Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, ROC.
Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, ROC.
Neuropharmacology. 2017 Sep 1;123:175-185. doi: 10.1016/j.neuropharm.2017.06.007. Epub 2017 Jun 7.
Activation of PI3K/Akt signaling, leading to upregulation of nitric oxide synthase II (NOS II)/peroxynitrite cascade in the rostral ventrolateral medulla (RVLM), the brain stem site that maintains blood pressure and sympathetic vasomotor tone, underpins cardiovascular depression induced by the organophosphate pesticide mevinphos. By exhibiting dual-specificity protein- and lipid-phosphatase activity, phosphatase and tensin homolog (PTEN) directly antagonizes the PI3K/Akt signaling by dephosphorylation of phosphatidylinositol-3,4,5-trisphosphate, the lipid product of PI3K. Based on the guiding hypothesis that PTEN may sustain brain stem cardiovascular regulation during mevinphos intoxication as a negative regulator of PI3K/Akt signaling in the RVLM, we aimed in this study to clarify the mechanistic role of PTEN in mevinphos-induced circulatory depression. Microinjection bilaterally of mevinphos (10 nmol) into the RVLM of anesthetized Sprague-Dawley rats induced a progressive hypotension and a decrease in baroreflex-mediated sympathetic vasomotor tone. There was progressive augmentation in PTEN activity as reflected by a decrease in the oxidized form of PTEN in the RVLM during mevinhpos intoxication, without significant changes in the mRNA or protein level of PTEN. Loss-of-function manipulations of PTEN in the RVLM by immunoneutralization, pharmacological blockade or siRNA pretreatment significantly potentiated the increase in Akt activity or NOS II/peroxynitrite cascade in the RVLM, enhanced the elicited hypotension and exacerbated the already reduced baroreflex-mediated sympathetic vasomotor tone. We conclude that augmented PTEN activity via a decrease of its oxidized form in the RVLM sustains brain stem cardiovascular regulation during mevinphos intoxication via downregulation of the NOS II/peroxynitrite cascade as a negative regulator of PI3K/Akt signaling.
PI3K/Akt 信号的激活导致头端腹外侧延髓（RVLM）中一氧化氮合酶 II（NOS II）/过氧亚硝酸盐级联的上调，RVLM 是维持血压和交感血管张力的脑干部位，这支持了有机磷农药 mevinphos 引起的心血管抑制。通过表现出双重特异性蛋白和脂质磷酸酶活性，磷酸酶和张力蛋白同系物（PTEN）通过去磷酸化磷脂酰肌醇-3,4,5-三磷酸（PI3K 的脂质产物）直接拮抗 PI3K/Akt 信号。基于 PTEN 可能作为 RVLM 中 PI3K/Akt 信号的负调节剂在 mevinphos 中毒期间维持脑干心血管调节的指导假设，我们旨在本研究中阐明 PTEN 在 mevinphos 诱导的循环抑制中的机制作用。在麻醉的 Sprague-Dawley 大鼠 RVLM 双侧微注射 mevinphos（10 nmol）会引起进行性低血压和压力反射介导的交感血管张力降低。在 mevinphos 中毒期间，RVLM 中的 PTEN 活性逐渐增加，反映为 PTEN 的氧化形式减少，而 PTEN 的 mRNA 或蛋白水平没有明显变化。通过免疫中和、药理学阻断或 siRNA 预处理在 RVLM 中对 PTEN 的功能丧失操作，显著增强了 Akt 活性或 NOS II/过氧亚硝酸盐级联在 RVLM 中的增加，增强了诱发的低血压并恶化了已经降低的压力反射介导的交感血管张力。我们得出结论，RVLM 中其氧化形式减少导致的 PTEN 活性增加通过下调 NOS II/过氧亚硝酸盐级联作为 PI3K/Akt 信号的负调节剂来维持 mevinphos 中毒期间的脑干心血管调节。
