Document Detail


Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation.
MedLine Citation:
PMID:  22685116     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Hypoxic vasodilation is a physiological response to low oxygen tension that increases blood supply to match metabolic demands. Although this response has been characterized for >100 years, the underlying hypoxic sensing and effector signaling mechanisms remain uncertain. We have shown that deoxygenated myoglobin in the heart can reduce nitrite to nitric oxide (NO·) and thereby contribute to cardiomyocyte NO· signaling during ischemia. On the basis of recent observations that myoglobin is expressed in the vasculature of hypoxia-tolerant fish, we hypothesized that endogenous nitrite may contribute to physiological hypoxic vasodilation via reactions with vascular myoglobin to form NO·.
METHODS AND RESULTS: We show in the present study that myoglobin is expressed in vascular smooth muscle and contributes significantly to nitrite-dependent hypoxic vasodilation in vivo and ex vivo. The generation of NO· from nitrite reduction by deoxygenated myoglobin activates canonical soluble guanylate cyclase/cGMP signaling pathways. In vivo and ex vivo vasodilation responses, the reduction of nitrite to NO·, and the subsequent signal transduction mechanisms were all significantly impaired in mice without myoglobin. Hypoxic vasodilation studies in myoglobin and endothelial and inducible NO synthase knockout models suggest that only myoglobin contributes to systemic hypoxic vasodilatory responses in mice.
CONCLUSIONS: Endogenous nitrite is a physiological effector of hypoxic vasodilation. Its reduction to NO· via the heme globin myoglobin enhances blood flow and matches O(2) supply to increased metabolic demands under hypoxic conditions.
Authors:
Matthias Totzeck; Ulrike B Hendgen-Cotta; Peter Luedike; Michael Berenbrink; Johann P Klare; Heinz-Juergen Steinhoff; Dominik Semmler; Sruti Shiva; Daryl Williams; Anja Kipar; Mark T Gladwin; Juergen Schrader; Malte Kelm; Andrew R Cossins; Tienush Rassaf
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-09
Journal Detail:
Title:  Circulation     Volume:  126     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-17     Completed Date:  2012-10-02     Revised Date:  2013-07-19    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  325-34     Citation Subset:  AIM; IM    
Affiliation:
Department of Medicine, Division of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Duesseldorf, Germany.
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MeSH Terms
Descriptor/Qualifier:
Adaptation, Physiological / physiology
Animals
Anoxia / metabolism*,  physiopathology*
Cardiac Output / physiology
Guanylate Cyclase / metabolism
Mice
Mice, Mutant Strains
Muscle, Smooth, Vascular / physiology
Myoglobin / genetics,  metabolism*
Nitric Oxide / biosynthesis*,  metabolism
Nitric Oxide Synthase Type II / genetics,  metabolism
Nitric Oxide Synthase Type III / genetics,  metabolism
Nitrites / metabolism*
Oxygen / blood
Receptors, Cytoplasmic and Nuclear / metabolism
Signal Transduction / physiology
Vasodilation / physiology*
Grant Support
ID/Acronym/Agency:
P01HL103455/HL/NHLBI NIH HHS; R01 HL096973/HL/NHLBI NIH HHS; R01 HL098032/HL/NHLBI NIH HHS; R01HL096973/HL/NHLBI NIH HHS; R01HL098032/HL/NHLBI NIH HHS; //Biotechnology and Biological Sciences Research Council
Chemical
Reg. No./Substance:
0/Myoglobin; 0/Nitrites; 0/Receptors, Cytoplasmic and Nuclear; 10102-43-9/Nitric Oxide; 7782-44-7/Oxygen; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos2 protein, mouse; EC 1.14.13.39/Nos3 protein, mouse; EC 4.6.1.2/Guanylate Cyclase; EC 4.6.1.2/soluble guanylyl cyclase
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