Nitric Oxide Synthases and Heart Failure ― Lessons from Genetically Manipulated Mice

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  • SHIBATA Kiyoko
    Department of Second Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.
  • SHIMOKAWA Hiroaki
    Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan.
  • YANAGIHARA Nobuyuki
    Department of Pharmacology, School of Medicine University of Occupational and Environmental Health, Japan.
  • OTSUJI Yutaka
    Department of Second Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.
  • TSUTSUI Masato
    Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Japan.

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Other Title
  • 一酸化窒素合成酵素と心不全― 遺伝子改変マウスからの教訓

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Abstract

Nitric oxide (NO) is synthesized by three distinct NO synthase (NOS) isoforms (neuronal, inducible, and endothelial NOS), all of which are expressed in the human heart. The roles of NOSs in the pathogenesis of heart failure have been described in pharmacological studies with NOS inhibitors. Recently, genetically engineered animals have been used. We have generated mice in which all 3 NOS isoforms are completely disrupted (triple n/i/eNOS-/- mice). Morphological, echocardiographic, and hemodynamic analysis were performed in wild-type, singly nNOS-/-, iNOS-/-, eNOS-/-, and triple n/i/eNOS-/- mice. Importantly, significant left ventricular (LV) hypertrophy and diastolic dysfunction was noted only in n/i/eNOS-/- mice, and those pathology was similar to diastolic heart failure in humans. Finally, treatment with an angiotensin II type 1 (AT1) receptor blocker, significantly prevented those abnormalities. These results provide the evidence that AT1 receptor pathway plays a center role in the pathogenesis of cardiac disorders in the n/i/eNOS-/- mice. Our studies with triple n/i/eNOS-/- mice provide pivotal insights into an understanding of the pathophysiology of NOSs in human heart failure.

Journal

  • Journal of UOEH

    Journal of UOEH 35 (2), 147-158, 2013

    The University of Occupational and Environmental Health, Japan

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