Matsuda Naoyuki, Hayashi Yukio, Takahashi Yoshika, Hattori Yuichi
Department of Pharmacology, School of Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
J Pharmacol Exp Ther. 2006 Dec;319(3):1348-54. doi: 10.1124/jpet.106.109785. Epub 2006 Sep 26.
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.
内皮功能障碍在脓毒症的病理生理学中起关键作用。内皮型一氧化氮合酶（eNOS）的改变可能导致内皮功能受损。我们研究了在兔脂多糖诱导的脓毒症模型中，eNOS磷酸化和激活的调节机制是否发生改变。诱导脓毒症后，在肠系膜动脉中观察到eNOS磷酸化随时间显著降低，eNOS表达也显著下降。同样，Akt磷酸化逐渐且显著降低，尽管总Akt保持不变。此外，膜池中的磷脂酰肌醇3激酶（PI3-K）两个亚基的量减少，而PI3-K异二聚体的总量没有变化，表明向膜的转位减少。氟伐他汀体内治疗可恢复脓毒症肠系膜血管中eNOS磷酸化的降低。这可能是Akt磷酸化恢复的结果。用PI3-K抑制剂渥曼青霉素治疗可部分抑制氟伐他汀诱导的脓毒症期间Akt和eNOS磷酸化增加，并且氟伐他汀可稍微改善PI3-K异二聚体向膜转位的减少。氟伐他汀还几乎使脓毒症诱导的eNOS表达损伤恢复正常。值得注意的是，用氟伐他汀治疗的兔子脓毒症存活率有显著改善。目前的结果表明，PI-3K/Akt通路的血管异常参与了脓毒症中eNOS磷酸化和激活的损伤。我们还认为，氟伐他汀可能部分通过其对Akt依赖型eNOS磷酸化的恢复作用来改善血管内皮功能障碍。它可能对脓毒症治疗有潜在用途。
