This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dawson, D. Articles by Casadei, B. Search for Related Content PubMed PubMed Citation Articles by Dawson, D. Articles by Casadei, B. Related Collections Contractile function Animal models of human disease Genetically altered mice Heart failure - basic studies

(Circulation. 2005;112:3729-3737.)
© 2005 American Heart Association, Inc.

Heart Failure

nNOS Gene Deletion Exacerbates Pathological Left Ventricular Remodeling and Functional Deterioration After Myocardial Infarction

Dana Dawson, MBBS, MRCP^*; Craig A. Lygate, PhD, MRPharmS^*; Mei-Hua Zhang, PhD; Karen Hulbert, BSc; Stefan Neubauer, MD, FRCP; Barbara Casadei, MD, DPhil, FRCP

From the Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, England.

Correspondence to Barbara Casadei, MD, DPhil, FRCP, University Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail barbara.casadei{at}cardiov.ox.ac.uk

Received February 4, 2005; revision received August 1, 2005; accepted September 1, 2005.

Background— The neuronal isoform of nitric oxide synthase (nNOS) has been implicated in the regulation of basal and ß-adrenergic inotropy in normal and chronically infarcted hearts. Furthermore, myocardial nNOS expression and activity increase in failing hearts, raising the possibility that nNOS may influence left ventricular (LV) remodeling progression and functional deterioration after myocardial infarction (MI)

Methods and Results— We compared LV remodeling at 1, 4, and 8 weeks after MI in nNOS-knockout mice (nNOS^–/–) and their wild-type (WT) littermates matched for infarct size by using a highly accurate 3-dimensional echocardiographic technique. Basal LV hemodynamics and the inotropic response to dobutamine infusion (4 and 16 ng · g^–1 · min^–1) were also evaluated 8 weeks after MI. Sham-operated nNOS^–/– mice showed enhanced basal LV contractility (P<0.03 versus WT, as evaluated by preload-recruitable stroke work) but an attenuated inotropic response to dobutamine infusion (P<0.01 versus WT). Both basal and ß-adrenergic LV relaxations were significantly impaired in nNOS^–/– mice. Survival after MI did not differ between groups. However, nNOS^–/– mice developed a faster and more severe LV dilation compared with WT mice (P<0.05 for both end-systolic and end-diastolic volume indices). WT mice maintained a positive inotropic response to dobutamine 8 weeks after MI. In contrast, infarcted nNOS^–/– mice responded to dobutamine with a dramatic fall in LV contractility (P<0.01 for preload-recruitable stroke work).

Conclusions— nNOS plays a crucial role in preventing adverse LV remodeling and maintaining myocardial ß-adrenergic reserve after MI. Taken together, our findings suggest that upregulation of myocardial nNOS in infarcted hearts may be an important adaptive mechanism.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				D. E. Burger, X. Lu, M. Lei, F.-L. Xiang, L. Hammoud, M. Jiang, H. Wang, D. L. Jones, S. M. Sims, and Q. Feng Neuronal Nitric Oxide Synthase Protects Against Myocardial Infarction-Induced Ventricular Arrhythmia and Mortality in Mice Circulation, October 6, 2009; 120(14): 1345 - 1354. [Abstract] [Full Text] [PDF]

				J. L. Durand, S. Mukherjee, F. Commodari, A. P. De Souza, D. Zhao, F. S. Machado, H. B. Tanowitz, and L. A. Jelicks Role of NO Synthase in the Development of Trypanosoma cruzi-Induced Cardiomyopathy in Mice Am J Trop Med Hyg, May 1, 2009; 80(5): 782 - 787. [Abstract] [Full Text] [PDF]

				T. M. A. Mohamed, D. Oceandy, S. Prehar, N. Alatwi, Z. Hegab, F. M. Baudoin, A. Pickard, A. O. Zaki, R. Nadif, E. J. Cartwright, et al. Specific Role of Neuronal Nitric-oxide Synthase when Tethered to the Plasma Membrane Calcium Pump in Regulating the {beta}-Adrenergic Signal in the Myocardium J. Biol. Chem., May 1, 2009; 284(18): 12091 - 12098. [Abstract] [Full Text] [PDF]

				X. Loyer, A. M. Gomez, P. Milliez, M. Fernandez-Velasco, P. Vangheluwe, L. Vinet, D. Charue, E. Vaudin, W. Zhang, Y. Sainte-Marie, et al. Cardiomyocyte Overexpression of Neuronal Nitric Oxide Synthase Delays Transition Toward Heart Failure in Response to Pressure Overload by Preserving Calcium Cycling Circulation, June 24, 2008; 117(25): 3187 - 3198. [Abstract] [Full Text] [PDF]

