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)

1. Epidemiological studies have suggested that moderate consumption of natural dietary polyphenolic compounds might reduce the risk of cardiovascular disease and also protect against cancer. The present study investigates the effects of delphinidin, an anthocyanin present in red wine, on bovine aortic endothelial cells apoptosis. 2. Based on flow cytometry, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis and detection of mitochondrial cytochrome c release, we show that delphinidin (10(-2) g l(-1)) alone had no effect either on necrosis or on apoptosis, but it significantly reduced apoptosis elicited by actinomycin D (1 micro g ml(-1), 24 h) and 7beta-hydroxycholesterol (10 micro g ml(-1), 18 h). 3. The protective effect of delphinidin was abolished by inhibitors of nitric oxide-synthase (NOS) (L-NA, 100 micro M and SMT, 100 micro M), guanylyl cyclase (ODQ, 100 micro M) and MAP kinase (PD98059, 30 micro M). 4. Western blot analysis and protein detection by confocal microscopy demonstrate that the antiapoptotic effect of delphinidin was associated with an increased endothelial NOS expression mediated by a MAP kinase pathway. 5. Finally, delphinidin alone had no effect on cytosolic-free calcium ([Ca(2+)](i)), but normalized the changes in [Ca(2+)](i) produced by actinomycin D towards the control values, suggesting that the antiapoptotic effect of delphinidin is associated with the maintenance of [Ca(2+)](i) in the physiological range. 6. All of the observed effects of delphinidin may preserve endothelium integrity, the alteration of which lead to pathologies including cardiovascular diseases, such as atherosclerosis, and is often associated with cancers. In conclusion, the protective effect of delphinidin against endothelial cell apoptosis contributes to understand the potential benefits of a consumption rich in polyphenols.
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PMID:Delphinidin, an active compound of red wine, inhibits endothelial cell apoptosis via nitric oxide pathway and regulation of calcium homeostasis. 1287 27

Flash photolysis studies on the five-coordinate heme nitrosyl of Alcaligenes xylosoxidans cytochrome c' were carried out to investigate the ramifications of its proximal nitrosyl ligand on NO release. Delta absorbance spectra recorded 5 ms after photolysis indicate that approximately 5% of the photolyzed hemes are converted to a five-coordinate high spin ferrous state, revealing that reattachment of the endogenous His ligand is fast enough to trap some of the photolyzed heme. Analysis of NO rebinding suggests that the photolyzed ferrous protein is initially in a strained conformation, which relaxes on a millisecond time scale. The strained ferrous heme appears to contain a significantly labilized Fe-His bond, which allows direct second-order rebinding to the proximal face at high NO-concentrations. In contrast, the NO-binding properties of the relaxed conformation are similar to those previously observed in stopped-flow studies, which showed that a five-coordinate heme-nitrosyl is formed via a six-coordinate intermediate. The discovery of a rapid proximal His ligand reattachment to NO-dissociated heme reveals a novel "kinetic trap" mechanism for lowering the five-coordinate heme nitrosyl population in response to decreased ambient NO concentrations. Thus, NO dissociation from the five-coordinate heme nitrosyl, whether thermal or photochemical, is followed by rapid, and only slowly reversible, His reattachment which acts to kinetically trap the heme in its five-coordinate ferrous state. Because return to the five-coordinate heme nitrosyl requires two NO-dependent steps, the protein uses a kind of kinetic amplification of the thermodynamic dissociation that occurs in response to decreased NO concentrations. The implications of this "kinetic-trap" mechanism for NO release from soluble guanylate cyclase are discussed.
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PMID:A novel kinetic trap for NO release from cytochrome c': a possible mechanism for NO release from activated soluble guanylate cyclase. 1290 95

