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

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)


Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion injury (IRI). We previously found that treatment with NG-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−/−) 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−/− mice was more severe than that in AL-fed wild-type mice. Furthermore, CR did not exert cardioprotection in eNOS−/− mice. eNOS−/− 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−/− mice. In eNOS−/− 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−/−mice. Finally, combination therapy with resveratrol and hydralazine attenuated myocardial IRI and reduced infarct size in eNOS−/− 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
Issue number8
Publication statusPublished - 2015


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

ASJC Scopus subject areas

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


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