Cardiomyocyte overexpression of neuronal nitric oxide synthase delays transition toward heart failure in response to pressure overload by preserving calcium cycling

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.