Spontaneous Development of Left Ventricular Hypertrophy and Diastolic Dysfunction in Mice Lacking All Nitric Oxide Synthases

Abstract

Background: The role of the nitric oxide synthase (NOS) system in cardiac architecture and function remains unknown. This point was addressed in mice that lack all 3 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. At 5 months of age, but not at 2 months of age, significant left ventricular (LV) hypertrophy was noted in n/i/eNOS^-/- mice and to a lesser extent in eNOS^-/- mice, but not in nNOS^-/- or iNOS^-/- mice, compared with WT mice. Importantly, significant LV diastolic dysfunction (as evaluated by echocardiographic E/A wave ratio and hemodynamic -dP/dt and Tau), with preserved LV systolic function (as assessed by echocardiographic fractional shortening and hemodynamic +dP/dt), was noted only in n/i/eNOS^-/- mice, and this was associated with enhanced LV end-diastolic pressure and increased lung wet weight, all of which are characteristics consistent with diastolic heart failure in humans. Finally, long-term oral treatment with an angiotensin II type 1 (AT₁) receptor blocker, olmesartan, significantly prevented all these abnormalities of n/i/eNOS^-/- mice. Conclusions: These results provide the first direct evidence that the complete disruption of all NOSs results in LV hypertrophy and diastolic dysfunction in mice in vivo through the AT₁ receptor pathway, demonstrating a pivotal role of the endogenous NOS system in maintaining cardiac homeostasis. (Circ J 2010; 74: 2681-2692)