October 25, 2022

Vascular dysfunction during sepsis

Regulation of the enzyme Sirtuin 1 in blood vessel endothelial cells may drive altered metabolism and vascular dysfunction during sepsis, Vanderbilt researchers have discovered.

Sepsis — an exaggerated response to infection — is a life-threatening emergency and common cause of morbidity and mortality. During sepsis, overproduction of inflammatory signaling molecules causes blood vessels to lose tone and become leaky. 

Ryan Stark, MD, and colleagues examined the impact of Sirtuin 1 (SIRT1), an enzyme that regulates cellular homeostasis, on the function of blood vessel endothelial cells in response to an infectious challenge. 

They reported in the journal Clinical and Translational Medicine that loss of SIRT1 impairs endothelial barrier integrity and vascular relaxation, related to perturbations in mediators of SIRT1 activity (eNOS and FOXO1). They showed that in endothelial cells exposed to an infectious challenge, loss of SIRT1 impairs the “metabolic shift” that is thought to play a role in the host defense to pathogen challenge. 

The findings demonstrate a role for SIRT1 in the endothelial pathology of sepsis. The researchers suggest that endothelial-specific SIRT1 regulation during sepsis may drive altered metabolism and vascular dysfunction.

Co-authors from the Department of Pediatrics at Vanderbilt University Medical Center included Stephen Koch, Cody Stothers, MD, PhD, Allison Pourquoi, Celia Lamb, Michael Miller, MD, PhD, and Hyehun Choi, PhD. The research was supported by the National Institutes of Health (grant GM138191).