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

Kiyoko Shibata, Yasuko Yatera, Yumi Furuno, Ken Sabanai, Naoya Morisada, Sei Nakata, Tsuyoshi Morishita, Fumio Yamazaki, Akihide Tanimoto, Yasuyuki Sasaguri, Hiromi Tasaki, Yasuhide Nakashima, Hiroaki Shimokawa, Nobuyuki Yanagihara, Yutaka Otsuji, Masato Tsutsui

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12 Citations (Scopus)

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 wildtype (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.

Original languageEnglish
Pages (from-to)2681-2692
Number of pages12
JournalCirculation Journal
Volume74
Issue number12
DOIs
Publication statusPublished - 2010 Dec 8

Keywords

  • Diastolic heart failure
  • Left ventricular hypertrophy
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Shibata, K., Yatera, Y., Furuno, Y., Sabanai, K., Morisada, N., Nakata, S., Morishita, T., Yamazaki, F., Tanimoto, A., Sasaguri, Y., Tasaki, H., Nakashima, Y., Shimokawa, H., Yanagihara, N., Otsuji, Y., & Tsutsui, M. (2010). Spontaneous development of left ventricular hypertrophy and diastolic dysfunction in mice lacking all nitric oxide synthases. Circulation Journal, 74(12), 2681-2692. https://doi.org/10.1253/circj.CJ-10-0277