Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

J. Biol. Chem. 276 (14): 11180-11188

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

ADP-ribosyl Cyclase and Cyclic ADP-ribose Hydrolase Act as a Redox Sensor
A PRIMARY ROLE FOR CYCLIC ADP-RIBOSE IN HYPOXIC PULMONARY VASOCONSTRICTION*

Heather L. WilsonDagger §, Michelle Dipp, Justyn M. ThomasDagger , Chetan LadDagger , Antony GalioneDagger ||, and A. Mark EvansDagger **

From the Dagger  University Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT and the  University Laboratory of Physiology, University of Oxford, Parks Road, Oxford, OX1 3PT, United Kingdom

Hypoxic pulmonary vasoconstriction is unique to pulmonary arteries and serves to match lung perfusion to ventilation. However, in disease states this process can promote hypoxic pulmonary hypertension. Hypoxic pulmonary vasoconstriction is associated with increased NADH levels in pulmonary artery smooth muscle and with intracellular Ca2+ release from ryanodine-sensitive stores. Because cyclic ADP-ribose (cADPR) regulates ryanodine receptors and is synthesized from beta -NAD+, we investigated the regulation by beta -NADH of cADPR synthesis and metabolism and the role of cADPR in hypoxic pulmonary vasoconstriction. Significantly higher rates of cADPR synthesis occurred in smooth muscle homogenates of pulmonary arteries, compared with homogenates of systemic arteries. When the beta -NAD+:beta -NADH ratio was reduced, the net amount of cADPR accumulated increased. This was due, at least in part, to the inhibition of cADPR hydrolase by beta -NADH. Furthermore, hypoxia induced a 10-fold increase in cADPR levels in pulmonary artery smooth muscle, and a membrane-permeant cADPR antagonist, 8-bromo-cADPR, abolished hypoxic pulmonary vasoconstriction in pulmonary artery rings. We propose that the cellular redox state may be coupled via an increase in beta -NADH levels to enhanced cADPR synthesis, activation of ryanodine receptors, and sarcoplasmic reticulum Ca2+ release. This redox-sensing pathway may offer new therapeutic targets for hypoxic pulmonary hypertension.


* This work was supported by the Wellcome Trust and the BBSRC.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of a Special Biotechnology and Biological Sciences Research Council studentship. Present address: Inst. of Molecular Physiology, Sheffield University, Alfred Denny Bldg., Western Bank, Sheffield, S10 2TN, UK.

** Wellcome Trust Non-Clinical Lecturer. To whom correspondence should be addressed: Division of Biomedical Sciences, School of Biology, Buke Building, University of St. Andrew, St. Andrew, Fife, KY 169TS, UK. Tel: 44-1-334-463579; Fax: 44-1334-463600; E-mail: ame3@st-and.ac.uk.

|| Wellcome Trust Senior Research Fellow.


Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Hypoxic pulmonary vasoconstriction in the absence of pretone: essential role for intracellular Ca2+ release.
M. J. Connolly, J. Prieto-Lloret, S. Becker, J. P. T. Ward, and P. I. Aaronson (2013)
J. Physiol. 591, 4473-4498
   Abstract »    Full Text »    PDF »
Ca2+ responses of pulmonary arterial myocytes to acute hypoxia require release from ryanodine and inositol trisphosphate receptors in sarcoplasmic reticulum.
J. Wang, L. A. Shimoda, and J. T. Sylvester (2012)
Am J Physiol Lung Cell Mol Physiol 303, L161-L168
   Abstract »    Full Text »    PDF »
Hypoxic Pulmonary Vasoconstriction.
J. T. Sylvester, L. A. Shimoda, P. I. Aaronson, and J. P. T. Ward (2012)
Physiol Rev 92, 367-520
   Abstract »    Full Text »    PDF »
Cyclic Adenosine Diphosphate Ribose Activates Ryanodine Receptors, whereas NAADP Activates Two-pore Domain Channels.
O. A. Ogunbayo, Y. Zhu, D. Rossi, V. Sorrentino, J. Ma, M. X. Zhu, and A. M. Evans (2011)
J. Biol. Chem. 286, 9136-9140
   Abstract »    Full Text »    PDF »
A Single Residue in a Novel ADP-ribosyl Cyclase Controls Production of the Calcium-mobilizing Messengers Cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate.
L. Ramakrishnan, H. Muller-Steffner, C. Bosc, V. D. Vacquier, F. Schuber, M.-J. Moutin, L. Dale, and S. Patel (2010)
J. Biol. Chem. 285, 19900-19909
   Abstract »    Full Text »    PDF »
Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms.
N. Sommer, A. Dietrich, R. T. Schermuly, H. A. Ghofrani, T. Gudermann, R. Schulz, W. Seeger, F. Grimminger, and N. Weissmann (2008)
Eur. Respir. J. 32, 1639-1651
   Abstract »    Full Text »    PDF »
Ca2+ signaling in hypoxic pulmonary vasoconstriction: effects of myosin light chain and Rho kinase antagonists.
J. Wang, L. Weigand, J. Foxson, L. A. Shimoda, and J. T. Sylvester (2007)
Am J Physiol Lung Cell Mol Physiol 293, L674-L685
   Abstract »    Full Text »    PDF »
Integrin Ligands Mobilize Ca2+ from Ryanodine Receptor-gated Stores and Lysosome-related Acidic Organelles in Pulmonary Arterial Smooth Muscle Cells.
A. Umesh, M. A. Thompson, E. N. Chini, K.-P. Yip, and J. S. K. Sham (2006)
J. Biol. Chem. 281, 34312-34323
   Abstract »    Full Text »    PDF »
AMP-activated protein kinase underpins hypoxic pulmonary vasoconstriction and carotid body excitation by hypoxia in mammals.
A. M. Evans (2006)
Exp Physiol 91, 821-827
   Abstract »    Full Text »    PDF »
Oxygen sensors in hypoxic pulmonary vasoconstriction.
N. Weissmann, N. Sommer, R. T. Schermuly, H. A. Ghofrani, W. Seeger, and F. Grimminger (2006)
Cardiovasc Res 71, 620-629
   Abstract »    Full Text »    PDF »
Hypoxia Regulates Bone Morphogenetic Protein Signaling Through C-Terminal-Binding Protein 1.
X. Wu, M. S. Chang, S. A. Mitsialis, and S. Kourembanas (2006)
Circ. Res. 99, 240-247
   Abstract »    Full Text »    PDF »
AMP-activated protein kinase and the regulation of Ca2+ signalling in O2-sensing cells.
A. M. Evans (2006)
J. Physiol. 574, 113-123
   Abstract »    Full Text »    PDF »
Hypoxic pulmonary vasoconstriction: mechanisms and controversies.
P. I. Aaronson, T. P. Robertson, G. A. Knock, S. Becker, T. H. Lewis, V. Snetkov, and J. P. T. Ward (2006)
J. Physiol. 570, 53-58
   Abstract »    Full Text »    PDF »
Does AMP-activated Protein Kinase Couple Inhibition of Mitochondrial Oxidative Phosphorylation by Hypoxia to Calcium Signaling in O2-sensing Cells?.
A. M. Evans, K. J. W. Mustard, C. N. Wyatt, C. Peers, M. Dipp, P. Kumar, N. P. Kinnear, and D. G. Hardie (2005)
J. Biol. Chem. 280, 41504-41511
   Abstract »    Full Text »    PDF »
Oxidant and redox signaling in vascular oxygen sensing mechanisms: basic concepts, current controversies, and potential importance of cytosolic NADPH.
M. S. Wolin, M. Ahmad, and S. A. Gupte (2005)
Am J Physiol Lung Cell Mol Physiol 289, L159-L173
   Abstract »    Full Text »    PDF »
Capacitative calcium entry: a central role in hypoxic pulmonary vasoconstriction?.
J. P. T. Ward, T. P. Robertson, and P. I. Aaronson (2005)
Am J Physiol Lung Cell Mol Physiol 289, L2-L4
   Full Text »    PDF »
CD38/cyclic ADP-ribose signaling: role in the regulation of calcium homeostasis in airway smooth muscle.
D. A. Deshpande, T. A. White, S. Dogan, T. F. Walseth, R. A. Panettieri, and M. S. Kannan (2005)
Am J Physiol Lung Cell Mol Physiol 288, L773-L788
   Abstract »    Full Text »    PDF »
