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)

Chlamydia pneumoniae is a respiratory pathogen that has been linked to cardiovascular disease. We have recently shown that C. pneumoniae activates platelets, leading to oxidation of low-density lipoproteins. The aim of the present study was to evaluate the inhibitory effects of different pharmacological agents on platelet aggregation and secretion induced by C. pneumoniae. Platelet interaction with C. pneumoniae was studied by analyzing platelet aggregation and ATP-secretion with Lumi-aggregometry. Platelet aggregation and ATP-secretion induced by C. pneumoniae was markedly inhibited by the NO-donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), an effect that was counteracted by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Pre-treatment of platelets with the 12-lipoxygenase (12-LOX) inhibitors cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC) and 5,6,7-trikydroxyflavone (baicalein) completely blocked the activation, whereas the cyclooxygenase (COX) inhibitors 2-acetyloxybenzoic acid (aspirin) and (8E)-8-[hydroxy-(pyridin-2-ylamino)methylidene]-9-methyl-10,10-dioxo-10$l;(6)thia-9-azabicyclo[4.4.0]deca-1,3,5-trien-7-one (piroxicam) had no inhibitory effects. Opposite to C. pneumoniae-induced activation, platelets stimulated by collagen were inhibited by the COX-inhibitors but were unaffected by the 12-LOX-inhibitors. The platelet activating factor (PAF) antagonist Ginkgolide B blocked the C. pneumoniae-induced platelet activation, whereas the responses to collagen were unaffected. Furthermore, the P2Y1 and P2Y12 purinergic receptor antagonists 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate (MRS2179) and N(6)-(2-methyl-thioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene-ATP (cangrelor) inhibited the aggregation and secretion caused by C. pneumoniae. It is well-known that the efficacy of COX inhibitors in the prevention and treatment of cardiovascular disease varies between different patients, and that patients with low responses to aspirin have a higher risk to encounter cardiovascular events. The findings in this study showing that platelets stimulated by C. pneumoniae are unaffected by COX inhibitors but sensitive to 12-LOX inhibitors, may thus be of importance in future management of atherosclerosis and thrombosis.
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PMID:Platelet activation triggered by Chlamydia pneumoniae is antagonized by 12-lipoxygenase inhibitors but not cyclooxygenase inhibitors. 1745 68

C-type natriuretic peptide (CNP) stimulates the differentiation and inhibits the proliferation of osteoblastic lineage cells. In this study, we examined whether the effects of CNP on osteoblastic functions change with aging using calvarial osteoblast-like cells from 25-week-old (young) and 120-week-old (aged) rats. CNP inhibited DNA synthesis and stimulated collagen synthesis and mineralized bone nodule formation. These effects were less pronounced in aged rat cells, suggesting the age-related attenuation of CNP-induced signaling. They were also blocked by the treatment of young rat cells with KT5823, a protein kinase G (PKG) inhibitor, but not by the treatment of aged rat cells with KT5823. CNP stimulated cGMP production in young rat cells, but not in aged rat cells. Natriuretic peptide receptor (NPR)-B, which has a guanylyl cyclase activity domain, and NPR-C, which has no enzyme activity domain, were predominantly expressed in young and aged rat cells, respectively. C-ANF, an NPR-C agonist, mimicked the effects of CNP on the proliferation and differentiation of aged rat cells; these effects were inhibited by the treatment with pertussis toxin (PTX), a Gi protein inhibitor. CNP and C-ANF evoked intracellular levels of inositol-1,4,5-triphosphate and Ca(2+), which are markers for phospholiase C (PLC) activation, in aged rat cells, and the effects of these two peptides were also blocked by the treatment with PTX. From these results, we concluded that CNP acts as a positive regulator of bone formation by osteoblasts and that the signaling pathway for CNP is switched from NPR-B/cGMP/PKG to NPR-C/G(i) protein/PLC with aging.
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PMID:The receptor attributable to C-type natriuretic peptide-induced differentiation of osteoblasts is switched from type B- to type C-natriuretic peptide receptor with aging. 1756 43

