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:2.7.11.12 (PKG)
2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acclimatization to chronic hypoxia involves numerous compensatory changes in many tissues, including blood vessels. The present data demonstrate that in addition to well-documented changes in contractility, chronic hypoxia also produces important changes in the mechanisms mediating endothelium-dependent vasodilatation. At the level of the endothelium, hypoxia attenuates endothelial release of NO and this appears to be mediated through reductions in eNOS specific activity; chronic hypoxia has little effect on eNOS abundance. In contrast, chronic hypoxia depresses the abundance of sGC, which functions as the downstream vascular receptor for NO released from the endothelium. The decreased abundance of sGC produced by chronic hypoxia occurs without changes in sGC specific activity and results in decreased rates of NO-induced cGMP synthesis. Nonetheless, the vasodilator efficacy of NO is enhanced in hypoxic arteries, which suggests that mechanisms downstream from sGC are upregulated by hypoxia. Consistent with this view, chronic hypoxia significantly depresses PDE activity, which serves to prolong cGMP half-life and enhance its vasodilator effects. It remains possible that chronic hypoxia may also enhance PKG activity and/or the abundance of its substrates; this possibility remains a promising topic for future investigation. Overall, it is important to recognize that the mechanisms of adaptation to chronic hypoxia identified in the present study may be somewhat unique to adult carotid arteries. Adaptive responses to chronic hypoxia can vary considerably between small and large arteries, and also between immature and adult arteries . Still, the present data clearly demonstrate that both the endothelium and vascular smooth muscle of major arteries are profoundly influenced by chronic hypoxia, and thereby participate fully in whole-body adaptation to reduced oxygen availability.
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PMID:Chronic hypoxia modulates endothelium-dependent vasorelaxation through multiple independent mechanisms in ovine cranial arteries. 1692 75

Thromboxane (TX) A(2) plays a central role in hemostasis, regulating platelet activation status and vascular tone. We have recently established that the TP beta isoform of the human TXA(2) receptor (TP) undergoes rapid, agonist-induced homologous desensitization of signalling largely through a G protein-coupled receptor kinase (GRK) 2/3-dependent mechanism with a lesser role for protein kinase (PK) C. Herein, we investigated the mechanism of desensitization of signalling by the TP alpha isoform. TP alpha undergoes profound agonist-induced desensitization of signalling (intracellular calcium mobilization and inositol 1,4,5 trisphosphate generation) in response to the TXA(2) mimetic U46619 but, unlike that of TP beta, this is independent of GRKs. Similar to TP beta, TP alpha undergoes partial agonist-induced desensitization that occurs through a GF 109203X-sensitive, PKC mechanism where Ser(145) within intracellular domain (IC)(2) represents the key phospho-target. TP alpha also undergoes more profound sustained PKC- and PKG-dependent desensitization where Thr(337) and Ser(331), respectively, within its unique C-tail domain were identified as the phospho-targets. Desensitization was impaired by the nitric oxide synthase (NOS), soluble guanylyl cyclase (sGC) and PKG inhibitors L-NAME, LY 83583 and KT5823, respectively, indicating that homologous desensitization of TP alpha involves nitric oxide generation and signalling. Consistent with this, U46619 led to rapid phosphorylation/activation of endogenous eNOS. Collectively, data herein suggest a mechanism whereby agonist-induced PKC phosphorylation of Ser(145) partially and transiently impairs TP alpha signalling while PKG- and PKC-phosphorylation at both Ser(331) and Thr(337), respectively, within its C-tail domain profoundly desensitizes TP alpha, effectively terminating its signalling. Hence, in addition to the agonist-mediated PKC feedback mechanism, U46619-activation of the NOS/sGC/PKG pathway plays a significant role in inducing homologous desensitization of TP alpha.
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PMID:Homologous desensitization of signalling by the alpha (alpha) isoform of the human thromboxane A2 receptor: a specific role for nitric oxide signalling. 1746 90

Experiments were designed to elucidate the involvement of nitric oxide (NO) in the antihyperalgesic effect induced by the activation of peripheral mu-opioid receptors on osteosarcoma-induced thermal hyperalgesia in mice. Since this pathway has previously been shown to be involved in the antihyperalgesic effect induced by some drugs--including opiates--on inflammatory pain, experiments were also performed in inflamed mice. The intraplantar administration of loperamide (15 microg) abolishes the thermal hyperalgesia that appears 4 weeks after the intratibial inoculation of NCTC 2472 cells in C3H/HeJ mice. The blockade of this effect by coadministering a peripheral opioid receptor antagonist (naloxone methiodide), a nitric oxide synthase (NOS) inhibitor (L-NMMA), a soluble guanylyl cyclase inhibitor (ODQ), a PKG inhibitor (KT-5823) or a K(+)(ATP)-channel blocker (glibenclamide) shows the involvement of a NO/cGMP/K(+)(ATP)-channel pathway. Accordingly the administration of loperamide produced, in osteosarcoma-bearing mice, an increase in the concentrations of NO metabolites, nitrites and nitrates, extracted from paws. The selective inhibitor of eNOS L-NIO, but not the inhibitors of nNOS (N-omega-propyl-L-arginine) or iNOS (1400w), blocked the effect of loperamide on osteosarcoma-induced hyperalgesia and also the endogenous opioid peripheral hypoalgesia that appears during the initial stages of the development of this osteosarcoma. Although this pathway also participates in the inhibitory effect of loperamide on the thermal hyperalgesia induced by administration of complete Freund's adjuvant, only selective inhibitors of nNOS or iNOS antagonized this effect. Our results demonstrate that the activation of a NO/cGMP/K(+)(ATP)-channel triggered by eNOS participates in the peripheral antihyperalgesic of loperamide on osteosarcoma-induced thermal hyperalgesia.
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PMID:Involvement of nitric oxide in the inhibition of bone cancer-induced hyperalgesia through the activation of peripheral opioid receptors in mice. 1754 51

