Phosphorylation of Endothelial Nitric-Oxide Synthase Is Diminished in Mesenteric Arteries from Septic Rabbits Depending on the Altered Phosphatidylinositol 3-Kinase/Akt Pathway: Reversal Effect of Fluvastatin Therapy

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Abstract
Endothelial dysfunction plays a crucial role in the pathophysiology of sepsis. Alterations in endothelial nitric-oxide synthase (eNOS) may contribute to the impaired endothelial function. We investigated whether the regulatory mechanism for eNOS phosphorylation and activation is altered in a rabbit lipopolysaccharide-induced septic model. Following induction of sepsis, a time-dependent marked reduction in eNOS phosphorylation was observed in mesenteric arteries, with a significant decrease in eNOS expression. Likewise, Akt phosphorylation was progressively and profoundly reduced, although total Akt remained unchanged. Furthermore, the amounts of the two subunits of phosphatidylinositol 3-kinase (PI3-K) in the membranous pool were diminished without changes in the total amount of the PI3-K heterodimer, indicating a decrease in translocation to the membranes. In vivo treatment with fluvastatin restored the decrease in eNOS phosphorylation in septic mesenteric vessels. This was possibly the result of the recovery of Akt phosphorylation. Treatment with the PI3-K inhibitor wortmannin partially inhibited the fluvastatin-induced increases in phosphorylation of Akt and eNOS, and the decrease in translocation of PI3-K heterodimer to the membranes during sepsis was slightly improved by fluvastatin. Sepsis-induced impairment of eNOS expression was also nearly normalized by fluvastatin. It is noteworthy that rabbits treated with fluvastatin exhibited a dramatic improvement in sepsis survival. The present results showed vascular abnormalities of the PI3-K/Akt pathway involved in the impairment of eNOS phosphorylation and activation in sepsis. We also suggest that fluvastatin would ameliorate vascular endothelial dysfunction, in part, presumably via its recovery effect on Akt-dependent eNOS phosphorylation. It may be potentially useful for therapy of sepsis.