Nitric oxide ((.-)NO) is an important physiological signaling molecule and potent vasodilator. Recently, we have shown abnormal (.-)NO metabolism in the plasma of patients with systemic sclerosis (SSc), a disease that features excessive collagen overproduction as well as vascular dysfunction. The current study investigates the effects of (.-)NO and peroxynitrite (ONOO(-)) on secretion of type I collagen by SSc dermal fibroblasts, compared with those from normal dermal fibroblasts (CON) and a dermal fibroblast cell line (AG). Dermal fibroblasts were incubated with (.-)NO donors (SNP, DETA-NONOate) with or without the antioxidant ascorbic acid, or ONOO(-) for 24-72 h. In CON and AG fibroblasts, type I collagen was dose dependently decreased by SNP or DETA-NONOate. However, (.-)NO had no effect in SSc fibroblasts. Furthermore, the inhibition of collagen synthesis by (.-)NO was reversed by ascorbic acid and was not affected by 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanyl cyclase, or 8-bromoguanosine cyclic 3',5'-monophosphate, a cGMP agonist. SNP also showed a significant up-regulation of matrix metalloproteinase-1 (MMP-1) protein and activity levels, an essential collagenase involved in collagen degradation, in the AG fibroblasts. Additionally, (.-)NO-treated fibroblasts had lower prolyl hydroxylase activity, an enzyme important in the post-translational processing of collagen, while there was no effect on total protein levels. There were no significant effects on type I collagen levels when dermal fibroblasts were treated with ONOO(-). Taken together, ()NO inhibits collagen secretion in normal dermal fibroblasts but regulation is lost in SSc fibroblasts, while ONOO(-) itself is ineffective. (.-)NO inhibition of collagen was by cGMP-independent regulatory mechanisms and in part may be due to up-regulation of MMP-1 and/or inhibition of prolyl hydroxylase. These differences may contribute to the observed pathology of SSc.
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PMID:Effect of nitric oxide and peroxynitrite on type I collagen synthesis in normal and scleroderma dermal fibroblasts. 1760 34

Atrial natriuretic peptide, besides its role in the regulation of volume homeostasis, has been noted to exert cytoprotective effects in several cell types from hypoxia. The present study was performed to explore the effect of ANP on high glucose-activated transforming growth factor-beta1 (TGF-beta1), Smad and collagen synthesis in renal proximal epithelial cells. Cultured NRK-52E cells were divided into five groups: (1) normal glucose (5.5 mM), (2) high glucose (35 mM), (3) D-mannitol (29.5 mM), (4) high glucose plus ANP (10(-6)-10(-9) M), and (5) high glucose plus ANP (10(-6) M) and guanylate cyclase inhibitor LY83583 (10(-7) M) groups. Messenger RNA levels of TGF-beta1, Smad2, and collagens were measured by RT-PCR. ELISA, immunocytochemistry and Western blotting were used to detect protein levels of TGF-beta1, Smad2, phospho-Smad 2/3 and collagen type 1. We found high glucose to significantly increase mRNA levels of TGF-beta1, Smad 2, collagen types I and III and protein levels of TGF-beta1, phospho-Smad 2/3 and collagen type 1, but mannitol did not affect their expression. The addition of ANP significantly attenuated high glucose-enhanced mRNA and protein levels of TGF-beta1, Smad and collagens. LY83583 blocked the influence of ANP on high glucose-activated TGF-beta1, Smad and collagen synthesis. This is the first study to demonstrate that activation of TGF-beta1, Smad and collagen synthesis stimulated by high glucose can also be inhibited by exogenous ANP in renal tubular epithelial cells.
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PMID:Atrial natriuretic peptide attenuates high glucose-activated transforming growth factor-beta, Smad and collagen synthesis in renal proximal tubular cells. 1796 May 94

Mineralocorticoid receptor (MR) blockers attenuate cardiac remodeling in experimental models of heart failure, myocardial infarction and pressure-overload, in which the renin-angiotensin-aldosterone system is activated. Mice lacking the gene encoding guanylyl cyclase-A (GC-A), a common receptor for atrial and brain natriuretic peptide (ANP and BNP, respectively), show marked cardiac hypertrophy and fibrosis, which are almost completely inhibited by both genetic and pharmacological blockade of type 1 angiotensin II receptors. However, the effect of eplerenone, a specific MR blocker, on cardiac remodeling in GC-A knockout (GC-A KO) mice remains unknown. Male 12-week-old GC-A KO mice were assigned to control, eplerenone and hydralazine groups (n=6-7/group). Treatment with eplerenone at a dose of 100 mg/kg body weight/d reduced heart weight/body weight ratios, interstitial fibrosis and blood pressure to levels similar to those seen in wild type mice, in association with reduced transcription of atrial natriuretic peptide, brain natriuretic peptide, transforming growth factor-beta1, collagen I and collagen III. Although hydralazine (5 mg/kg body weight/d) exerted a similar effect on blood pressure, it did not inhibit the cardiac remodeling in GC-A KO mice. In conclusion, eplerenone attenuates cardiac remodeling in GC-A KO mice, most likely in a blood pressure-independent manner, which suggests that signaling downstream of MR is involved in the ventricular remodeling of GC-A KO mice.
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PMID:The specific mineralocorticoid receptor blocker eplerenone attenuates left ventricular remodeling in mice lacking the gene encoding guanylyl cyclase-A. 1871 75

