雷帕霉素靶蛋白信号通路在普伐他汀治疗子痫前期样小鼠模型中调节脂肪酸氧化中的作用。
Role of mammalian target of rapamycin signaling pathway in regulation of fatty acid oxidation in a preeclampsia-like mouse model treated with pravastatin.
机构信息
Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.
出版信息
Chin Med J (Engl). 2019 Mar 20;132(6):671-679. doi: 10.1097/CM9.0000000000000129.
BACKGROUND
Fatty acid oxidation (FAO) disorder is involved in the pathogenesis of some cases of preeclampsia (PE). Several studies show that mammalian target of rapamycin (mTOR) signaling pathway is related to FAO. Pravastatin (Pra) can promote FAO in Nω-nitro-L-arginine methyl ester (L-NAME) PE-like mouse model in our previous study. This study aimed to investigate the effect of mTOR signaling pathway in PE-like model treated with Pra.
METHODS
Pregnant mice were randomly injected with L-NAME as PE-like model group or saline as control group respectively, from gestational 7th to 18th day. Giving Pra (L-NAME + Pra, Control + Pra, n = 8) or normal saline (NS; L-NAME + NS, Control + NS, n = 8) from gestational 8th to 18th day, the mice were sacrificed on day 18 and their liver and placental tissues were collected. Then the activation of mTOR and its substrates in the liver and placenta were detected. And the association between mTOR activation and serum free fatty acid (FFA) levels and the expression of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) were evaluated using Pearson correlation test. Differences between groups were analyzed using independent t-test or one-way analysis of variance (ANOVA).
RESULTS
Both in the maternal liver and placenta, the activation of mTOR protein and its effect on substrates increased significantly in the L-NAME + NS group and decreased significantly in the L-NAME + Pra group. The p-mTOR/mTOR protein ratio decreased in the L-NAME + Pra group significantly than that in the L-NAME + NS group both in liver and placenta (liver: 0.74 ± 0.08 vs. 0.85 ± 0.06, t = 2.95, P < 0.05; placenta: 0.63 ± 0.06 vs. 0.77 ± 0.06, t = 4.64, P < 0.05). The activation of mTOR protein in the liver and placenta negatively correlated with the expression of LCHAD in the L-NAME + NS group (liver: r = -0.745, P < 0.05; placenta: r = -0.833, P < 0.05) and that in the maternal liver negatively correlated with the expression of LCHAD (r = -0.733, P < 0.05) and positively with the serum FFA levels (r = 0.841, P < 0.05) in the L-NAME + Pra group.
CONCLUSION
The inhibition of mTOR signaling pathway might be involved in the regulation of FAO in mouse model treated with Pra.
背景
脂肪酸氧化（FAO）障碍与子痫前期（PE）的一些病例的发病机制有关。几项研究表明，哺乳动物雷帕霉素靶蛋白（mTOR）信号通路与 FAO 有关。在我们之前的研究中，普伐他汀（Pra）可促进 Nω-硝基-L-精氨酸甲酯（L-NAME）PE 样小鼠模型中的 FAO。本研究旨在探讨 mTOR 信号通路在 Pra 处理的 PE 样模型中的作用。
方法
从妊娠第 7 天到第 18 天，随机给妊娠小鼠注射 L-NAME 作为 PE 样模型组或生理盐水作为对照组。从妊娠第 8 天到第 18 天给予 Pra（L-NAME+Pra、Control+Pra，n=8）或生理盐水（NS；L-NAME+NS、Control+NS，n=8），第 18 天处死小鼠，采集肝脏和胎盘组织。然后检测肝脏和胎盘组织中 mTOR 及其底物的激活情况。采用 Pearson 相关检验评估 mTOR 激活与血清游离脂肪酸（FFA）水平和长链 3-羟酰基辅酶 A 脱氢酶（LCHAD）表达之间的关系。采用独立 t 检验或单因素方差分析（ANOVA）分析组间差异。
结果
在母体肝脏和胎盘组织中，L-NAME+NS 组 mTOR 蛋白及其对底物的激活显著增加，L-NAME+Pra 组显著降低。L-NAME+Pra 组 mTOR/mTOR 蛋白比值在肝脏和胎盘组织中均显著低于 L-NAME+NS 组（肝脏：0.74±0.08 与 0.85±0.06，t=2.95，P<0.05；胎盘：0.63±0.06 与 0.77±0.06，t=4.64，P<0.05）。L-NAME+NS 组肝脏和胎盘组织中 mTOR 蛋白的激活与 LCHAD 的表达呈负相关（肝脏：r=-0.745，P<0.05；胎盘：r=-0.833，P<0.05），而母体肝脏中 mTOR 蛋白的激活与 LCHAD 的表达呈负相关（r=-0.733，P<0.05），与 L-NAME+Pra 组血清 FFA 水平呈正相关（r=0.841，P<0.05）。
结论
mTOR 信号通路的抑制可能参与了 Pra 处理的小鼠模型中 FAO 的调节。
Zotero 插件