Abstract
The mechanism by which hypoxia [low partial pressure of O2 (pO2)] elicits signaling to regulate pulmonary arterial pressure is incompletely understood. We considered the possibility that, in addition to its effects on smooth muscle, hypoxia may influence pulmonary vascular tone through an effect on RBCs. We report that exposure of native RBCs to sustained hypoxia is accompanied by a buildup of heme iron-nitrosyl (FeNO) species that are deficient in pO2-governed intramolecular transfer of NO to cysteine thiol, yielding a deficiency in the vasodilator S-nitrosohemoglobin (SNO-Hb). S-nitrosothiol (SNO)-deficient RBCs produce impaired vasodilator responses in vitro and exaggerated pulmonary vasoconstrictor responses in vivo and are defective in oxygenating the blood. RBCs from hypoxemic patients with elevated pulmonary arterial pressure (PAP) exhibit a similar FeNO/SNO imbalance and are thus deficient in pO2-coupled vasoregulation. Chemical restoration of SNO-Hb levels in both animals and patients restores the vasodilator activity of RBCs, and this activity is associated with improved oxygenation and lower PAPs.
| Original language | English |
|---|---|
| Pages (from-to) | 14801-14806 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 102 |
| Issue number | 41 |
| DOIs | |
| Publication status | Published - 11 Oct 2005 |
| Externally published | Yes |
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Keywords
- Hemoglobin
- Red blood cell vasodilation
- S-nitrosylation
ASJC Scopus subject areas
- Genetics
- General
Cite this
A nitric oxide processing defect of red blood cells created by hypoxia : Deficiency of S-nitrosohemoglobin in pulmonary hypertension. / McMahon, Timothy J.; Ahearn, Gregory S.; Moya, Martin P.; Gow, Andrew J.; Huang, Yuh Chin T; Luchsinger, Benjamin P.; Nudelman, Raphael; Yan, Yun; Krichman, Abigail D.; Bashore, Thomas M.; Califf, Robert M.; Singel, David J.; Piantadosi, Claude A.; Tapson, Victor F.; Stamler, Jonathan S.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 41, 11.10.2005, p. 14801-14806.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A nitric oxide processing defect of red blood cells created by hypoxia
T2 - Deficiency of S-nitrosohemoglobin in pulmonary hypertension
AU - McMahon, Timothy J.
AU - Ahearn, Gregory S.
AU - Moya, Martin P.
AU - Gow, Andrew J.
AU - Huang, Yuh Chin T
AU - Luchsinger, Benjamin P.
AU - Nudelman, Raphael
AU - Yan, Yun
AU - Krichman, Abigail D.
AU - Bashore, Thomas M.
AU - Califf, Robert M.
AU - Singel, David J.
AU - Piantadosi, Claude A.
AU - Tapson, Victor F.
AU - Stamler, Jonathan S.
PY - 2005/10/11
Y1 - 2005/10/11
N2 - The mechanism by which hypoxia [low partial pressure of O2 (pO2)] elicits signaling to regulate pulmonary arterial pressure is incompletely understood. We considered the possibility that, in addition to its effects on smooth muscle, hypoxia may influence pulmonary vascular tone through an effect on RBCs. We report that exposure of native RBCs to sustained hypoxia is accompanied by a buildup of heme iron-nitrosyl (FeNO) species that are deficient in pO2-governed intramolecular transfer of NO to cysteine thiol, yielding a deficiency in the vasodilator S-nitrosohemoglobin (SNO-Hb). S-nitrosothiol (SNO)-deficient RBCs produce impaired vasodilator responses in vitro and exaggerated pulmonary vasoconstrictor responses in vivo and are defective in oxygenating the blood. RBCs from hypoxemic patients with elevated pulmonary arterial pressure (PAP) exhibit a similar FeNO/SNO imbalance and are thus deficient in pO2-coupled vasoregulation. Chemical restoration of SNO-Hb levels in both animals and patients restores the vasodilator activity of RBCs, and this activity is associated with improved oxygenation and lower PAPs.
AB - The mechanism by which hypoxia [low partial pressure of O2 (pO2)] elicits signaling to regulate pulmonary arterial pressure is incompletely understood. We considered the possibility that, in addition to its effects on smooth muscle, hypoxia may influence pulmonary vascular tone through an effect on RBCs. We report that exposure of native RBCs to sustained hypoxia is accompanied by a buildup of heme iron-nitrosyl (FeNO) species that are deficient in pO2-governed intramolecular transfer of NO to cysteine thiol, yielding a deficiency in the vasodilator S-nitrosohemoglobin (SNO-Hb). S-nitrosothiol (SNO)-deficient RBCs produce impaired vasodilator responses in vitro and exaggerated pulmonary vasoconstrictor responses in vivo and are defective in oxygenating the blood. RBCs from hypoxemic patients with elevated pulmonary arterial pressure (PAP) exhibit a similar FeNO/SNO imbalance and are thus deficient in pO2-coupled vasoregulation. Chemical restoration of SNO-Hb levels in both animals and patients restores the vasodilator activity of RBCs, and this activity is associated with improved oxygenation and lower PAPs.
KW - Hemoglobin
KW - Red blood cell vasodilation
KW - S-nitrosylation
UR - http://www.scopus.com/inward/record.url?scp=26844439856&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=26844439856&partnerID=8YFLogxK
U2 - 10.1073/pnas.0506957102
DO - 10.1073/pnas.0506957102
M3 - Article
C2 - 16203976
AN - SCOPUS:26844439856
VL - 102
SP - 14801
EP - 14806
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 41
ER -