Recently, we showed that genetic factors determine flow-dependent vascular remodeling. Among five inbred mouse strains, the SJL strain developed the largest intima in response to low flow. Because SJL mice have a spontaneous mutation in superoxide dismutase 2 (SOD-2) we tested the hypothesis that strain-specific variations in vascular function are due to alterations in redox and nitric oxide (NO) pathways. Vasorelaxation to acetylcholine was significantly impaired in aortic rings from SJL compared to C3H or FVB mice (up to 40%). Relaxation to the endothelium-independent vasodilator sodium nitroprusside (SNP) in SJL mice was also significantly impaired at low concentrations, with decreases in sensitivity and maximal relaxation to SNP compared to C3H and FVB mice. Western blot analyses showed significantly decreased expression (approximately 40%) of eNOS, PKG and SOD-2 proteins in SJL vasculature compared to C3H. Intact aortas from SJL showed significantly increased nitrotyrosine and decreased SOD-2 expression compared to C3H by immunohistochemistry. Basal levels of superoxide in aortas from SJL were not significantly different than C3H as measured by dihydroethidine. In summary, relatively small alterations in redox (SOD-2) and NO pathways (eNOS and PKG) may contribute to significantly impaired vasorelaxation in SJL mice.
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PMID:Impaired vasorelaxation in inbred mice is associated with alterations in both nitric oxide and super oxide pathways. 1766 89

The purpose of this study was to examine the modulating effects of protein kinase A (PKA) on the performance of signal systems triggered while activating alpha2-adrenoceptors and eNOS in the course of a wound process in patients with type 2 diabetes mellitus. Patients with the diabetic foot were shown to have impaired adrenergic responsiveness, accompanied by reduced eNOS activity and PKA inhibition. The positive therapeutic effect was noted with the increased stimulating effect of the PKA system on PKG on days 3 to 5 and on eNOS on days 10-14 of therapy. The preserving eNOS activity deficit was compensated for by the PKA-induced increase in PKG stimulation. The modulating effects of PKA are a compensatory intracellular mechanism of adaptation when NO production is decreased, which may be used to develop new therapeutic corrections of the dysregeneratory syndrome.
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PMID:[Modulating effects of protein kinase A on intracellular signal systems in the course of skin wound healing in patients with diabetes mellitus]. 1845 57

Nitric oxide in the gut is produced by nNOS in enteric neurons and by eNOS in smooth muscle cells. The eNOS in smooth muscle is activated by vasoactive intestinal peptide (VIP) released from enteric neurons. In the present study, we examined the effect of nitric oxide on VIP-induced eNOS activation in smooth muscle cells isolated from human intestine and rabbit stomach. NOS activity was measured as formation of the 1:1 co-product, l-citrulline from l-arginine. VIP caused an increase in l-citrulline production that was inhibited by NO in a concentration dependent manner (IC(50)~25 microM; maximal inhibition 72% at 100 microM NO). Basal l-citrulline production, however, was unaffected by NO. The effect was not mediated by cGMP/PKG since the PKG inhibitor KT5823 had no effect on eNOS autoinhibition. The autoinhibition was selective for NO since the co-product l-citrulline had no effect on VIP-induced NOS activation. Similar effects were obtained in rabbit gastric and human intestinal smooth muscle cells. The results suggest that NO produced in smooth muscle cells as a result of the activation of eNOS by VIP exerts an autoinhibitory restraint on eNOS thereby regulating the balance of the VIP/cAMP/PKA and NO/cGMP/PKG pathways that regulate the relaxation of gut smooth muscle.
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PMID:Autoinhibition of endothelial nitric oxide synthase (eNOS) in gut smooth muscle by nitric oxide. 1892 58

