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

Am J Physiol Heart Circ Physiol. 2015 Apr 15;308(8):H894-903. doi: 10.1152/ajpheart.00333.2014. Epub 2015 Feb 13.

Abstract

Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion injury (IRI). We previously found that treatment with N(G)-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.

Keywords: ischemia-reperfusion; myocardial infarction; nitric oxide synthase; resveratrol; sirtuin 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caloric Restriction*
  • Hydralazine / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Reperfusion Injury / diet therapy
  • Myocardial Reperfusion Injury / drug therapy
  • Myocardial Reperfusion Injury / enzymology*
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism*
  • Resveratrol
  • Sirtuin 1 / metabolism
  • Stilbenes / therapeutic use
  • Vasodilator Agents / therapeutic use

Substances

  • Stilbenes
  • Vasodilator Agents
  • Hydralazine
  • Nitric Oxide Synthase Type III
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Resveratrol