Abstract 15023: Spontaneous Development of Left Ventricular Hypertrophy and Diastolic Dysfunction in Mice Lacking All Nitric Oxide Synthases
Background: The role of nitric oxide synthases (nNOS, iNOS, and eNOS) in cardiac remodeling has been examined in pharmacological studies with NOS inhibitors. However, due to the non-specificity of the agents, its authentic role still remains to be fully elucidated. We addressed this point in mice lacking all three NOS genes.
Methods and Results: Morphological, echocardiographic, and hemodynamic analyses were performed in wild-type (WT), singly nNOS−/−, iNOS−/−, eNOS−/−, and triply n/i/eNOS−/− mice (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 left ventricular (LV) hypertrophy (LVH, mm) was noted in n/i/eNOS−/− mice (1.3±0.1, P<0.01) and to a lesser extent in eNOS−/− mice (1.1±0.1, P<0.05), but not in nNOS−/− or iNOS−/− mice, as compared with WT mice (1.0±0.2). Importantly, significant LV diastolic dysfunction (as evaluated by hemodynamic -dP/dt [mmHg/s] and Tau [ms]), with preserved LV systolic function (as assessed by echocardiographic fractional shortening and hemodynamic +dP/dt), was noted only in n/i/eNOS−/− mice (2505±60 and 42±4, both P<0.05), but not in any singly NOS−/− mice, compared with WT mice (4038±344 and 19±2), and this was associated with enhanced LV end-diastolic pressure (6.2±1.0 vs. 1.7±0.2 mmHg in WT, P<0.05). A significant increase in urinary 8-isoprostane (IP), a marker of oxidative stress, was also noted only in n/i/eNOS−/− mice compared with WT mice (16±3 vs. 3±3 ng/day, P<0.05). Finally, long-term oral treatment with the angiotensin II type 1 (AT1) receptor blocker olmesartan, but not with the equi-potent antihypertensive drug hydralazine, significantly prevented all these abnormalities of n/i/eNOS−/− mice (1.0±0.3 in LVH, 4099±302 in -dP/dt, 24±7 in Tau, 2.5±0.4 in LVEDP, and 3.9±1.0 in 8-IP, all P<0.05), suggesting a minor role of hypertension in the development of cardiac abnormalities in the triply mutant model.
Conclusions: These results provide the first direct evidence that the complete disruption of all NOS genes results in LVH and diastolic dysfunction in mice in vivo through the AT1 receptor pathway, demonstrating a pivotal role of the endogenous NO/NOS system in maintaining cardiac homeostasis.
- © 2010 by American Heart Association, Inc.