Reperfusion of ischemic tissue can precipitate cell death. Much of this cell killing is related to the return of physiological pH after the tissue acidosis of ischemia. The mitochondrial permeability transition (MPT) is a key mechanism contributing to this pH-dependent reperfusion injury in hepatocytes, myocytes, and other cell types. When ATP depletion occurs after the MPT, necrotic cell death ensues. If ATP levels are maintained, at least in part, the MPT initiates apoptosis caused by mitochondrial swelling and release of cytochrome c and other proapoptotic factors. Cyclosporin A and acidotic pH inhibit opening of permeability transition pores and protect cells against oxidative stress and ischemia/reperfusion injury, whereas Ca(2+), mitochondrial reactive oxygen species, and pH above 7 promote mitochondrial inner membrane permeabilization. Reperfusion with nitric oxide (NO) donors also blocks the MPT via a guanylyl cyclase and protein kinase G-dependent signaling pathway, which in turn prevents reperfusion-induced cell killing. In isolated mitochondria, a combination of cGMP, cytosolic extract, and ATP blocks the Ca(2+)-induced MPT, an effect that is reversed by protein kinase G inhibition. Thus, NO prevents pH-dependent cell killing after ischemia/reperfusion by a guanylyl cyclase/cGMP/protein kinase G signaling cascade that blocks the MPT.
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PMID:Nitric oxide: a signaling molecule against mitochondrial permeability transition- and pH-dependent cell death after reperfusion. 1554 14

Simple MO arguments provide a qualitative explanation for the near-linear ON-Mn-NO arrangement observed for the trans-{Mn(NO)2}8 anion [Mn(Pc)(NO)2]-, which is unexpected for an Enemark-Feltham electron count n>6. The metal center in this species may be described as low-spin d6("t2g6") and the two unpaired electrons occupy a pair of eu orbitals composed of NO(pi*) components, giving rise to a triplet ground state. In a certain sense, these eu SOMOs may be likened to the SOMO (singly occupied molecular orbital) of the allyl radical. The electronic structure of this species is quite different from that of diamagnetic dinitrosylheme intermediates, which have been spectroscopically characterized in synthetic studies as well as proposed for soluble guanylate cyclase and cytochrome c'. Some speculative remarks are offered as to why this proposal is not an unreasonable one from an electronic-structural perspective.
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PMID:Understanding the unexpected linearity of the trans-{Mn(NO)2}8 unit in a phthalocyanine complex: some thoughts on dinitrosylheme intermediates in biology. 1559 91

Nicorandil has been shown to inhibit myocyte apoptosis by opening of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels and nitrate-like effect against oxidative stress. However, the detailed mechanism of nicorandil-mediated cardioprotection under hypoxic conditions remains to be largely unknown. The present study examined whether nicorandil can inhibit apoptosis via regulation of Bcl-2 family proteins in hypoxic myocytes. Neonatal rat cardiac myocytes were exposed to hypoxia for 7 hours. Hypoxia-induced myocyte apoptosis (13.9+/-0.9%) under glucose-rich conditions. Myocyte apoptosis was accompanied by loss of mitochondrial membrane potential (Deltapsi(m)), cytochrome c release from mitochondria into cytosol, and activation of caspase-3. Hypoxia also significantly increased Bax and decreased Bcl-2 mRNA and protein expression, thereby increasing Bax/Bcl-2 ratio. Nicorandil 100 micromol/l significantly decreased the percentage of apoptotic myocytes (7.2+/-0.5%) by inhibiting loss of Deltapsi(m) and translocation of cytochrome c. These effects of nicorandil were partially but significantly inhibited by cotreatment of either 500 micromol/l 5-hydroxydecanoate, a selective mitoK(ATP) channel antagonist, or 10 micromol/l 1H-[1,2,4]oxidazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase. Moreover, nicorandil significantly inhibited the hypoxia-induced changes in Bax and Bcl-2 expression, and concomitant increased Bax and decreased Bcl-2 immunoreactivity in mitochondria. These effects of nicorandil in Bax and Bcl-2 expression were significantly blunted by cotreatment of ODQ and 5-HD, respectively. Cotreatment of KT5823, an inhibitor of protein kinase G, significantly blocked the effect of nicorandil on Bax expression and 8-bromo-cyclic guanosine 3',5' monophosphate (8-bromo-cGMP), a cGMP analog, mimicked the effect of nicorandil on Bax expression. The present study demonstrates that nicorandil regulates Bcl-2 family proteins via opening of mitoK(ATP) channels and nitric oxide-cGMP signaling and inhibits hypoxia-induced mitochondrial death pathway.
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PMID:Nicorandil regulates Bcl-2 family proteins and protects cardiac myocytes against hypoxia-induced apoptosis. 1652 5

