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

Access this Article

Search this Article

Author(s)

    • 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
    • OTSUJI Yutaka
    • Second Department of Internal Medicine, University of Occupational and Environmental Health
    • TSUTSUI Masato
    • Department of Pharmacology, University of Occupational and Environmental Health

Abstract

<b><i>Background:</i></b> 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. <b><i>Methods and Results:</i></b> Morphological, echocardiographic, and hemodynamic analyses were performed in wild-type (WT), singly nNOS<sup>-/-</sup>, iNOS<sup>-/-</sup>, eNOS<sup>-/-</sup>, and triply n/i/eNOS<sup>-/-</sup> mice. At 5 months of age, but not at 2 months of age, significant left ventricular (LV) hypertrophy was noted in n/i/eNOS<sup>-/-</sup> mice and to a lesser extent in eNOS<sup>-/-</sup> mice, but not in nNOS<sup>-/-</sup> or iNOS<sup>-/-</sup> 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<sup>-/-</sup> 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<sub>1</sub>) receptor blocker, olmesartan, significantly prevented all these abnormalities of n/i/eNOS<sup>-/-</sup> mice. <b><i>Conclusions:</i></b> 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<sub>1</sub> receptor pathway, demonstrating a pivotal role of the endogenous NOS system in maintaining cardiac homeostasis. (<i>Circ J</i> 2010; <b>74:</b> 2681-2692)<br>

Journal

  • Circulation Journal

    Circulation Journal 74(12), 2681-2692, 2010-11-25

    The Japanese Circulation Society

References:  35

Cited by:  4

Codes

  • NII Article ID (NAID)
    10027424618
  • NII NACSIS-CAT ID (NCID)
    AA11591968
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    13469843
  • Data Source
    CJP  CJPref  J-STAGE 
Page Top