To the Editor:
Isbell et al.1 studied hypoxic blood pressure responses in an elegant model in which the mouse hemoglobin β-chain was replaced with human hemoglobin β-chain with or without an alanine substitution for the cysteine at position 93 (βCys93). However, the role of a nitric oxide (NO)-thiol (S-nitrosothiol, SNO) modification of βCys93 in signaling oxyhemoglobin desaturation was not studied in these mice. NO transfer between thiols during erythrocytic oxyhemoglobin desaturation signals altered vascular structure and gene expression in chronic hypoxia2, increased minute ventilation (physiological ventilatory response) in acute hypoxia3 and matching of acute hemoglobin desaturation to local blood flow4. None of these responses was studied; instead, acute blood pressure changes were measured in normoxic mice. These changes do not reflect control of regional blood flow and would not be predicted to change in the βCys93-mutant mouse. Hence, the experiments reported provide no in vivo information about hypoxic responses mediated by βCys93.
Moreover, assuming that human β-chain hemoglobin behaves in the mouse as it does in the human, the presence of <1% prenatal mouse hemoglobin could normalize responses: the normal erythrocytic ratio of SNO to hemoglobin is less than 1:1,000 (ref. 4), so if 10% of fetal hemoglobin were SNO modified, the mutant mouse could have SNO-βCys93–mediated responses. Furthermore, concerns about the validity of the iodine-based assay employed in this paper remain, despite attempts at its validation5,6. Finally, the results shown in the vascular ring studies suggests that the control erythrocytes with an unmutated human hemoglobin β-chain were SNO depleted. Specifically, both control and βCys93-mutant erythrocytes caused minimal responses compared to those in previously published experiments, either because of the rapid ex vivo decay of the deoxyhemoglobin βCys93-SNO bond2,7,8 or because the rings were not healthy.
References
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Palmer, L.A. et al. J. Clin. Invest. 117, 2592–2601 (2007).
Lipton, A.J. et al. Nature 413, 171–174 (2001).
Singel, D.J. & Stamler, J.S. Annu. Rev. Physiol. 67, 99–145 (2005).
Gaston, B. et al. Am. J. Respir. Crit. Care Med. 173, 1186–1193 (2006).
Hausladen, A. et al. Proc. Natl. Acad. Sci. USA 104, 2157–2162 (2007).
Doctor, A. et al. Proc. Natl. Acad. Sci. USA 102, 5709–5714 (2005).
Marozkina, N.V. et al. Circ. Res. 103, 441–443 (2008).
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Palmer, L., Doctor, A. & Gaston, B. SNO-hemoglobin and hypoxic vasodilation. Nat Med 14, 1009 (2008). https://doi.org/10.1038/nm1008-1009a
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DOI: https://doi.org/10.1038/nm1008-1009a