title: Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury.
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.
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; shimmura@z5.keio.jp.
authors: Ken
authors: K
authors: Shinmura
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Tokyo, Japan; and.
authors: Kayoko
authors: K
authors: Tamaki
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors: Kentaro
authors: K
authors: Ito
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors: Xiaoxiang
authors: X
authors: Yan
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors: Tsunehisa
authors: T
authors: Yamamoto
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors: Yoshinori
authors: Y
authors: Katsumata
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors: Tomohiro
authors: T
authors: Matsuhashi
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors: Motoaki
authors: M
authors: Sano
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors: Keiichi
authors: K
authors: Fukuda
authors: Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Tokyo, Japan; and.
authors: Makoto
authors: M
authors: Suematsu
authors: Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan; Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan.
authors: Isao
authors: I
authors: Ishii
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D006830:Hydralazine / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000178:diet therapy / Q000188:drug therapy / Q000201:enzymology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: D013267:Stilbenes; D014665:Vasodilator Agents; D006830:Hydralazine; D052250:Nitric Oxide Synthase Type III; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: ischemia-reperfusion; myocardial infarction; nitric oxide synthase; resveratrol; sirtuin 1