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 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.

Mitochondrial dysfunction in rat splenocytes following hemorrhagic shock

“…We also found an increase in the expression of HK2, the first enzyme in the glycolytic process, following HI. This is consistent with our previous observation of a situation similar to Warburg effect following tissue hypoxia in HI (43). The difference being that whereas aerobic glycolysis is postulated in cancer cells (Warburg effect), in conditions such as observed in HI, the decrease in OXPHOS and increase in glycolysis may be attributed to deficiency of oxygen (44).…”

Mitochondrial function in hypoxic ischemic injury and influence of aging

“…Resveratrol also abolished the increase in c-MYC levels (Yuan et al , 2009), and decreased PGC-1α, NRF2, and mitochondrial complex I activity associated with hemorrhage (Jian et al , 2014). It holds promise to reverse cardiovascular decline in aged animals with ischemia (Jian et al , 2011a).…”

“…Administration of the sirtuin activator resveratrol in the setting of hemorrhagic shock restores SIRT1 activity and improves left ventricular function, cardiac contractility, and survival in resuscitated animals and improves lifespan in non-resuscitated animals (Ayub et al , 2015; Jian et al , 2012) A shift in cellular energetics from oxidative phosphorylation in the mitochondria to glycolysis in the cytosol associated with increased PDK1 (an inhibitor of pyruvate dehydrogenase complex) after severe hemorrhage is reversed with administration of resveratrol (Jian et al , 2014). Resveratrol also abolished the increase in c-MYC levels (Yuan et al , 2009), and decreased PGC-1α, NRF2, and mitochondrial complex I activity associated with hemorrhage (Jian et al , 2014).…”

“…It holds promise to reverse cardiovascular decline in aged animals with ischemia (Jian et al , 2011a). Consequently, resveratrol induced increases in SIRT1 activity after hemorrhage appear to improve outcomes by affecting mitochondrial function (Jian et al , 2014). Similar experiments on the effect of hemorrhage on rat myocytes have demonstrated that resveratrol inhibits apoptotic pathways, Akt (protein kinase B) dependent inflammation, and injury (Tsai et al , 2012).…”

Oxidative stress response and Nrf2 signaling in aging

“…Furthermore, c-Myc directly interacted with Nrf2 and lowered Nrf2 binding to EpRE [370]. Indeed, c-Myc was negatively associated with expression of Nrf2-target genes in various tissues of mice [157, 371]. Consistently, Burdo et al showed that c-Myc phosphorylation reduced nuclear Nrf2 in rat neurons and down-regulated GCLC expression while inhibition of c-Myc phosphorylation reversed such changes [372].…”