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(Circulation. 2008;117:3187-3198.)
© 2008 American Heart Association, Inc.

Heart Failure

Cardiomyocyte Overexpression of Neuronal Nitric Oxide Synthase Delays Transition Toward Heart Failure in Response to Pressure Overload by Preserving Calcium Cycling

Xavier Loyer, PhD^*; Ana Maria Gómez, PhD^*; Paul Milliez, MD, PhD; Maria Fernandez-Velasco, PhD; Peter Vangheluwe, PhD; Laurent Vinet, BSc; Dominique Charue, BSc; Emilie Vaudin, BSc; Wei Zhang, BSc; Yannis Sainte-Marie, PhD; Estelle Robidel, BSc; Isabelle Marty, PhD; Bernd Mayer, PhD; Frédéric Jaisser, MD, PhD; Jean-Jacques Mercadier, MD, PhD; Sylvain Richard, PhD; Ajay M. Shah, MD, FRCP; Jean-Pierre Bénitah, PhD; Jane-Lise Samuel, MD, PhD; Christophe Heymes, PhD

From the Institut National de la Santé et de la Recherché Médicale (INSERM), Unit 689, Centre de Recherché Cardiovasculaire Lariboisière (X.L., P.M., D.C., E.V., W.Z., Y.S.-M., E.R., J.-L.S., C.H.), Paris, France; INSERM U637, UM1 (A.M.G., M.F.-V., S.R., J.-P.B.), CHU Arnaud de Villeneuve, Montpellier, France; INSERM U698, Centre Hospitalo-Universitaire Bichat (L.V., J.-J.M.), Paris, France; Department of Pharmacology and Toxicology, Karl Franzens Universität Graz (B.M.), Graz, Austria; INSERM U772, Collège de France (F.J.), Paris, France; King’s College London School of Medicine, Cardiovascular Division (A.M.S.), The James Black Centre, London, United Kingdom; Laboratory of Ca-transport ATPases (P.V.), Campus Gasthuisberg, Leuven, Belgium; and Grenoble Institut of Neurosciences (I.M.), INSERM U836, Grenoble, France.

Correspondence to Christophe Heymes, INSERM U689, Hôpital Lariboisière, 41 Boulevard de la Chapelle, 75475 Paris Cedex 10, France. E-mail christophe.heymes{at}inserm.fr

Received September 24, 2007; accepted April 18, 2008.

Background— Defects in cardiomyocyte Ca²⁺ cycling are a signature feature of heart failure (HF) that occurs in response to sustained hemodynamic overload, and they largely account for contractile dysfunction. Neuronal nitric oxide synthase (NOS1) influences myocyte excitation-contraction coupling through modulation of Ca²⁺ cycling, but the potential relevance of this in HF is unknown.

Methods and Results— We generated a transgenic mouse with conditional, cardiomyocyte-specific NOS1 overexpression (double-transgenic [DT]) and studied cardiac remodeling, myocardial Ca²⁺ handling, and contractility in DT and control mice subjected to transverse aortic constriction (TAC). After TAC, control mice developed eccentric hypertrophy with evolution toward HF as revealed by a significantly reduced fractional shortening. In contrast, DT mice developed a greater increase in wall thickness (P<0.0001 versus control+TAC) and less left ventricular dilatation than control+TAC mice (P<0.0001 for both end-systolic and end-diastolic dimensions). Thus, DT mice displayed concentric hypertrophy with fully preserved fractional shortening (43.7±0.6% versus 30.3±2.6% in control+TAC mice, P<0.05). Isolated cardiomyocytes from DT+TAC mice had greater shortening, intracellular Ca²⁺ transients, and sarcoplasmic reticulum Ca²⁺ load (P<0.05 versus control+TAC for all parameters). These effects could be explained, at least in part, through modulation of phospholamban phosphorylation status.

Conclusions— Cardiomyocyte NOS1 may be a useful target against cardiac deterioration during chronic pressure-overload–induced HF through modulation of calcium cycling.

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