Spontaneous development of left ventricular hypertrophy and diastolic dysfunction in mice lacking all nitric oxide synthases.
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.


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 (AT(1)) 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 AT(1) receptor pathway, demonstrating a pivotal role of the endogenous NOS system in maintaining cardiac homeostasis.
Second Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan.
Kiyoko
K
Shibata
Yasuko
Y
Yatera
Yumi
Y
Furuno
Ken
K
Sabanai
Naoya
N
Morisada
Sei
S
Nakata
Tsuyoshi
T
Morishita
Fumio
F
Yamazaki
Akihide
A
Tanimoto
Yasuyuki
Y
Sasaguri
Hiromi
H
Tasaki
Yasuhide
Y
Nakashima
Hiroaki
H
Shimokawa
Nobuyuki
N
Yanagihara
Yutaka
Y
Otsuji
Masato
M
Tsutsui
D000818:Animals; D004452:Echocardiography; D006706:Homeostasis; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism
D044140:Receptor, Angiotensin, Type 1; D019001:Nitric Oxide Synthase