Mitigating sepsis-induced vascular endothelial dysfunction through Niban phosphorylation.

Abstract

INTRODUCTION: Endothelial dysfunction is a hallmark of sepsis pathophysiology, driven by inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, leading to vascular abnormalities and organ failure. Niban, a multifunctional cellular stress response protein, regulates endothelial homeostasis, with its phosphorylation playing a critical role in mitigating ER stress. We hypothesized that sepsis-induced endothelial dysfunction in the aorta is driven by reduced Niban phosphorylation, which increases ER stress, but can be restored by NiPp, a cell-permeant phosphopeptide mimetic designed to replicate phosphorylated Niban. METHODS: Rats were subjected to a cecal slurry model of polymicrobial sepsis. Molecular markers of ER stress and Niban phosphorylation were analyzed using Western blot, and the vascular reactivity of septic aortae was assessed in muscle baths. Ex vivo NiPp treatment on septic aortic dysfunction was also evaluated. The effects of ER stressors or circulating sepsis mediators, including lipopolysaccharides, interleukin-1β, and cell-free hemoglobin, on endothelial function in healthy aortic rings were tested with or without NiPp. RESULTS: Septic aortas exhibited reduced Niban and endothelial nitric oxide synthase phosphorylation, as well as increased glucose-regulated protein 78 levels. Ex vivo treatment with NiPp improved endothelial dysfunction in septic rat aortas. Moreover, NiPp improved endothelium-dependent relaxation in aortic rings exposed to the ER stressor or any of the circulating sepsis mediators ex vivo. CONCLUSION: Together, these findings highlight reduced Niban phosphorylation as an important driver of vascular endothelial dysfunction during sepsis, and suggest a mechanistic link between sepsis, reduced Niban phosphorylation, and heightened ER stress.