Publication Date:
2012-11-06
Description:
Models of unregulated nitric oxide (NO) diffusion do not consistently account for the biochemistry of NO synthase (NOS)-dependent signalling in many cell systems. For example, endothelial NOS controls blood pressure, blood flow and oxygen delivery through its effect on vascular smooth muscle tone, but the regulation of these processes is not adequately explained by simple NO diffusion from endothelium to smooth muscle. Here we report a new model for the regulation of NO signalling by demonstrating that haemoglobin (Hb) alpha (encoded by the HBA1 and HBA2 genes in humans) is expressed in human and mouse arterial endothelial cells and enriched at the myoendothelial junction, where it regulates the effects of NO on vascular reactivity. Notably, this function is unique to Hb alpha and is abrogated by its genetic depletion. Mechanistically, endothelial Hb alpha haem iron in the Fe(3+) state permits NO signalling, and this signalling is shut off when Hb alpha is reduced to the Fe(2+) state by endothelial cytochrome b5 reductase 3 (CYB5R3, also known as diaphorase 1). Genetic and pharmacological inhibition of CYB5R3 increases NO bioactivity in small arteries. These data reveal a new mechanism by which the regulation of the intracellular Hb alpha oxidation state controls NOS signalling in non-erythroid cells. This model may be relevant to haem-containing globins in a broad range of NOS-containing somatic cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531883/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531883/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Straub, Adam C -- Lohman, Alexander W -- Billaud, Marie -- Johnstone, Scott R -- Dwyer, Scott T -- Lee, Monica Y -- Bortz, Pamela Schoppee -- Best, Angela K -- Columbus, Linda -- Gaston, Benjamin -- Isakson, Brant E -- HL007284/HL/NHLBI NIH HHS/ -- HL059337/HL/NHLBI NIH HHS/ -- HL088554/HL/NHLBI NIH HHS/ -- HL101871/HL/NHLBI NIH HHS/ -- HL107963/HL/NHLBI NIH HHS/ -- HL112904/HL/NHLBI NIH HHS/ -- R00 HL112904/HL/NHLBI NIH HHS/ -- R01 HL088554/HL/NHLBI NIH HHS/ -- R21 HL107963/HL/NHLBI NIH HHS/ -- England -- Nature. 2012 Nov 15;491(7424):473-7. doi: 10.1038/nature11626. Epub 2012 Oct 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23123858" target="_blank"〉PubMed〈/a〉
Keywords:
Adrenergic alpha-1 Receptor Agonists/pharmacology
;
Animals
;
Cells, Cultured
;
Diffusion
;
Endothelial Cells/drug effects/enzymology/*metabolism
;
Gene Expression Profiling
;
*Gene Expression Regulation/drug effects
;
Hemoglobins/genetics/*metabolism
;
Humans
;
Iron/chemistry
;
Mice
;
Nitric Oxide/*metabolism
;
Nitric Oxide Synthase/metabolism
;
Oxidation-Reduction
;
Peptide Fragments/genetics/*metabolism
;
Phenylephrine/pharmacology
;
*Signal Transduction
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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