Selective Inhibition of SIRT2 Improves Outcomes in a Lethal Septic Model.

Area of Science:

• Biochemistry
• Immunology
• Pharmacology

Background:

• Sirtuins (SIRTs) are a class of histone deacetylases with seven isoforms (SIRT1-7).
• SIRT1 inhibition with EX-527 reduced mortality in a mouse model of septic shock.
• The role of SIRT2 in sepsis pathophysiology remained largely unexplored.

Purpose of the Study:

• To investigate the therapeutic potential of selective SIRT2 inhibition using AGK2 in a mouse model of lethal septic shock.
• To determine if AGK2 treatment could decrease mortality and attenuate the inflammatory response during sepsis.

Main Methods:

• C57BL/6J mice were administered AGK2 or vehicle control before undergoing cecal ligation and puncture (CLP) to induce septic shock.
• Survival rates, cytokine levels (TNF-α, IL-6) in blood and peritoneal fluid, and splenocyte cytokine production were assessed.
• Coagulopathy was evaluated using Thrombelastography (TEG), and bone marrow atrophy was quantified via histological analysis.

Main Results:

• AGK2 treatment significantly reduced mortality in CLP-induced septic shock.
• AGK2 administration decreased circulating levels of TNF-α and IL-6, and suppressed their production in cultured splenocytes.
• Sepsis-induced coagulopathy and bone marrow atrophy were significantly attenuated by AGK2 treatment.

Conclusions:

• Selective inhibition of SIRT2 with AGK2 demonstrates significant therapeutic benefits in a preclinical model of septic shock.
• AGK2 effectively mitigates key pathological features of sepsis, including the "cytokine storm," coagulopathy, and bone marrow atrophy.
• Targeting SIRT2 represents a promising strategy for managing lethal septic shock.