Angiotensin II plays a key role in the development of cardiac hypertrophy. The contribution of the angiotensin II type 1 receptor (AT1) in angiotensin II-induced cardiac hypertrophy is well established, but the role of AT2 signaling remains controversial. Previously, we have shown that natriuretic peptide receptor/guanylyl cyclase-A (GCA) signaling protects the heart from hypertrophy at least in part by inhibiting AT1-mediated pro-hypertrophic signaling. Here, we investigated the role of AT2 in cardiac hypertrophy observed in mice lacking GCA. Real-time RT-PCR and immunoblotting approaches indicated that the cardiac AT2 gene was overexpressed in GCA-deficient mice. Mice lacking AT2 alone did not exhibit an abnormal cardiac phenotype. In contrast, GCA-deficiency-induced increases in heart to body weight ratio, cardiomyocyte cross-sectional area, and collagen accumulation as evidenced by van Gieson staining were attenuated when AT2 was absent. Furthermore, the up-regulated cardiac expression of hypertrophy-related genes in GCA-null animals was also suppressed. Pharmacological blockade of AT2 with PD123319 similarly attenuated cardiac hypertrophy in GCA-deficient mice. In addition, whereas the AT1 antagonist olmesartan attenuated cardiac hypertrophy in GCA-deficient mice, this treatment was without effect on cardiac hypertrophy in GCA/AT2-double null mice, notwithstanding its potent antihypertensive effect in these animals. These results suggest that the interplay of AT2 and AT1 may be important in the development of cardiac hypertrophy. Collectively, our findings support the assertion that GCA inhibits AT2-mediated pro-hypertrophic signaling in heart and offer new insights into endogenous cardioprotective mechanisms during disease pathogenesis.
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PMID:Guanylyl cyclase-A inhibits angiotensin II type 2 receptor-mediated pro-hypertrophic signaling in the heart. 1937 6

Cardiac fibrosis is a hallmark of cardiovascular remodeling associated with hypertension. The purpose of this study was to explore the effect and mechanism of soluble guanylate cyclase (sGC) stimulator BAY 41-2272, leading to intracellular cyclic guanosine monophosphate (cGMP) elevation, on the remodeling process induced by pressure overload. Seven-week-old male Wistar rats with hypertension induced by suprarenal aortic constriction (AC) were treated orally with 2 mg kg(-1) day(-1) of BAY 41-2272 for 14 days. BAY 41-2272 had no effects on blood pressure, but decreased AC-induced collagen accumulation in the left ventricle (LV), inhibiting the number of myofibroblasts and gene expressions of transforming growth factor-beta1 and type 1 collagen. In addition, the antifibrotic action of BAY 41-2272 was accompanied by reducing AC-induced angiotensin-converting enzyme (ACE) mRNA and its enzymatic activity, and angiotensin II concentration in LV. In cultured cardiac fibroblasts, BAY 41-2272 inhibited ACE synthesis and myofibroblast transformation, accompanied by elevating the intracellular cGMP concentration. These results suggest that sGC stimulator BAY 41-2272 might be effective to reduce fibrosis in hypertensive heart disease by attenuating angiotensin II generation through myofibroblast transformation.
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PMID:Pressure-independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure-overloaded rat heart. 1942 80

