Document Detail

Regulation of endothelial nitric-oxide synthase (NOS) S-glutathionylation by neuronal NOS: evidence of a functional interaction between myocardial constitutive NOS isoforms.
MedLine Citation:
PMID:  23091050     Owner:  NLM     Status:  MEDLINE    
Myocardial constitutive No production depends on the activity of both endothelial and neuronal NOS (eNOS and nNOS, respectively). Stimulation of myocardial β(3)-adrenergic receptor (β(3)-AR) produces a negative inotropic effect that is dependent on eNOS. We evaluated whether nNOS also plays a role in β(3)-AR signaling and found that the β(3)-AR-mediated reduction in cell shortening and [Ca(2+)](i) transient amplitude was abolished both in eNOS(-/-) and nNOS(-/-) left ventricular (LV) myocytes and in wild type LV myocytes after nNOS inhibition with S-methyl-L-thiocitrulline. LV superoxide (O(2)(·-)) production was increased in nNOS(-/-) mice and reduced by L-N(ω)-nitroarginine methyl ester (L-NAME), indicating uncoupling of eNOS activity. eNOS S-glutathionylation and Ser-1177 phosphorylation were significantly increased in nNOS(-/-) myocytes, whereas myocardial tetrahydrobiopterin, eNOS Thr-495 phosphorylation, and arginase activity did not differ between genotypes. Although inhibitors of xanthine oxidoreductase (XOR) or NOX2 NADPH oxidase caused a similar reduction in myocardial O(2)(·-), only XOR inhibition reduced eNOS S-glutathionylation and Ser-1177 phosphorylation and restored both eNOS coupled activity and the negative inotropic and [Ca(2+)](i) transient response to β(3)-AR stimulation in nNOS(-/-) mice. In summary, our data show that increased O(2)(·-) production by XOR selectively uncouples eNOS activity and abolishes the negative inotropic effect of β(3)-AR stimulation in nNOS(-/-) myocytes. These findings provide unequivocal evidence of a functional interaction between the myocardial constitutive NOS isoforms and indicate that aspects of the myocardial phenotype of nNOS(-/-) mice result from disruption of eNOS signaling.
Winifred O Idigo; Svetlana Reilly; Mei Hua Zhang; Yin Hua Zhang; Raja Jayaram; Ricardo Carnicer; Mark J Crabtree; Jean-Luc Balligand; Barbara Casadei
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-22
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-24     Completed Date:  2013-02-26     Revised Date:  2014-06-10    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  43665-73     Citation Subset:  IM    
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MeSH Terms
Arginase / genetics,  metabolism
Calcium Signaling / drug effects,  physiology*
Citrulline / analogs & derivatives,  pharmacology
Enzyme Inhibitors / pharmacology
Heart Ventricles / cytology,  enzymology
Isoenzymes / antagonists & inhibitors,  genetics,  metabolism
Membrane Glycoproteins / genetics,  metabolism
Mice, Knockout
Muscle Proteins / antagonists & inhibitors,  genetics,  metabolism*
Myocardium / cytology,  enzymology*
Myocytes, Cardiac / cytology,  enzymology*
NADPH Oxidase / genetics,  metabolism
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide Synthase Type I / antagonists & inhibitors,  genetics,  metabolism*
Nitric Oxide Synthase Type III / antagonists & inhibitors,  genetics,  metabolism*
Phosphorylation / drug effects,  physiology
Receptors, Adrenergic, beta-3 / genetics,  immunology
Superoxides / metabolism
Thiourea / analogs & derivatives,  pharmacology
Xanthine Dehydrogenase / genetics,  metabolism
Grant Support
090532//Wellcome Trust; RG/11/15/29375//British Heart Foundation; //British Heart Foundation; //Wellcome Trust
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Isoenzymes; 0/Membrane Glycoproteins; 0/Muscle Proteins; 0/Receptors, Adrenergic, beta-3; 11062-77-4/Superoxides; 156719-41-4/S-methylthiocitrulline; 29VT07BGDA/Citrulline; EC Oxide Synthase Type I; EC Oxide Synthase Type III; EC protein, mouse; EC protein, mouse; EC Dehydrogenase; EC protein, mouse; EC Oxidase; EC; GYV9AM2QAG/Thiourea; V55S2QJN2X/NG-Nitroarginine Methyl Ester

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