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

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  • Shibata Kiyoko
    Second Department of Internal Medicine, University of Occupational and Environmental Health
  • Yatera Yasuko
    Second Department of Internal Medicine, University of Occupational and Environmental Health
  • Furuno Yumi
    Second Department of Internal Medicine, University of Occupational and Environmental Health
  • Sabanai Ken
    Department of Pharmacology, University of Occupational and Environmental Health
  • Morisada Naoya
    Department of Pediatrics, University of Occupational and Environmental Health
  • Nakata Sei
    Second Department of Internal Medicine, University of Occupational and Environmental Health
  • Morishita Tsuyoshi
    Second Department of Internal Medicine, University of Occupational and Environmental Health
  • Yamazaki Fumio
    Division of Human Information and Life Sciences, University of Occupational and Environmental Health
  • Tanimoto Akihide
    Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences
  • Sasaguri Yasuyuki
    Department of Pathology, University of Occupational and Environmental Health
  • Tasaki Hiromi
    Second Department of Internal Medicine, University of Occupational and Environmental Health
  • Nakashima Yasuhide
    Second Department of Internal Medicine, University of Occupational and Environmental Health
  • Shimokawa Hiroaki
    Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
  • Yanagihara Nobuyuki
    Department of Pharmacology, University of Occupational and Environmental Health
  • Otsuji Yutaka
    Second Department of Internal Medicine, University of Occupational and Environmental Health
  • Tsutsui Masato
    Department of Pharmacology, University of Occupational and Environmental Health Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus

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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)<br>

Journal

  • Circulation Journal

    Circulation Journal 74 (12), 2681-2692, 2010

    The Japanese Circulation Society

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