title: Resveratrol restores sirtuin 1 (SIRT1) activity and pyruvate dehydrogenase kinase 1 (PDK1) expression after hemorrhagic injury in a rat model.
abstract: Severe hemorrhage leads to decreased blood flow to tissues resulting in decreased oxygen and nutrient availability affecting mitochondrial function. A mitoscriptome profiling study demonstrated alteration in several genes related to mitochondria, consistent with the mitochondrial functional decline observed after trauma hemorrhage (T-H). Our experiments led to the identification of sirtuin 1 (SIRT1) as a potential target in T-H. Administration of resveratrol (a naturally occurring polyphenol and activator of SIRT1) after T-H improved left ventricular function and tissue ATP levels. Our hypothesis was that mitochondrial function after T-H depends on SIRT1 activity. In this study, we evaluated the activity of SIRT1, a mitochondrial functional modulator, and the mitochondrial-glycolytic balance after T-H. We determined the changes in protein levels of pyruvate dehydrogenase kinase (PDK)-1 and nuclear c-Myc, peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and NF-E2-related factor (NRF)2 after T-H and after treatment with resveratrol or a combination of sirtinol (a SIRT1 inhibitor) and resveratrol. We have also tested the activity of mitochondrial complex 1. SIRT1 enzyme activity was significantly decreased after T-H, whereas resveratrol treatment restored the activity. We found elevated PDK1 and c-Myc levels and decreased PGC-1α, NRF2 and mitochondrial complex I activity after T-H. The reduced SIRT1 activity after T-H may be related to declining mitochondrial function, since resveratrol was able to reinstate SIRT1 activity and mitochondrial function. The elevated level of PDK1 (an inhibitor of pyruvate dehydrogenase complex) after T-H indicates a possible shift in cellular energetics from mitochondria to glycolysis. In conclusion, SIRT1 modulation alters left ventricular function after T-H through regulation of cellular energetics.
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Bixi
authors.initials: B
authors.lastname: Jian
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Shaolong
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Irshad H
authors.initials: IH
authors.lastname: Chaudry
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Raghavan
authors.initials: R
authors.lastname: Raju
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006470:Hemorrhage / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: C000631434:Pdk1 protein, rat; D010975:Platelet Aggregation Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013267:Stilbenes; D017346:Protein Serine-Threonine Kinases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol