Pathophysiological relevance of NO signaling in the cardiovascular system: Novel insight from mice lacking all NO synthases

Masato Tsutsui, Hiroaki Shimokawa, Yutaka Otsuji, Nobuyuki Yanagihara

Research output: Contribution to journalReview articlepeer-review

58 Citations (Scopus)


Nitric oxide (NO) exerts a variety of biological actions under both physiological and pathological conditions. NO is synthesized by three distinct NO synthase (NOS) isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS), all of which are expressed in the human cardiovascular system. The roles of endogenous NO in the cardiovascular system have been investigated in pharmacological studies with NOS inhibitors and in studies with mice that lack each NOS isoform. However, in the pharmacological studies, the specificity of the NOS inhibitors continues to be an issue of debate, while in each of the NOS isoform-deficient mice, a compensatory mechanism by other NOSs that are not genetically deleted is apparently involved. Thus, the authentic roles of endogenous NO are still poorly understood. To address this issue, genetically engineered mice in which all three NOS genes are completely disrupted have been developed. In the triply n/i/eNOS-/- mice, but not in singly eNOS-/- mice, several cardiovascular phenotypes, including arteriosclerosis/atherosclerosis, myocardial infarction, and dyslipidemia, have been described. Furthermore, by using the triply NOS-/- mice, the roles of the NOS system in endothelium-dependent hyperpolarization and stain-induced NO production have been elucidated. These results provide novel insight into the cardiovascular role of the endogenous NO/NOS system at the molecular level. This review, based on the research outcomes obtained from the triply NOS-/- genetic model, summarizes the latest knowledge of the pathophysiological relevance of NO signaling in the cardiovascular system.

Original languageEnglish
Pages (from-to)499-508
Number of pages10
JournalPharmacology and Therapeutics
Issue number3
Publication statusPublished - 2010 Dec


  • Cardiovascular disease
  • Knockout mice
  • Lipid metabolism
  • Myocardial infarction
  • Nitric oxide
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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