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

• DOI: 10.1161/circulationaha.107.741702
• Publication Date: 2008-06-10T00:54:36Z
• Authors: Xavier Loyer; Ana Maria Gómez; Paul Milliez; Maria Fernandez-V...; Peter Vangheluwe; Laurent Vinet; Dominique Charue; Emilie Vaudin; Wei Zhang; Yannis Sainte-Marie; Estelle Robidel; Isabelle Marty; Bernd Mayer; Frédéric Jaisser; Jean-Jacques Merc...; Sylvain Richard; Ajay M. Shah; Jean-Pierre Bénitah; Jane-Lise Samuel; Christophe Heymes
• Keywords: MESH: Signal Transduction; MESH: Myocardial Contraction; Left; [SDV.BBM]Life Sciences [q-bio]/Biochemistry; MESH: Myocytes, Cardiac; heart failure; MESH: Nitric Oxide Synthase Type I; Blood Pressure; Cell Separation; Nitric Oxide Synthase Type I; Transgenic; MESH: Ventricular Function, Left; Ventricular Function, Left; Mice; MESH: Myocytes; MESH: Reverse Transcriptase Polymerase Chain Reaction; MESH: Animals; Myocytes, Cardiac; Aorta; remodeling; 0303 health sciences; nitric oxide synthase; Reverse Transcriptase Polymerase Chain Reaction; MESH: Aorta; MESH: Blood Pressure; 3. Good health; MESH: Calcium; Disease Progression; MESH: Disease Progression; hypertrophy; Cardiac; Signal Transduction; MESH: Enzyme Activation; MESH: Mice, Transgenic; 610; Mice, Transgenic; MESH: Cell Separation; 03 medical and health sciences; MESH: Ventricular Function; [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology; Animals; Humans; [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology; Molecular Biology; MESH: Mice; Heart Failure; MESH: Humans; calcium; Animal; Myocardial Contraction; Enzyme Activation; Disease Models, Animal; MESH: Heart Failure; Calcium; MESH: Disease Models; MESH: Disease Models, Animal

Background—

Defects in cardiomyocyte Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ transients, and sarcoplasmic reticulum Ca 2+ 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.