PMID- 26873964 OWN - NLM STAT- MEDLINE DCOM- 20160906 LR - 20200930 IS - 1522-1539 (Electronic) IS - 0363-6135 (Linking) VI - 310 IP - 8 DP - 2016 Apr 15 TI - Cardiac Sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia-reperfusion. PG - H1003-14 LID - 10.1152/ajpheart.00676.2015 [doi] AB - 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. CI - Copyright (c) 2016 the American Physiological Society. FAU - Yamamoto, Tsunehisa AU - Yamamoto T AD - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; FAU - Tamaki, Kayoko AU - Tamaki K AD - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; Department of General Medicine, Hyogo College of Medicine, Nishinomiya, Japan. FAU - Shirakawa, Kohsuke AU - Shirakawa K AD - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; FAU - Ito, Kentaro AU - Ito K AD - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; FAU - Yan, Xiaoxiang AU - Yan X AD - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; FAU - Katsumata, Yoshinori AU - Katsumata Y AD - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; FAU - Anzai, Atsushi AU - Anzai A AD - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; FAU - Matsuhashi, Tomohiro AU - Matsuhashi T AD - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; FAU - Endo, Jin AU - Endo J AD - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; FAU - Inaba, Takaaki AU - Inaba T AD - Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; and. FAU - Tsubota, Kazuo AU - Tsubota K AD - Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; and. FAU - Sano, Motoaki AU - Sano M AD - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; FAU - Fukuda, Keiichi AU - Fukuda K AD - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; FAU - Shinmura, Ken AU - Shinmura K AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160212 PL - United States TA - Am J Physiol Heart Circ Physiol JT - American journal of physiology. Heart and circulatory physiology JID - 100901228 RN - 0 (Antioxidants) RN - 0 (C3 protein, mouse) RN - 0 (Complement C3) RN - 0 (Stilbenes) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 1.14.13.39 (Nos3 protein, mouse) RN - EC 3.5.1.- (Sirt1 protein, mouse) RN - EC 3.5.1.- (Sirt1 protein, rat) RN - EC 3.5.1.- (Sirtuin 1) RN - Q369O8926L (Resveratrol) SB - IM MH - Animals MH - Antioxidants/pharmacology MH - *Caloric Restriction MH - Cells, Cultured MH - *Complement Activation MH - Complement C3/deficiency/genetics/immunology/*metabolism MH - Disease Models, Animal MH - Genotype MH - Isolated Heart Preparation MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Myocardial Reperfusion Injury/enzymology/genetics/immunology/pathology/physiopathology/*prevention & control MH - Myocytes, Cardiac/drug effects/*enzymology/pathology MH - Nitric Oxide Synthase Type III/metabolism MH - Oxidative Stress MH - Phenotype MH - Phosphorylation MH - Rats, Sprague-Dawley MH - Resveratrol MH - Sirtuin 1/deficiency/genetics/*metabolism MH - Stilbenes/pharmacology MH - Time Factors MH - Ventricular Function, Left OTO - NOTNLM OT - Sirt1 OT - antioxidant OT - cardiomyocyte OT - complement OT - ischemia-reperfusion OT - sirtuin EDAT- 2016/02/14 06:00 MHDA- 2016/09/07 06:00 CRDT- 2016/02/14 06:00 PHST- 2015/08/25 00:00 [received] PHST- 2016/02/04 00:00 [accepted] PHST- 2016/02/14 06:00 [entrez] PHST- 2016/02/14 06:00 [pubmed] PHST- 2016/09/07 06:00 [medline] AID - ajpheart.00676.2015 [pii] AID - 10.1152/ajpheart.00676.2015 [doi] PST - ppublish SO - Am J Physiol Heart Circ Physiol. 2016 Apr 15;310(8):H1003-14. doi: 10.1152/ajpheart.00676.2015. Epub 2016 Feb 12.