The ubiquitous anion nitrite (NO(2)(-)) has recently emerged as an endocrine storage form of nitric oxide (NO) and a signalling molecule that mediates a number of biological responses. Although the role of NO in regulating cardiac function has been investigated in depth, the physiological signalling effects of nitrite on cardiac function have only recently been explored. We now show that remarkably low concentrations of nitrite (1 nM) significantly modulate cardiac contractility in isolated and perfused Langendorff rat heart. In particular, nitrite exhibits potent negative inotropic and lusitropic activities as evidenced by a decrease in left ventricular pressure and relaxation, respectively. Furthermore, we demonstrate that the nitrite-dependent effects are mediated by NO formation but independent of NO synthase (NOS) activity. Specifically, nitrite infusion in the Langendorff system produces NO and cGMP/PKG-dependent negative inotropism, as evidenced by the formation of cellular iron-nitrosyl complexes and inhibition of biological effect by NO scavengers and by PKG inhibitors. These data are consistent with the hypothesis that nitrite represents an eNOS-independent source of NO in the heart which modulates cardiac contractility through the NO-cGMP/PKG pathway. The observed high potency of nitrite supports a physiological function of nitrite as a source of cardiomyocyte NO and a fundamental signalling molecule in the heart.
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PMID:Nitrite exerts potent negative inotropy in the isolated heart via eNOS-independent nitric oxide generation and cGMP-PKG pathway activation. 1924 61

In the classical pathway, the opposing activities of guanylyl cyclases (GC) and phosphodiesterases (PDE), and the effect of the cGMP-dependent protein kinase (cGK) on its targets, determine the biological responses to NO signaling. Here we tested the hypothesis that vascular dysfunction may be due to altered expression and activity of these effectors of NO signaling. Every other set of rat second order mesenteric resistance arteries (MA) were ligated, resulting in chronic low flow (LF) in the upstream MA1 and high flow (HF) in the adjacent MA1 without tissue ischemia. eNOS and iNOS were up-regulated in HF and LF MA1, respectively, in the sub-acute phase (four days) of vascular remodeling. The Day4 HF/LF MA1s were under increased control of NO as indicated by reduced sensitivity to the vasoconstrictor phenylephrine and its normalization with the NOS antagonist L-NAME. PDE5 mRNA and protein were also significantly up-regulated in the HF/LF MA1 with no change in sGC or PKG1, an effect that was dependent upon NO synthesis. The PDE5 inhibitor Sildenafil was several-fold more powerful in relaxing the HF/LF MA1s, and pre-treatment with Sildenafil uncovered an increased responsiveness of HF/LF MA1s to the NO donor DEA/NO. We conclude that induction of PDE5 de-sensitizes this systemic resistance artery to sustained NO signaling under chronic HF/LF. Treatment with PDE5 antagonists, in contrast to NO donors, may more specifically and effectively increase blood flow to chronically hypo-perfused tissues.
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PMID:Induction of PDE5 and de-sensitization to endogenous NO signaling in a systemic resistance artery under altered blood flow. 1937 6

Visfatin is a novel adipocyte-derived cytokine. We hypothesized that visfatin could directly affect vascular reactivity. To test the hypothesis, effects of visfatin on contraction of isolated blood vessels were examined. In endothelium-intact rat aorta, pretreatment with visfatin (100 ng/ml, 30 min) inhibited noradrenaline (NA; 1 nM-1 microM)-induced contraction. In NA (100 nM)-pre-contracted aorta, visfatin (1-100 ng/ml) directly induced a relaxation. Although an N(G)-Nitro-L-arginine methyl ester (300 microM, 15 min) inhibited the relaxation, an insulin receptor inhibitor, AGL2263 (10 microM, 20 min) was ineffective. Visfatin (100 ng/ml, 20 min) induced a phosphorylation of eNOS at serine 1177 and a de-phosphorylation of eNOS at threonine 495. Visfatin also induced a phosphorylation of Akt at serine 473 and a substrate of cGMP-dependent protein kinase, vasodilator stimulated phosphoprotein at serine 239. Present study revealed for the first time that visfatin has a vasodilating effect on isolated blood vessels, which is mediated via endothelium-derived NO.
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PMID:Visfatin causes endothelium-dependent relaxation in isolated blood vessels. 1939 28

Pulmonary hypertension (PH) is an unremitting disease defined by a progressive increase in pulmonary vascular resistance leading to right-sided heart failure. Using mice with genetic deletions of caveolin 1 (Cav1) and eNOS (Nos3), we demonstrate here that chronic eNOS activation secondary to loss of caveolin-1 can lead to PH. Consistent with a role for eNOS in the pathogenesis of PH, the pulmonary vascular remodeling and PH phenotype of Cav1-/- mice were absent in Cav1-/-Nos3-/- mice. Further, treatment of Cav1-/- mice with either MnTMPyP (a superoxide scavenger) or l-NAME (a NOS inhibitor) reversed their pulmonary vascular pathology and PH phenotype. Activation of eNOS in Cav1-/- lungs led to the impairment of PKG activity through tyrosine nitration. Moreover, the PH phenotype in Cav1-/- lungs could be rescued by overexpression of PKG-1. The clinical relevance of the data was indicated by the observation that lung tissue from patients with idiopathic pulmonary arterial hypertension demonstrated increased eNOS activation and PKG nitration and reduced caveolin-1 expression. Together, these data show that loss of caveolin-1 leads to hyperactive eNOS and subsequent tyrosine nitration-dependent impairment of PKG activity, which results in PH. Thus, targeting of PKG nitration represents a potential novel therapeutic strategy for the treatment of PH.
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PMID:Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. 1948 14


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