title: 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.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Matsuda
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yoshika
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology* / Q000627:therapeutic use; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008638:Mesenteric Arteries / Q000201:enzymology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011817:Rabbits; D018805:Sepsis / Q000188:drug therapy / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects*; D016019:Survival Analysis; D014020:Tissue Extracts / Q000737:chemistry / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D014020:Tissue Extracts; D000077340:Fluvastatin; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D010749:Phosphoprotein Phosphatases; D000077191:Wortmannin