Endothelin-1, superoxide and adeninediphosphate ribose cyclase in shark vascular smooth muscle.
S. K. Fellner and L. Parker (2005)
J. Exp. Biol. 208, 1045-1052
   Abstract »    Full Text »    PDF »
Hypoxic pulmonary vasoconstriction.
R. Moudgil, E. D. Michelakis, and S. L. Archer (2005)
J Appl Physiol 98, 390-403
   Abstract »    Full Text »    PDF »
Hypoxic pulmonary vasoconstriction: redox events in oxygen sensing.
G. B. Waypa and P. T. Schumacker (2005)
J Appl Physiol 98, 404-414
   Abstract »    Full Text »    PDF »
Lysosome-Sarcoplasmic Reticulum Junctions: A TRIGGER ZONE FOR CALCIUM SIGNALING BY NICOTINIC ACID ADENINE DINUCLEOTIDE PHOSPHATE AND ENDOTHELIN-1.
N. P. Kinnear, F.-X. Boittin, J. M. Thomas, A. Galione, and A. M. Evans (2004)
J. Biol. Chem. 279, 54319-54326
   Abstract »    Full Text »    PDF »
Pharmacological Modulation of Sarcoplasmic Reticulum Function in Smooth Muscle.
R. Laporte, A. Hui, and I. Laher (2004)
Pharmacol. Rev. 56, 439-513
   Abstract »    Full Text »    PDF »
Hypoxic constriction and reactive oxygen species in porcine distal pulmonary arteries.
J. Q. Liu, J. S. K. Sham, L. A. Shimoda, P. Kuppusamy, and J. T. Sylvester (2003)
Am J Physiol Lung Cell Mol Physiol 285, L322-L333
   Abstract »    Full Text »    PDF »
Ca2+ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent.
T. P. Robertson, P. I. Aaronson, and J. P. T. Ward (2003)
Am J Physiol Lung Cell Mol Physiol 284, L1121-L1126
   Abstract »    Full Text »    PDF »
A Novel TRPM2 Isoform Inhibits Calcium Influx and Susceptibility to Cell Death.
W. Zhang, X. Chu, Q. Tong, J. Y. Cheung, K. Conrad, K. Masker, and B. A. Miller (2003)
J. Biol. Chem. 278, 16222-16229
   Abstract »    Full Text »    PDF »
The NO Pathway Acts Late during the Fertilization Response in Sea Urchin Eggs.
C. Leckie, R. Empson, A. Becchetti, J. Thomas, A. Galione, and M. Whitaker (2003)
J. Biol. Chem. 278, 12247-12254
   Abstract »    Full Text »    PDF »
Vasodilation by the Calcium-mobilizing Messenger Cyclic ADP-ribose.
F.-X. Boittin, M. Dipp, N. P. Kinnear, A. Galione, and A. M. Evans (2003)
J. Biol. Chem. 278, 9602-9608
   Abstract »    Full Text »    PDF »
Metabolic inhibition with cyanide induces calcium release in pulmonary artery myocytes and Xenopus oocytes.
Y.-X. Wang, Y.-M. Zheng, I. Abdullaev, and M. I. Kotlikoff (2003)
Am J Physiol Cell Physiol 284, C378-C388
   Abstract »    Full Text »    PDF »
Mitochondrial Reactive Oxygen Species Trigger Calcium Increases During Hypoxia in Pulmonary Arterial Myocytes.
G. B. Waypa, J. D. Marks, M. M. Mack, C. Boriboun, P. T. Mungai, and P. T. Schumacker (2002)
Circ. Res. 91, 719-726
   Abstract »    Full Text »    PDF »
Activation of the Cation Channel Long Transient Receptor Potential Channel 2 (LTRPC2) by Hydrogen Peroxide. A SPLICE VARIANT REVEALS A MODE OF ACTIVATION INDEPENDENT OF ADP-RIBOSE.
E. Wehage, J. Eisfeld, I. Heiner, E. Jungling, C. Zitt, and A. Luckhoff (2002)
J. Biol. Chem. 277, 23150-23156
   Abstract »    Full Text »    PDF »
A pivotal role for cADPR-mediated Ca2+ signaling: regulation of endothelin-induced contraction in peritubular smooth muscle cells.
F. BARONE, A. A. GENAZZANI, A. CONTI, G. C. CHURCHILL, F. PALOMBI, E. ZIPARO, V. SORRENTINO, A. GALIONE, and A. FILIPPINI (2002)
FASEB J 16, 697-705
   Abstract »    Full Text »    PDF »
Ca2+ release from ryanodine-sensitive store contributes to mechanism of hypoxic vasoconstriction in rat lungs.
Y. Morio and I. F. McMurtry (2002)
J Appl Physiol 92, 527-534
   Abstract »    Full Text »    PDF »
Divergent roles of glycolysis and the mitochondrial electron transport chain in hypoxic pulmonary vasoconstriction of the rat: identity of the hypoxic sensor.
R. M Leach, H. M Hill, V. A Snetkov, T. P Robertson, and J. P T Ward (2001)
J. Physiol. 536, 211-224
   Abstract »    Full Text »    PDF »
Hypoxic pulmonary vasoconstriction: a multifactorial response?.
N. Weissmann, F. Grimminger, A. Olschewski, and W. Seeger (2001)
Am J Physiol Lung Cell Mol Physiol 281, L314-L317
   Full Text »    PDF »
Hypoxic Pulmonary Vasoconstriction : A Radical View.
J. T. Sylvester (2001)
Circ. Res. 88, 1228-1230
   Full Text »    PDF »
Cyclic ADP-Ribose Is the Primary Trigger for Hypoxic Pulmonary Vasoconstriction in the Rat Lung In Situ.
M. Dipp and A. M. Evans (2001)
Circ. Res. 89, 77-83
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882