Resveratrol restores sirtuin 1 (SIRT1) activity and pyruvate dehydrogenase kinase 1 (PDK1) expression after hemorrhagic injury in a rat model

Bixi Jian, Shaolong Yang, Irshad H. Chaudry, Raghavan Pillai Raju

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 mitochondrialglycolytic 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.

Original languageEnglish (US)
Pages (from-to)10-16
Number of pages7
JournalMolecular Medicine
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2014

Fingerprint

Sirtuin 1
Hemorrhage
Wounds and Injuries
Left Ventricular Function
Mitochondria
NF-E2-Related Factor 2
Pyruvate Dehydrogenase Complex
pyruvate dehydrogenase (acetyl-transferring) kinase
resveratrol
Peroxisome Proliferator-Activated Receptors
Polyphenols
Glycolysis
Adenosine Triphosphate

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Resveratrol restores sirtuin 1 (SIRT1) activity and pyruvate dehydrogenase kinase 1 (PDK1) expression after hemorrhagic injury in a rat model. / Jian, Bixi; Yang, Shaolong; Chaudry, Irshad H.; Raju, Raghavan Pillai.

In: Molecular Medicine, Vol. 20, No. 1, 01.01.2014, p. 10-16.

Research output: Contribution to journalArticle

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