investigates how exercise training affects Oxidized LDL (Ox-LDL) mediated-platelet activation. Five-week-old male Wistar rats were assigned to either control or trained groups. Trained rats were treadmill-trained for 10 weeks after familiarization. The following measurements were taken in both control and trained groups: Ox-LDL-mediated platelet aggregability and [Ca2+]i, plasma and platelet-derived nitric oxide (NO) metabolite (nitrite plus nitrate) levels, and antiaggregating activity of NO derived from endothelial cells. Based on those measurements, major findings in this study can be summarized as follows: 1) the trained group had a higher plasma -NO metabolite level than the control group; 2) the trained group had a lower platelet aggregability and [Ca2+]i elevation and a higher platelet derived-NO metabolite level than the control group; 3) the trained group had lower Ox-LDL-potentiated platelet aggregability and [Ca2+]i elevation and Ox-LDL-attenuated NO metabolite in platelet than the control group; 4) treating the platelet with L-arginine inhibited Ox-LDL-potentiated platelet activation in both control and trained groups; 5) Ox-LDL enhances platelet aggregation directly although impairing NO bioactivity but not guanylate cyclase activity in both control and trained groups. Results in this study demonstrate that exercise training decreases Ox-LDL-potentiated platelet activation most likely by enhancing platelet-derived NO release.
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PMID:Effect of exercise training on oxidized LDL-mediated platelet function in rats. 1074 61

Vascular endothelial cell growth factor (VEGF) is essential for angiogenesis. Atrial natriuretic peptide (ANP) inhibits the production of VEGF, but whether this important vascular peptide also inter- rupts VEGF signaling to angiogenesis is unknown. In cultured bovine aortic endothelial cells, VEGF significantly stimulated extracellular signal-regulated protein kinase activity and phosphorylation, which was inhibited 60% by coincubation with ANP or a natriuretic peptide clearance receptor specific ligand (NPRC), C-type NAP-(4-23) [C-ANP-(4-23)]. VEGF also stimulated c-Jun N-terminal kinase (JNK) and p38 activities/phosphorylation that were prevented by the two natriuretic peptides (NP). A specific NP guanylate cyclase (GC) receptor antagonist, HS-142-1, blocked the actions of ANP [but not those of C-ANP-(4-23)], supporting the involvement of both GC and NPRC receptors. VEGF and expression of constituitively active JNK each stimulated the synthesis of cyclin D1 and increased the activity of the cyclin-dependent kinase-4, which was inhibited 55% by ANP. VEGF induced endothelial cell proliferation and migration, which was significantly blocked by NP or by expressing a dominant negative JNK-1. VEGF stimulated human microvascular endothelial cells to form capillary tubes, which was significantly inhibited by expressing dominant negative JNK-1 and by NP. Therefore, VEGF induction of critical steps in angiogenesis is enhanced through JNK activation. The actions are significantly prevented by NP, which act through both the NPRC and GC receptors to block growth factor signaling. Thus, NP are candidate antiangiogenesis factors that inhibit both the synthesis and function of VEGF.
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PMID:Natriuretic peptides suppress vascular endothelial cell growth factor signaling to angiogenesis. 1125 Sep 39

Nitric oxide (NO) was originally discovered as a vasodilator product of the endothelium. Over the last 15 years, this vascular mediator has been shown to have important antiplatelet actions as well. By activating guanylyl cyclase, inhibiting phosphoinositide 3-kinase, impairing capacitative calcium influx, and inhibiting cyclooxygenase-1, endothelial NO limits platelet activation, adhesion, and aggregation. Platelets are also an important source of NO, and this platelet-derived NO pool limits recruitment of platelets to the platelet-rich thrombus. A deficiency of bioactive NO is associated with arterial thrombosis in animal models, individuals with endothelial dysfunction, and patients with a deficiency of the extracellular antioxidant enzyme glutathione peroxidase-3. This enzyme catalyzes the reduction of hydrogen and lipid peroxides, which limits the availability of these reactive oxygen species to react with and inactivate NO. The complex biochemical reactions that underlie the function and inactivation of NO in the vasculature represent an important set of targets for therapeutic intervention for the prevention and treatment of arterial thrombotic disorders.
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PMID:Nitric oxide insufficiency, platelet activation, and arterial thrombosis. 1132 66

