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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.

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