Pressure overload associated with hypertension is an important pathological factor leading to heart remodeling and ultimately heart failure partially due to cardiomyocyte apoptosis. Here we show that endogenous NO signaling plays a critical role in mechanical stretch-induced cardiomyocyte apoptosis. Mechanical stretch induced elevated expression of both eNOS and inducible NO synthase (iNOS) and increased synthesis of NO. A sustained increase in iNOS expression was also found in hearts of hypertensive rats in vivo. Blockade of NO signaling by inhibitors of NOS (L-NAME and AMT) or downstream guanylyl cyclase (ODQ) strongly inhibited stretch-induced apoptosis, mitochondria depolarization, and cytochrome c release, suggesting that NO is required in stretch-induced cardiomyocyte apoptosis. The expression of iNOS, but not eNOS, was blocked by L-NAME and ODQ, indicating that the iNOS induction is NO dependent. The initial elevation of NO is likely due to Ca(2+)-dependent activation of eNOS because elimination of intracellular calcium by EGTA-AM inhibited both iNOS induction and NO elevation. Other calcium signaling inhibitors (nifedipine, ryanodine, thapsigargin, and ionic gadolinium) also attenuated the initial NO elevation. These data indicate that mechanical signals initiate Ca(2+)-dependent NO synthesis, which is further amplified by activation of NO-induced iNOS expression, to regulate cardiomyocyte apoptosis.
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PMID:Nitric oxide signaling in stretch-induced apoptosis of neonatal rat cardiomyocytes. 1687 24

Although the existence of cardiac mitochondrial cGMP has been reported previously [Kimura and Murad (1974) J. Biol. Chem. 249, 6910-6916], the physiological and pathophysiological properties of cGMP in cardiac mitochondria have remained unknown. The aim of the present study was to clarify whether cardiac mitochondrial cGMP regulates the apoptosis of cardiomyocytes. In the presence of GTP, the NO donors SNAP (S-nitroso-N-acetyl-DL-penicillamine; 1 mmol/l) and SNP (sodium nitroprusside; 1 mmol/l) each markedly increased the cGMP level in a highly purified mitochondrial protein fraction prepared from left ventricular myocytes of male Wistar rats, and these increases were inhibited by 1 micromol/l ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), an inhibitor of NO-sensitive guanylate cyclase. In purified mitochondria, both SNAP (1 mmol/l) and the membrane-permeant cGMP analogue 8-Br-cGMP (8-bromo-cGMP; 1 mmol/l), but not cGMP (1 mmol/l), increased cytochrome c release from succinate-energized mitochondria without inducing mitochondrial swelling and depolarization of the mitochondrial membrane as factors of activation of MPT (mitochondrial permeability transition). The cytochrome c release mediated by SNAP was inhibited in the presence of 1 micromol/l ODQ. On the other hand, 1 mmol/l SNAP induced apoptosis in primary cultured adult rat cardiomyocytes in a time-dependent manner, and this induction was significantly inhibited in the presence of ODQ. Furthermore, apoptosis induced in primary cultured cardiomyocytes by hypoxia/re-oxygenation was also inhibited by ODQ. These results suggest that the acceleration of cGMP production in cardiac mitochondria stimulates cytochrome c release from mitochondria in an MPT-independent manner, resulting in apoptosis.
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PMID:Cardiac mitochondrial cGMP stimulates cytochrome c release. 1696 61

We showed recently that mitochondrial ATP-dependent K(+) channel (mitoK(ATP)) opening is required for the inotropic response to ouabain. Because mitoK(ATP) opening is also required for most forms of cardioprotection, we investigated whether exposure to ouabain was cardioprotective. We also began to map the signaling pathways linking ouabain binding to Na(+)-K(+)-ATPase with the opening of mitoK(ATP). In Langendorff-perfused rat hearts, 10-80 microM ouabain given before the onset of ischemia resulted in cardioprotection against ischemia-reperfusion injury, as documented by an improved recovery of contractile function and a reduction of infarct size. In skinned cardiac fibers, a ouabain-induced protection of mitochondrial outer membrane integrity, adenine nucleotide compartmentation, and energy transfer efficiency was evidenced by a decreased release of cytochrome c and preserved half-saturation constant of respiration for ADP and adenine nucleotide translocase-mitochondrial creatine kinase coupling, respectively. Ouabain-induced positive inotropy was dose dependent over the range studied, whereas ouabain-induced cardioprotection was maximal at the lowest dose tested. Compared with bradykinin (BK)-induced preconditioning, ouabain was equally efficient. However, the two ligands clearly diverge in the intracellular steps leading to mitoK(ATP) opening from their respective receptors. Thus BK-induced cardioprotection was blocked by inhibitors of cGMP-dependent protein kinase (PKG) or guanylyl cyclase (GC), whereas ouabain-induced protection was not blocked by either agent. Interestingly, however, ouabain-induced inotropy appears to require PKG and GC. Thus 5-hydroxydecanoate (a selective mitoK(ATP) inhibitor), N-(2-mercaptopropionyl)glycine (MPG; a reactive oxygen species scavenger), ODQ (a GC inhibitor), PP2 (a src kinase inhibitor), and KT-5823 (a PKG inhibitor) abolished preconditioning by BK and blocked the inotropic response to ouabain. However, only PP2, 5-HD, and MPG blocked ouabain-induced cardioprotection.
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PMID:Ouabain protects rat hearts against ischemia-reperfusion injury via pathway involving src kinase, mitoKATP, and ROS. 1709 31