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

Nitric oxide (NO) is known to modulate platelet adhesion and aggregation, which are both mediated by fibrinogen receptor glycoprotein (GP)IIb/IIIa. To investigate effects of NO on GPIIb/IIIa activation and inactivation, platelets were exposed to NO donor 3-morpholino-sydnonimine (SIN-1) before and after stimulation with different agonists: thromboxane analog U-46619, epinephrine, adenosine diphosphate, human a-thrombin, and phorbol-12-myristate-13-acetate (0.02 micromol/l). (1) Flow cytometry analysis of SIN-1-pre-incubated samples using PAC-1 monoclonal antibody revealed an inhibition of receptor activation by 80.9 +/- 1.2, 71.3 +/- 1.8, 56 +/- 4.9, 87 +/- 3.4, and 56 +/- 5% (mean +/- SEM, relative to baseline). (2) Administration of SIN-1 after stimulation reversed receptor activation by 55 +/- 5.2, 56 +/- 2.0, 53 +/- 5.4, 42 +/- 4.3, and 44 +/- 5%, respectively. With 0.1 micromol/l phorbol-12-myristate-13-acetate, GPIIb/IIIa activation was irreversible. (3) SIN-1 effects could completely be blocked by equimolar addition of guanylyl cyclase inhibitor 1H(1,2,4)oxadiazolo(4,3-alpha)quinoxalin-1-on. (4) Spontaneous receptor closure after activation with human alpha-thrombin and adenosine diphosphate was not due to platelet-derived NO; SIN-1, however accelerated spontaneous receptor inactivation. (5) SIN-1-inactivated receptors still responded to stimulation. In conclusion, SIN-1 or NO modulates GPIIb/IIIa conformational change in vitro via guanosine 3',5'-monophosphate-dependent pathways. Whereas spontaneous receptor inactivation may be enhanced by exogenous NO, platelet-derived NO is not involved in receptor inactivation.
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PMID:Inactivation of platelet glycoprotein IIb/IIIa receptor by nitric oxide donor 3-morpholino-sydnonimine. 1294 73

Malignant gliomas, most of which show an elevated level of vascular endothelial cell growth factor (VEGF) expression, are well known for their hyper-vascularity. One of the possible inducers of VEGF in tumor cells is nitric oxide (NO), which is synthesized by NO synthase and stimulates soluble guanylate cyclase (GC) in tumor cells. Here, we report that 2 of 9 human glioma cell lines, CCF-STTG1 and U-87MG, overproduced cyclic GMP (cGMP) and showed increased expression of both or either subunits of soluble GC1, GUCY1A3 and GUCY1B3. Transfection of antisense GUCY1A3 or GUCY1B3 into these two glioma cell lines markedly reduced the content of cGMP and expression of VEGF. The angiogenic activity in vitro was subsequently inhibited, which was determined by induction of HUVEC cell growth. Furthermore, subcutaneous tumor formation by U-87MG cells in nude mice was dramatically suppressed to less than 0.05% in volume by transfection of either antisense GUCY1A3 or antisense GUCY1B3, which was accompanied by the significant decrease in vascular index to about 10%. These findings demonstrate that cGMP is an upstream mediator of VEGF expression in glioma cells and that soluble guanylate cyclases could be the target molecules for controlling neo-vascularization in a subset of human malignant gliomas.
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PMID:Inhibition of angiogenesis in human glioma cell lines by antisense RNA from the soluble guanylate cyclase genes, GUCY1A3 and GUCY1B3. 1520 57

Thrombosis and inflammation are intricately linked in several major clinical disorders, including disseminated intravascular coagulation and acute ischemic events. The damage-associated molecular pattern molecule high-mobility group box 1 (HMGB1) is upregulated by activated platelets in multiple inflammatory diseases; however, the contribution of platelet-derived HMGB1 in thrombosis remains unexplored. Here, we generated transgenic mice with platelet-specific ablation of HMGB1 and determined that platelet-derived HMGB1 is a critical mediator of thrombosis. Mice lacking HMGB1 in platelets exhibited increased bleeding times as well as reduced thrombus formation, platelet aggregation, inflammation, and organ damage during experimental trauma/hemorrhagic shock. Platelets were the major source of HMGB1 within thrombi. In trauma patients, HMGB1 expression on the surface of circulating platelets was markedly upregulated. Moreover, evaluation of isolated platelets revealed that HMGB1 is critical for regulating platelet activation, granule secretion, adhesion, and spreading. These effects were mediated via TLR4- and MyD88-dependent recruitment of platelet guanylyl cyclase (GC) toward the plasma membrane, followed by MyD88/GC complex formation and activation of the cGMP-dependent protein kinase I (cGKI). Thus, we establish platelet-derived HMGB1 as an important mediator of thrombosis and identify a HMGB1-driven link between MyD88 and GC/cGKI in platelets. Additionally, these findings suggest a potential therapeutic target for patients sustaining trauma and other inflammatory disorders associated with abnormal coagulation.
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PMID:Platelet-derived HMGB1 is a critical mediator of thrombosis. 2655 81

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