Abstract 3430: Left Ventricular Hypertrophy and Diastolic Dysfunction in Mice Lacking All Nitric Oxide Synthase Isoforms
We have recently succeeded in developing mice in which all three nitric oxide synthase isoforms (nNOS, iNOS, and eNOS) are completely disrupted (PNAS 2005). In this study, we examined cardiac morphology and function in those mice. Cardiac echocardiography and left ventricular (LV) hemodynamic measurement were performed in male wild-type (WT), singly nNOS−/−, iNOS−/−, eNOS−/−, and triply n/i/eNOS−/− mice at 2 and 5 months of age (n=5–8). At 2 months of age, no significant cardiac morphological or functional changes were detected in any strains studied. However, at 5 months of age, significant LV hypertrophy (wall thickness, mm) were noted in the triply n/i/eNOS−/− mice (1.3±0.1, P<0.01) and to a lesser extent in the singly eNOS−/− mice (1.1±0.1, P<0.05), but not in the singly nNOS−/− (0.8±0.1) or iNOS−/− mice (1.0±0.1), as compared with the WT mice (1.0±0.2). Furthermore, significant LV diastolic dysfunction (as evaluated by echocardiographic E/A ratio and by hemodynamic peak negative dP/dt), with preserved LV systolic function (as assessed by echocardiographic ejection fraction and by hemodynamic peak positive dP/dt), was noted only in the 5-month-old triply n/i/eNOS−/−mice (2.7±0.1 and 2505±60, both P<0.05), but not in any singly nNOS−/− (2.1±0.2 and 3833±402), iNOS−/− (2.0±0.1 and 3773±747), or eNOS−/− mice (2.0±0.3 and 2934±122), as compared with the WT mice (1.9±0.1 and 4038±344). In addition, significant cardiac fibrosis (fibrosis area, %, Masson-trichrome staining) was also detected only in the 5-month-old triply n/i/eNOS−/− mice (1.4±0.2, P<0.05) compared with the WT mice (0.3±0.1). Importantly, arterial blood pressure (mmHg, tail-cuff method) was significantly elevated in the triply n/i/eNOS−/− (143±3.1, P<0.05) than in the WT mice (104±7.3), but the hypertensive level was comparable to that in the singly eNOS−/− mice (140±8.5). Thus, mechanism(s) other than hypertension appears to be involved in the cardiac abnormalities of the triply n/i/eNOS−/− mice. These results provide the first evidence that genetic disruption of all NOSs results in LV hypertrophy and diastolic dysfunction in mice in vivo, suggesting a pivotal role of the NOS system in maintaining cardiac homeostasis.