title: Influence of aging and hemorrhage injury on Sirt1 expression: possible role of myc-Sirt1 regulation in mitochondrial function.
abstract: Trauma-hemorrhage (T-H) causes hypoxia and organ dysfunction. Mitochondrial dysfunction is a major factor for cellular injury due to T-H. Aging also has been known to cause progressive mitochondrial dysfunction. In order to study the effect of aging on T-H-induced mitochondrial dysfunction, we recently developed a rodent mitochondrial genechip with probesets representing mitochondrial and nuclear genes contributing to mitochondrial structure and function. Using this chip we recently identified signature mitochondrial genes altered following T-H in 6 and 22 month old rats; augmented expression of the transcription factor c-myc was the most pronounced. Based on reports of c-myc-IL6 collaboration and c-myc-Sirt1 negative regulation, we further investigated the expression of these regulatory factors with respect to aging and injury. Rats of ages 6 and 22 months were subjected to T-H or sham operation and left ventricular tissues were tested for cytosolic cytochrome c, mtDNA content, Sirt1 and mitochondrial biogenesis factors Foxo1, Ppara and Nrf-1. We observed increased cardiac cytosolic cytochrome c (sham vs T-H, p<0.03), decreased mitochondrial DNA content (sham vs T-H, p<0.05), and decreased Sirt1 expression (sham vs TH, p<0.05) following T-H and with progressing age. Additionally, expression of mitochondrial biogenesis regulating transcription factors Foxo1 and Nrf-1 was also decreased with T-H and aging. Based upon these observations we conclude that Sirt1 expression is negatively modulated by T-H causing downregulation of mitochondrial biogenesis. Thus, induction of Sirt1 is likely to produce salutary effects following T-H induced injury and hence, Sirt1 may be a potential molecular target for translational research in injury resolution.
authors.affiliation: Center for Surgical Research, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Bixi
authors.initials: B
authors.lastname: Jian
authors.forename: Shaolong
authors.initials: S
authors.lastname: Yang
authors.forename: Dongquan
authors.initials: D
authors.lastname: Chen
authors.forename: Irshad
authors.initials: I
authors.lastname: Chaudry
authors.forename: Raghavan
authors.initials: R
authors.lastname: Raju
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D006470:Hemorrhage / Q000378:metabolism / Q000473:pathology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014947:Wounds and Injuries / Q000378:metabolism / Q000473:pathology*; D000071161:Forkhead Box Protein O1
chemical_list: D045304:Cytochromes c; D004272:DNA, Mitochondrial; D051858:Forkhead Transcription Factors; D015850:Interleukin-6; D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D056564:Sirtuin 1; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C488368:Sirt1 protein, rat