Editors' ChoicePhysiology

A Redox Role for Cyclic ADP-Ribose

Science's STKE  10 Apr 2001:
Vol. 2001, Issue 77, pp. tw8
DOI: 10.1126/stke.2001.77.tw8

Hypoxic pulmonary vasoconstriction is a normal physiological response that coordinates pulmonary perfusion to respiratory ventilation. NADH (reduced nicotinamide adenine dinucleotide) is thought to have a role in pulmonary artery contraction. Oxidized NAD (NAD+) is a substrate used by ADP-ribosyl cyclase to make cyclic ADP-ribose (cADPR), which regulates ryanodine receptor-mediated Ca2+ release. Wilson et al. investigated whether the ratio of NAD+:NADH in pulmonary arteries functioned as an oxido-reductive sensing rheostat to control pulmonary vasoconstriction. cADPR production in pulmonary artery smooth muscle homogenates was increased when NADH was added, but concentrations of NAD+ were constant. This result suggests that the enzymatic breakdown of cADPR by cADPR hydrolase is inhibited by the presence of NADH. Pulmonary artery sections incubated in hypoxic conditions produced greatly increased amounts of cADPR, whereas, in other experiments, vasoconstriction was inhibited by pretreatment with a cADPR antagonist, indicating that cADPR, produced in response to lower oxygen tension, can mediate pulmonary artery smooth muscle contraction. The authors suggest that cADPR, cADP hydrolase, and ADP-ribosylase function together to link the redox state of pulmonary smooth cells to Ca2+ release from the ryanodine receptor-regulated sarcoplasmic reticulum and consequent vasoconstriction.

H. L. Wilson, M. Dipp, J. M. Thomas, C. Lad, A. Galione, A. M. Evans, ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase act as a redox sensor: A primary role for cyclic ADP-ribose in hypoxic pulmonary vasoconstriction. J. Biol. Chem. 276, 11180-11188 (2001). [Abstract] [Full Text]