Article (Scientific journals)
Cardiomyocyte-restricted overexpression of endothelial nitric oxide synthase (NOS3) attenuates beta-adrenergic stimulation and reinforces vagal inhibition of cardiac contraction.
MASSION, Paul; Dessy, Chantal; Desjardins, Fanny et al.
2004In Circulation, 110 (17), p. 2666-72
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Keywords :
Adrenergic beta-Agonists/pharmacology; Animals; Caveolae/chemistry; Caveolin 3; Caveolins/analysis; Gene Expression; Isoproterenol/antagonists & inhibitors; Mice; Mice, Transgenic; Muscarinic Agonists/pharmacology; Myocardial Contraction/drug effects; Myocytes, Cardiac/drug effects/enzymology/physiology; Neural Inhibition; Nitric Oxide Synthase/analysis/genetics/metabolism; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Vagus Nerve/physiology
Abstract :
[en] BACKGROUND: In the heart, nitric oxide synthases (NOS) modulate cardiac contraction in an isoform-specific manner, which is critically dependent on their cellular and subcellular localization. Defective NO production by NOS3 (endothelial NOS [eNOS]) in the failing heart may precipitate cardiac failure, which could be reversed by overexpression of NOS3 in the myocardium. METHODS AND RESULTS: We studied the influence of NOS3 in relation to its subcellular localization on the function of cardiomyocytes isolated from transgenic mice overexpressing NOS3 under the alpha-myosin heavy chain promoter (NOS3-TG). Immunoblot analysis demonstrated moderate (5-fold) NOS3 overexpression in cardiomyocytes from NOS3-TG heterozygotes. Caveolar localization of transgenic eNOS was demonstrated by immunofluorescence, coimmunoprecipitation with caveolin-3, sucrose gradient fractionation, and immunogold staining revealed by electron microscopy. Compared with wild-type littermate, contractility of NOS3-TG cardiomyocytes analyzed by videomicroscopy revealed a lower incidence of spontaneous arrhythmic contractions (n=32, P<0.001); an attenuation of the beta-adrenergic positive inotropic response (isoproterenol, 10(-7) mol/L: 62.1+/-7.8% versus 90.8+/-8.0% of maximum Ca2+ response; n=10 to 17; P<0.05); a potentiation of the muscarinic negative chronotropic response (carbamylcholine, 3.10(-8) mol/L: -63.9+/-14% versus -27.7+/-5.6% of basal rate; n=8 to 10; P<0.05), confirmed by telemetry in vivo; and an attenuation of the accentuated antagonism of beta-adrenergically stimulated contraction (-14.6+/-1.5% versus -3.5+/-1.5; n=7 to 11; P<0.05). Cardiomyocyte NOS inhibition reversed all 4 effects (P<0.05). CONCLUSIONS: Moderate overexpression of NOS3, targeted to caveolae in murine cardiomyocytes, potentiates the postsynaptic muscarinic response and attenuates the effect of high concentrations of catecholamines. Cardiomyocyte NOS3 may represent a promising therapeutic target to restore the sympathovagal balance and protect the heart against arrhythmia.
Disciplines :
Anesthesia & intensive care
Author, co-author :
MASSION, Paul ;  Centre Hospitalier Universitaire de Liège - CHU > Soins intensifs
Dessy, Chantal
Desjardins, Fanny
Pelat, Michel
Havaux, Xavier
Belge, Catharina
Moulin, Pierre
Guiot, Yves
Feron, Olivier
Janssens, Stefan
Balligand, Jean-Luc
Language :
English
Title :
Cardiomyocyte-restricted overexpression of endothelial nitric oxide synthase (NOS3) attenuates beta-adrenergic stimulation and reinforces vagal inhibition of cardiac contraction.
Publication date :
2004
Journal title :
Circulation
ISSN :
0009-7322
eISSN :
1524-4539
Publisher :
Lippincott Williams & Wilkins, Hagerstown, United States - Maryland
Volume :
110
Issue :
17
Pages :
2666-72
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 30 January 2012

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