Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury

Ken Shinmura, Kayoko Tamaki, Kentaro Ito, Xiaoxiang Yan, Tsunehisa Yamamoto, Yoshinori Katsumata, Tomohiro Matsuhashi, Motoaki Sano, Keiichi Fukuda, Makoto Suematsu, Isao Ishii

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21 Citations (Scopus)

Abstract

Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion injury (IRI). We previously found that treatment with N<sup>G</sup>-nitro-L-arginine methyl ester completely abrogates CR-induced cardioprotection and increases nuclear sirtuin 1 (Sirt1) expression. However, it remains unclear whether endothelial nitric oxide (NO) synthase (eNOS) plays a role in CR-induced cardioprotection and Sirt1 activation. We subjected eNOS-deficient (eNOS<sup>−/−</sup>) mice to either 3-mo ad libitum (AL) feeding or CR (−40%). Isolated perfused hearts were subjected to 25-min global ischemia followed by 60-min reperfusion. The degree of myocardial IRI in AL-fed eNOS<sup>−/−</sup> mice was more severe than that in AL-fed wild-type mice. Furthermore, CR did not exert cardioprotection in eNOS<sup>−/−</sup> mice. eNOS<sup>−/−</sup> mice exhibited elevated blood pressure and left ventricular hypertrophy compared with wild-type mice, although they underwent CR. Although nuclear Sir1 content was increased, the increases in cardiac Sirt1 activity with CR was absent in eNOS<sup>−/−</sup> mice. In eNOS<sup>−/−</sup> mice treated with hydralazine, blood pressure and left ventricular weight became comparable with CR-treated wild-type mice. However, CR-induced cardioprotection was not observed. Resveratrol enhanced cardiac Sirt1 activity but failed to mimic CR-induced cardioprotection in eNOS<sup>−/−</sup>mice. Finally, combination therapy with resveratrol and hydralazine attenuated myocardial IRI and reduced infarct size in eNOS<sup>−/−</sup> mice, and their effects were comparable with those observed in CR-treated wild-type mice. These results demonstrate the essential roles of eNOS in the development of CR-induced cardioprotection and Sirt1 activation during CR. The combination of a relatively low dose of resveratrol with an adequate vasodilator therapy might be useful for managing patients with endothelial dysfunction associated with impaired NO bioavailability.

Original languageEnglish
Pages (from-to)H894-H903
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume308
Issue number8
DOIs
Publication statusPublished - 2015

Fingerprint

Caloric Restriction
Nitric Oxide Synthase Type III
Reperfusion Injury
Sirtuin 1
Myocardial Reperfusion Injury
Hydralazine
Myocardial Ischemia
Blood Pressure
NG-Nitroarginine Methyl Ester
Left Ventricular Hypertrophy
Vasodilator Agents
Biological Availability
Reperfusion
Nitric Oxide

Keywords

  • Ischemia-reperfusion
  • Myocardial infarction
  • Nitric oxide synthase
  • Resveratrol
  • Sirtuin 1

ASJC Scopus subject areas

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

Cite this

Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury. / Shinmura, Ken; Tamaki, Kayoko; Ito, Kentaro; Yan, Xiaoxiang; Yamamoto, Tsunehisa; Katsumata, Yoshinori; Matsuhashi, Tomohiro; Sano, Motoaki; Fukuda, Keiichi; Suematsu, Makoto; Ishii, Isao.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 308, No. 8, 2015, p. H894-H903.

Research output: Contribution to journalArticle

Shinmura, Ken ; Tamaki, Kayoko ; Ito, Kentaro ; Yan, Xiaoxiang ; Yamamoto, Tsunehisa ; Katsumata, Yoshinori ; Matsuhashi, Tomohiro ; Sano, Motoaki ; Fukuda, Keiichi ; Suematsu, Makoto ; Ishii, Isao. / Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury. In: American Journal of Physiology - Heart and Circulatory Physiology. 2015 ; Vol. 308, No. 8. pp. H894-H903.
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