Journal of Applied Physiology AJP: Endocrinology and Metabolism
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J Appl Physiol 101: 1005, 2006. First published July 6, 2006; doi:10.1152/japplphysiol.00707.2006
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LETTER TO THE EDITOR

Last Word: Point:Counterpoint authors respond to commentaries on "Hypoxic pulmonary vasoconstriction is/is not mediated by increased production of reactive oxygen species"

To the Editor: Regarding the pro-con debate on reactive oxygen species (ROS) and hypoxic pulmonary vasoconstriction (HPV), Dr. Aaronson (1) raises questions about oxygen sensing, ROS/redox state, and HPV in the mice that lack the gp91 component of NADPH oxidase (2). We agree that the ROS levels measured at the lung surface in these mice are markedly diminished, indicating that the ROS measured by this technique are largely generated by NADPH oxidase and do not control HPV. This leaves ROS production by mitochondria and the cellular redox state as potential sensors. The paper showed that HPV was still present in mice lacking the isoform of NADPH oxidase that contains the gp91 subunit. It should not be interpreted to say that the mitochondria in the resistance pulmonary arteries of these mice do not produce ROS. We provide considerable evidence in the debate that mitochondrial production of ROS is likely to play an important role in normoxic pulmonary vasodilatation.

Dr. Aaronson (1) also suggests that the intracellular milieu in most cells is relatively reduced, leaving little room for hypoxia to reduce it further. The pulmonary artery smooth muscle cells live at a much higher oxygen tension than systemic smooth muscle cells, so redox conditions may be different. Certainly hypoxia has been shown to make the lungs more reduced in terms of NAD(P)H-to-NAD(P) ratios (4, 5) and GSH (6). Thus changes in redox status and/or mitochondrial ROS, and/or other NADPH oxidase isoforms could act as oxygen sensors.

In regard to the letter from Professors Acker and Fandrey (1), we discussed hypoxia-inducible factor (HIF) in the setting of the fawn-hooded rat, in which we show that a reduction in mitochondrial function and ROS result in activation of HIF. This can be reversed by exogenous H2O2, suggesting that a decrease in ROS signals this effect of hypoxia.

Our main difference of opinion with Dr. Packer (1) relates to the assertion that H2O2 causes constriction in all vessels. The reference restriction prevents us from documenting the many papers that have demonstrated H2O2 to cause vasodilatation. The reader should refer to the section on vasodilatation in a recent review (3) or enter "hydrogen peroxide and vasodilatation" in PubMed.

REFERENCES

  1. Aaronson PI, Berchner-Pfannschmidt U, Acker H, Fandrey J, Gupte SA, Wolin MS, Packer CS, Peleaz NJ, Evans AM, and Gonzalez C. Comments on Point:Counterpoint series "Hypoxic pulmonary vasoconstriction is/is not mediated by increased production of reactive oxygen species." J Appl Physiol 101: 1001–1002, 2006.
  2. Archer S, Reeve H, Michelakis E, Puttagunta L, Waite R, Nelson DP, Dinauer MC, and Weir EK. O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase. Proc Natl Acad Sci USA 96: 7944–7949, 1999.[Abstract/Free Full Text]
  3. Cai H. Hydrogen peroxide regulation of endothelial function: origins, mechanisms, and consequences. Cardiovasc Res 68: 26–36, 2005.[Abstract/Free Full Text]
  4. Chander A, Dhariwal K, and Viswanathan R. Pyridine nucleotides in lung and liver of hypoxic rats. Life Sci 26: 1935–1945, 1980.[CrossRef][Web of Science][Medline]
  5. Leach R, Hill H, Snetkov V, Robertson T, and Ward J. Divergent roles of glycolysis and the mitochondrial electron transport chain in hypoxic pulmonary vasoconstriction of the rat: identity of the hypoxic sensor. J Physiol 536: 211–124, 2001.[Abstract/Free Full Text]
  6. Reeve H, Michelakis E, Nelson D, Weir E, and Archer S. Alterations in a redox oxygen sensing mechanism in chronic hypoxia. J Appl Physiol 90: 2249–2256, 2001.[Abstract/Free Full Text]

E. Kenneth Weir
Stephen L. Archer
 Department of Veterans Affairs Medical Center
Cardiology 111-C
Minneapolis, Minnesota
e-mail: weirx002{at}umn.edu





This Article
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
101/3/1005    most recent
00707.2006v1
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Right arrow Alert me when this article is cited
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Google Scholar
Right arrow Articles by Weir, E. K.
Right arrow Articles by Archer, S. L.
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Right arrow Articles by Weir, E. K.
Right arrow Articles by Archer, S. L.

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