title: Cardiac Sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia-reperfusion.
abstract: Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion (I/R) injury. We previously found the essential roles of endothelial nitric oxide synthase in the development of CR-induced cardioprotection and Sirt1 activation during CR (Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury.Am J Physiol Heart Circ Physiol 308: H894-H903, 2015). However, the exact mechanism by which Sirt1 in cardiomyocytes mediates the cardioprotective effect of CR remains undetermined. We subjected cardiomyocyte-specific Sirt1 knockout (CM-Sirt1(-/-)) mice and the corresponding control mice to either 3-mo ad libitum feeding or CR (-40%). Isolated perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. The recovery of left ventricle function after I/R was improved, and total lactate dehydrogenase release into the perfusate during reperfusion was attenuated in the control mice treated with CR, but a similar cardioprotective effect of CR was not observed in the CM-Sirt1(-/-)mice. The expression levels of cardiac complement component 3 (C3) at baseline and the accumulation of C3 and its fragments in the ischemia-reperfused myocardium were attenuated by CR in the control mice, but not in the CM-Sirt1(-/-)mice. Resveratrol treatment also attenuated the expression levels of C3 protein in cultured neonatal rat ventricular cardiomyocytes. Moreover, the degree of myocardial I/R injury in conventional C3 knockout (C3(-/-)) mice treated with CR was similar to that in the ad libitum-fed C3(-/-)mice, although the expression levels of Sirt1 were enhanced by CR. These results demonstrate that cardiac Sirt1 plays an essential role in CR-induced cardioprotection against I/R injury by suppressing cardiac C3 expression. This is the first report suggesting that cardiac Sirt1 regulates the local complement system during CR.
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Tsunehisa
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; Department of General Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Tamaki
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Shirakawa
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ito
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katsumata
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Anzai
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuhashi
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Jin
authors.initials: J
authors.lastname: Endo
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; and.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Inaba
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; and.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; Department of General Medicine, Hyogo College of Medicine, Nishinomiya, Japan shimmura@hyo-med.ac.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Shinmura
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D031204:Caloric Restriction; D002478:Cells, Cultured; D003167:Complement Activation; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005838:Genotype; D000067268:Isolated Heart Preparation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D013997:Time Factors; D016277:Ventricular Function, Left
chemical_list: D000975:Antioxidants; C545610:C3 protein, mouse; D003176:Complement C3; D013267:Stilbenes; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Sirt1; antioxidant; cardiomyocyte; complement; ischemia-reperfusion; sirtuin