Reference : Cardiomyocyte-restricted overexpression of endothelial nitric oxide synthase (NOS3) atte...
Scientific journals : Article
Human health sciences : Anesthesia & intensive care
Cardiomyocyte-restricted overexpression of endothelial nitric oxide synthase (NOS3) attenuates beta-adrenergic stimulation and reinforces vagal inhibition of cardiac contraction.
MASSION, Paul mailto [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 [> > > >]
Lippincott Williams & Wilkins
Yes (verified by ORBi)
[en] 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
[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.

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