Abstract
Sepsis is a life-threatening response to infection associated with inflammation, oxidative stress and mitochondrial dysfunction. We investigated differential effects of three forms of vitamin E, which accumulate in different cellular compartments, on oxidative stress, mitochondrial function, mRNA and protein expression profiles associated with the human Toll-like receptor (TLR) -2 and -4 pathways. Human endothelial cells were exposed to lipopolysaccharide (LPS)/peptidoglycan G (PepG) to mimic sepsis, MitoVitE, α-tocopherol, or Trolox. Oxidative stress, mitochondrial function, mitochondrial membrane potential and metabolic activity were measured. NFκB-P65, total and phosphorylated inhibitor of NFκB alpha (NFκBIA), and STAT-3 in nuclear extracts, interleukin (IL)-6 and IL-8 production in culture supernatants and cellular mRNA expression of 32 genes involved in Toll-like receptor-2 and -4 pathways were measured. Exposure to LPS/PepG caused increased total radical production (p = 0.022), decreased glutathione ratio (p = 0.016), reduced membrane potential and metabolic activity (both p < 0.0001), increased nuclear NFκB-P65 expression (p = 0.016) and increased IL-6/8 secretion (both p < 0.0001). MitoVitE, α- tocopherol and Trolox were similar in reducing oxidative stress, NFκB activation and interleukin secretion. MitoVitE had widespread downregulatory effects on gene expression. Despite differences in site of actions, all forms of vitamin E were protective under conditions mimicking sepsis. These results challenge the concept that protection inside mitochondria provides better protection.
Highlights
Sepsis is a complex syndrome and is a leading cause of morbidity and mortality worldwide
We investigated the relative effects of MitoVitE, α-tocopherol and Trolox on oxidative stress, mitochondrial function and expression of key genes and proteins involved in the toll-like receptor (TLR)-2 and -4 signalling pathways in human endothelial cells cultured in an environment mimicking acute bacterial sepsis
We found that exposure of human endothelial cells to LPS/peptidoglycan G (PepG) resulted in mitochondrial dysfunction and oxidative stress, associated with changes in expression of genes and selected proteins
Summary
Sepsis is a complex syndrome and is a leading cause of morbidity and mortality worldwide. It is characterized by a dysregulated immune response to infection, usually bacterial, leading to a systemic inflammatory response, oxidative stress, depletion of intracellular antioxidants, and organ failure [1,2]. Vitamin E belongs to a group of compounds that includes both tocopherols and tocotrienols [5]. Vitamin E sequesters into the hydrophobic interior of membranes and α-tocopherol is the most biologically active form. Tocopherol is able to protect cell membranes from oxidation, reacting with lipid radicals produced during lipid peroxidation [5]. MitoVitE is essentially the chromanol moiety of vitamin E bound to a triphenyl phosphonium (TPP) cation and accumulates within mitochondria as a Antioxidants 2020, 9, 195; doi:10.3390/antiox9030195 www.mdpi.com/journal/antioxidants
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