Severe dyslipidaemia, atherosclerosis, and sudden cardiac death in mice lacking all NO synthases fed a high-fat diet

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

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Aims The precise role of the nitric oxide synthase (NOS) system in lipid metabolism remains to be elucidated. We addressed this point in mice that we have recently developed and that lack all three NOS isoforms. Methods and results Wild-type (WT), singly, doubly, and triply NOS-/- mice were fed either a regular or high-cholesterol diet for 3-5 months. The high-cholesterol diet significantly increased serum low-density lipoprotein (LDL) cholesterol levels in all the genotypes when compared with the regular diet. Importantly, when compared with the WT genotype, the serum LDL cholesterol levels in the high-cholesterol diet were significantly and markedly elevated only in the triply NOS-/- genotype, but not in any singly or doubly NOS-/- genotypes, and this was associated with remarkable atherosclerosis and sudden cardiac death, which occurred mainly in the 4-5 months after the high-cholesterol diet. Finally, hepatic LDL receptor expression was markedly reduced only in the triply NOS-/- genotype, accounting for the diet-induced dyslipidaemia in the genotype. Conclusion These results provide the first direct evidence that complete disruption of all NOS genes causes severe dyslipidaemia, atherosclerosis, and sudden cardiac death in response to a high-fat diet in mice in vivo through the down-regulation of the hepatic LDL receptor, demonstrating the critical role of the whole endogenous NOS system in maintaining lipid homeostasis.

Original languageEnglish
Pages (from-to)675-682
Number of pages8
JournalCardiovascular Research
Volume87
Issue number4
DOIs
Publication statusPublished - 2010 Sep 1

Keywords

  • Atherosclerosis
  • Nitric oxide
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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