on October 18, 2004
Published online before print October 18, 2004, doi: 10.1161/01.CIR.0000145608.80855.BC
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on March 15, 2004
From the Unit of Pharmacology and Therapeutics (P.B.M., C.D., F.D., M.P., C.B., O.F., J.-L.B.), FATH 5349, Unit of Cardiology (X.H.), Department of Medicine, Unit of Anatomopathology (P.M., Y.G.), Université Catholique de Louvain, Brussels, Belgium, and Division of Cardiology (S.J.), Katholieke Universiteit Leuven, Leuven, Belgium. * To whom correspondence should be addressed. E-mail: balligand{at}mint.ucl.ac.be.
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 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.
Revised on June 10, 2004
Accepted on June 17, 2004
Cardiomyocyte-Restricted Overexpression of Endothelial Nitric Oxide Synthase (NOS3) Attenuates
Paul B. Massion MD, 
-Adrenergic Stimulation and Reinforces Vagal Inhibition of Cardiac Contraction
-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 
-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 -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).
Key words: contractility • nitric oxide synthase • arrhythmia • acetylcholine • catecholamines
This article has been cited by other articles:
 |
|
 |
|
  K. E. Brack, V. H. Patel, R. Mantravardi, J. H. Coote, and G. A. Ng Direct evidence of nitric oxide release from neuronal nitric oxide synthase activation in the left ventricle as a result of cervical vagus nerve stimulation J. Physiol., June 15, 2009; 587(12): 3045 - 3054. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Balligand, O. Feron, and C. Dessy eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues Physiol Rev, April 1, 2009; 89(2): 481 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, M. J. Kohr, D. G. Wheeler, and M. T. Ziolo Endothelial nitric oxide synthase decreases {beta}-adrenergic responsiveness via inhibition of the L-type Ca2+ current Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1473 - H1480. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Saliez, C. Bouzin, G. Rath, P. Ghisdal, F. Desjardins, R. Rezzani, L.F. Rodella, J. Vriens, B. Nilius, O. Feron, et al. Role of Caveolar Compartmentation in Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxation: Ca2+ Signals and Gap Junction Function Are Regulated by Caveolin in Endothelial Cells Circulation, February 26, 2008; 117(8): 1065 - 1074. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Moniotte, C. Belge, B. Sekkali, P.B. Massion, B. Rozec, C. Dessy, and J.-L. Balligand Sepsis is associated with an upregulation of functional {beta}3 adrenoceptors in the myocardium Eur J Heart Fail, December 1, 2007; 9(12): 1163 - 1171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Lemmens, K. Doggen, and G. W. De Keulenaer Role of Neuregulin-1/ErbB Signaling in Cardiovascular Physiology and Disease: Implications for Therapy of Heart Failure Circulation, August 21, 2007; 116(8): 954 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Seddon, A. M. Shah, and B. Casadei Cardiomyocytes as effectors of nitric oxide signalling Cardiovasc Res, July 15, 2007; 75(2): 315 - 326. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Takimoto, D. Belardi, C. G. Tocchetti, S. Vahebi, G. Cormaci, E. A. Ketner, A. L. Moens, H. C. Champion, and D. A. Kass Compartmentalization of Cardiac {beta}-Adrenergic Inotropy Modulation by Phosphodiesterase Type 5 Circulation, April 24, 2007; 115(16): 2159 - 2167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Ichinose, E. S. Buys, T. G. Neilan, E. M. Furutani, J. G. Morgan, D. S. Jassal, A. R. Graveline, R. J. Searles, C. C. Lim, M. Kaneki, et al. Cardiomyocyte-Specific Overexpression of Nitric Oxide Synthase 3 Prevents Myocardial Dysfunction in Murine Models of Septic Shock Circ. Res., January 5, 2007; 100(1): 130 - 139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Casadei The emerging role of neuronal nitric oxide synthase in the regulation of myocardial function Exp Physiol, November 1, 2006; 91(6): 943 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Elrod, J. J.M. Greer, N. S. Bryan, W. Langston, J. F. Szot, H. Gebregzlabher, S. Janssens, M. Feelisch, and D. J. Lefer Cardiomyocyte-Specific Overexpression of NO Synthase-3 Protects Against Myocardial Ischemia-Reperfusion Injury Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1517 - 1523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Davidson and M. R. Duchen Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance Cardiovasc Res, July 1, 2006; 71(1): 10 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Martin, K. Emanuel, C. E. Sears, Y.-H. Zhang, and B. Casadei Are myocardial eNOS and nNOS involved in the {beta}-adrenergic and muscarinic regulation of inotropy? A systematic investigation Cardiovasc Res, April 1, 2006; 70(1): 97 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Feron and J.-L. Balligand Caveolins and the regulation of endothelial nitric oxide synthase in the heart Cardiovasc Res, March 1, 2006; 69(4): 788 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Godecke On the impact of NO-globin interactions in the cardiovascular system Cardiovasc Res, February 1, 2006; 69(2): 309 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Balligand "La Donna e Mobile...": Is Cardiac Neuronal Nitric Oxide Synthase Such a Disconcerting Enzyme? Circulation, December 13, 2005; 112(24): 3668 - 3671. [Full Text] [PDF]
|
|
|
|
|
|
F. U. Muller Increased eNOS expression as a compensatory mechanism reducing {beta}-adrenergic responsiveness? Cardiovasc Res, September 1, 2005; 67(4): 575 - 577. [Full Text] [PDF]
|
|
|
|
|
|
E.J.F. Danson, Y.H. Zhang, C.E. Sears, A.R. Edwards, B. Casadei, and D.J. Paterson Disruption of inhibitory G-proteins mediates a reduction in atrial {beta}-adrenergic signaling by enhancing eNOS expression Cardiovasc Res, September 1, 2005; 67(4): 613 - 623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Wehling-Henricks, M. C. Jordan, K. P. Roos, B. Deng, and J. G. Tidball Cardiomyopathy in dystrophin-deficient hearts is prevented by expression of a neuronal nitric oxide synthase transgene in the myocardium Hum. Mol. Genet., July 15, 2005; 14(14): 1921 - 1933. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. O-Uchi, K. Komukai, Y. Kusakari, T. Obata, K. Hongo, H. Sasaki, and S. Kurihara {alpha}1-Adrenoceptor stimulation potentiates L-type Ca2+ current through Ca2+/calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes PNAS, June 28, 2005; 102(26): 9400 - 9405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Gonzales, F. A. Chung, S. Miranda, L. B. Valdez, T. Zaobornyj, J. Bustamante, and A. Boveris Heart mitochondrial nitric oxide synthase is upregulated in male rats exposed to high altitude (4,340 m) Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2568 - H2573. [Abstract] [Full Text] [PDF]
|
|