				S. Pons, V. Griol-Charhbili, C. Heymes, P. Fornes, D. Heudes, A. Hagege, X. Loyer, P. Meneton, J.-F. Giudicelli, J.-L. Samuel, et al. Tissue kallikrein deficiency aggravates cardiac remodelling and decreases survival after myocardial infarction in mice Eur J Heart Fail, April 1, 2008; 10(4): 343 - 351. [Abstract] [Full Text] [PDF]

				Y. H. Zhang, M. H. Zhang, C. E. Sears, K. Emanuel, C. Redwood, A. El-Armouche, E. G. Kranias, and B. Casadei Reduced Phospholamban Phosphorylation Is Associated With Impaired Relaxation in Left Ventricular Myocytes From Neuronal NO Synthase-Deficient Mice Circ. Res., February 1, 2008; 102(2): 242 - 249. [Abstract] [Full Text] [PDF]

				G. Lim, L. Venetucci, D. A. Eisner, and B. Casadei Does nitric oxide modulate cardiac ryanodine receptor function? Implications for excitation-contraction coupling Cardiovasc Res, January 15, 2008; 77(2): 256 - 264. [Abstract] [Full Text] [PDF]

				V. W.T. Liu and P. L. Huang Cardiovascular roles of nitric oxide: A review of insights from nitric oxide synthase gene disrupted mice Cardiovasc Res, January 1, 2008; 77(1): 19 - 29. [Abstract] [Full Text] [PDF]

				M. H. Vandsburger, B. A. French, P. A. Helm, R. J. Roy, C. M. Kramer, A. A. Young, and F. H. Epstein Multi-parameter in vivo cardiac magnetic resonance imaging demonstrates normal perfusion reserve despite severely attenuated {beta}-adrenergic functional response in neuronal nitric oxide synthase knockout mice Eur. Heart J., November 2, 2007; 28(22): 2792 - 2798. [Abstract] [Full Text] [PDF]

				X. Loyer, P. Oliviero, T. Damy, E. Robidel, F. Marotte, C. Heymes, and J.-L. Samuel Effects of sex differences on constitutive nitric oxide synthase expression and activity in response to pressure overload in rats Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2650 - H2658. [Abstract] [Full Text] [PDF]

				J. M. Stewart, M. S. Medow, C. T. Minson, and I. Taneja Cutaneous neuronal nitric oxide is specifically decreased in postural tachycardia syndrome Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2161 - H2167. [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]

				H. Thibault, L. Gomez, E. Donal, G. Pontier, M. Scherrer-Crosbie, M. Ovize, and G. Derumeaux Acute myocardial infarction in mice: assessment of transmurality by strain rate imaging Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H496 - H502. [Abstract] [Full Text] [PDF]

				N. Burkard, A. G. Rokita, S. G. Kaufmann, M. Hallhuber, R. Wu, K. Hu, U. Hofmann, A. Bonz, S. Frantz, E. J. Cartwright, et al. Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility Circ. Res., February 16, 2007; 100(3): e32 - e44. [Abstract] [Full Text] [PDF]

				D. Oceandy, E. J. Cartwright, M. Emerson, S. Prehar, F. M. Baudoin, M. Zi, N. Alatwi, L. Venetucci, K. Schuh, J. C. Williams, et al. Neuronal Nitric Oxide Synthase Signaling in the Heart Is Regulated by the Sarcolemmal Calcium Pump 4b Circulation, January 30, 2007; 115(4): 483 - 492. [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]

				L. Nunez, M. Vaquero, R. Gomez, R. Caballero, P. Mateos-Caceres, C. Macaya, I. Iriepa, E. Galvez, A. Lopez-Farre, J. Tamargo, et al. Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism Cardiovasc Res, October 1, 2006; 72(1): 80 - 89. [Abstract] [Full Text] [PDF]

				R. Hataishi, A. C. Rodrigues, J. G. Morgan, F. Ichinose, G. Derumeaux, K. D. Bloch, M. H. Picard, and M. Scherrer-Crosbie Nitric oxide synthase 2 and pressure-overload-induced left ventricular remodelling in mice Exp Physiol, May 1, 2006; 91(3): 633 - 639. [Abstract] [Full Text] [PDF]

				H. Post and B. Pieske Arginase: a modulator of myocardial function Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1747 - H1748. [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]

				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]