Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Biochemistry & Molecular Biophysics

First Advisor

Joseph A. Baur

Second Advisor

Harry Ischiropoulos

Abstract

Both acute blood loss and severe infection activate common cellular pathways leading to shock – a pathologic condition characterized by systemic inflammation, oxidative stress, and mitochondrial dysfunction. Sirtuins, a highly conserved group of NAD-dependent enzymes, play a critical role in cellular survival and many of the benefits associated with sirtuin activation are thought to be secondary to decreased inflammation, reduced oxidative stress, and improved mitochondrial physiology. As such, we hypothesized that sirtuin pathways play a crucial role in shock and could be could be targeted to improve outcomes following acute blood loss and severe infection. In a series of in vivo and in vitro experiments recapitulating hemorrhagic shock and severe sepsis, we explored the impact of sirtuin activation on inflammation, mitochondrial function, and survival. Following decompensated hemorrhagic shock, resuscitation with resveratrol, a SIRT1 activator, significantly improved renal mitochondrial function and decreased oxidative damage. Similarly, resuscitation with nicotinamide monononucleotide (NMN), a key biosynthetic NAD precursor, was found to mitigate inflammation, support cellular energetics and improve both physiologic resilience and survival. In contrast, impaired expression of either SIRT1 or SIRT3 resulted in a pro-inflammatory phenotype with accelerated mortality in sepsis. Interestingly, deletion of SIRT1 did not significantly worsen the degree of mitochondrial dysfunction observed in septic liver, but was associated with decreased CI and CII respiration in kidney. Deletion of SIRT3 did not significantly impact the degree of mitochondrial dysfunction observed in either liver or kidney. Taken together, these data strongly suggest that SIRT1 and SIRT3 play a key role in the pathophysiology of shock. Although further research is needed to determine if SIRT1 and SIRT3 overexpression improves outcomes or if pharmacologically manipulating NAD metabolism in conjunction with sirtuin activation provides added benefit, targeting sirtuins appears beneficial in hemorrhagic and septic shock.

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