Nitric oxide (NO) is an intercellular signaling molecule; among its many and varied roles are the control of blood flow and blood pressure via activation of the heme enzyme, soluble guanylate cyclase. A growing body of evidence suggests that an additional target for NO is the mitochondrial oxygen-consuming heme/copper enzyme, cytochrome c oxidase. This review describes the molecular mechanism of this interaction and the consequences for its likely physiological role. The oxygen reactive site in cytochrome oxidase contains both heme iron (a(3)) and copper (Cu(B)) centers. NO inhibits cytochrome oxidase in both an oxygen-competitive (at heme a(3)) and oxygen-independent (at Cu(B)) manner. Before inhibition of oxygen consumption, changes can be observed in enzyme and substrate (cytochrome c) redox state. Physiological consequences can be mediated either by direct "metabolic" effects on oxygen consumption or via indirect "signaling" effects via mitochondrial redox state changes and free radical production. The detailed kinetics suggest, but do not prove, that cytochrome oxidase can be a target for NO even under circumstances when guanylate cyclase, its primary high affinity target, is not fully activated. In vivo organ and whole body measures of NO synthase inhibition suggest a possible role for NO inhibition of cytochrome oxidase. However, a detailed mapping of NO and oxygen levels, combined with direct measures of cytochrome oxidase/NO binding, in physiology is still awaited.
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PMID:Nitric oxide regulation of mitochondrial oxygen consumption II: Molecular mechanism and tissue physiology. 1732 2

The bacterial heme protein Alcaligenes xylosoxidans cytochrome c' (AXCP) forms a novel five-coordinate heme-nitrosyl (5c-NO) complex in which NO resides at the proximal heme face in place of the endogenous protein ligand. Intriguingly, AXCP shares NO-binding properties with the eukaryotic NO-sensor, soluble guanylate cyclase (sGC), including 5c-NO formation via two NO-dependent reactions. For both proteins, a model has been proposed in which NO binds to the vacant distal face to form a transient six-coordinate heme-nitrosyl (6c-NO) species, which then converts to a proximal 5c-NO complex via a putative dinitrosyl intermediate. To shed light on this novel reaction mechanism, activation parameters have been determined for distal and proximal NO-binding reactions in AXCP from the effect of temperature and hydrostatic pressure on rate constants. The unusually slow 6c-NO formation reaction has a near-zero entropy of activation and a positive volume of activation (DeltaV(double dagger) = +14.1 cm(3) mol(-1)), consistent with a rate-determining step involving movement of the Leu 16 residue to allow NO binding to the crowded distal site. For the 6c-NO --> 5c-NO conversion, the large positive entropy of activation (DeltaS(double dagger) = +103 J K(-1) mol(-1)) and volume of activation (DeltaV(double dagger) = +24.1 cm(3) mol(-1)) suggest that the putative dinitrosyl intermediate forms via a dissociative mechanism in which the endogenous His ligand dissociates prior to the attack of the second NO molecule on the proximal heme face. These results have important implications for distal vs proximal NO binding in AXCP, as well as mechanisms of 5c-NO formation in heme proteins.
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PMID:Activation parameters for heme-NO binding in alcaligenes xylosoxidans cytochrome c': the putative dinitrosyl intermediate forms via a dissociative mechanism. 1933 78


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