Collagen-induced platelet activation is a complex process involving multiple signaling pathways. The role(s) of MAP kinases (ERKs and p38(MAPK)) are unclear, although at high, but not low, collagen concentrations p38(MAPK) is involved in cPLA(2)-mediated arachidonic acid release, prior to thromboxane generation. Cyclic nucleotides are conventionally regarded as mediators of platelet inhibition. However recent studies suggested a role for cGMP early in a MAP kinase pathway in platelet activation. In the current study the roles and relationships of MAP kinases, cyclic nucleotides and cPLA(2) in platelet activation by low-dose collagen and a thromboxane analogue (U46619) have been evaluated. Stimulants of neither adenylate cyclase (PGI(2)) nor guanylate cyclase (NaNP) alone had any effect on the basal phosphorylation of either MAP kinase. PGI(2) inhibited ERK/p38(MAPK) phosphorylation in response to both agonists which was unaffected by a cPLA(2) inhibitor (AACOCF(3)). NaNP inhibited collagen-induced ERK/p38(MAPK) phosphorylation, which was enhanced by AACOCF(3) and reversed by a guanylate cyclase inhibitor (ODQ). However NaNP had no effect on U46619-induced p38(MAPK) phosphorylation. Thus adenylate cyclase activation inhibits low-dose collagen-induced MAP kinase phosphorylation both prior, and distal, to thromboxane release. The study also supports an inhibitory, rather than stimulatory, role for guanylate cyclase in platelet signaling.
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PMID:Cyclic nucleotides inhibit MAP kinase activity in low-dose collagen-stimulated platelets. 1959 42

In order to investigate the effects of vasonatrin peptide (VNP), a novel man-made natriuretic peptide, on liver fibrosis, mice received carbon tetrachloride (CCl(4)) injection for 12weeks and with or without VNP treatment during the last 6weeks. Hematoxylin-eosin (HE) staining and Sirius red staining were performed to evaluate the status of liver fibrosis. After treatment of VNP, DNA and collagen synthesis of cultured HSC-T6 hepatic stellate cells were assessed by [(3)H]-thymidine and [(3)H]-proline incorporation, respectively. Additionally, involved signaling pathway was identified by radioimmunoassay to detect the levels of intracellular cGMP and by mimicking experiments using 8-br-cGMP (a membrane-permeable cGMP analog). Also, blocking experiments were performed using HS-142-1, an antagonist of guanylyl cyclase-coupled natriuretic peptide receptor (NPR), or KT-5823, the cGMP-dependent protein kinase (PKG) inhibitor. As a result, VNP markedly alleviated CCl(4)-induced liver fibrosis in mice. In vitro, HSC-T6 cells demonstrated a dose-dependent reduction of DNA and collagen synthesis in the presence VNP. In addition, VNP significantly increased the intracellular levels of cGMP. These effects of VNP were mimicked by 8-br-cGMP, although inhibited by HS-142-1 or KT-5823. Taken together, VNP ameliorates liver fibrosis by inhibiting collagen production from hepatic stellate cells via guanylyl cyclase-coupled NPR/cGMP/PKG pathway, indicating that VNP might be a new effective reagent in the treatment of liver fibrosis.
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PMID:Protecting effects of vasonatrin peptide against carbon tetrachloride-induced liver fibrosis. 2061 96

Increases in [cyclic-3',5'-GMP] in aspirin-treated platelet-rich plasma and washed platelet preparations resulted from stimulation by all excitatory agonists tested, and by other agents which induced aggregate formation. The maximal increase observed was approximately 4-fold above the resting level. The increase in [cyclic-3',5'-GMP] correlated closely in both time-, and agonist dose-dependence with aggregation as measured by an increase in light transmittance. It was delayed in time, and occurred at a higher agonist concentration, than the initial phase of aggregation as measured by loss of single platelets. The extent of increase in [cyclic-3',5'-GMP] was independent of the signal transduction pathway used by the agonist/agent. Inhibition of aggregation by removal of Ca(2+), failure to induce contact, addition of antibodies or antagonists to the glycoprotein IIb/IIIa complex or the presence of an inhibitory agonist such as PGI(2) prevented the increase in [cyclic-3',5'-GMP]. Contact with collagen fibrils causing adhesion to this matrix, or aggregate formation induced by ristocetin or by certain lectins also caused an increase in [cyclic-3',5'-GMP]. Contact of platelets either with other platelets or with a matrix therefore results in stimulation of guanylate cyclase. The mechanism responsible for such stimulation remains unclear but does not appear simply to be attributable to activation of nitric oxide synthase by Ca(2+).
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PMID:Platelet-Platelet Contact is Required to Observe Guanylate Cyclase Activation in Stimulated Platelets. 2104 59


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