Neuroinflammation contributes to autophagy flux blockage in the neurons of rostral ventrolateral medulla in stress-induced hypertension rats.
Neuroinflammation contributes to autophagy flux blockage in the neurons of rostral ventrolateral medulla in stress-induced hypertension rats.
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神经炎症导致应激性高血压大鼠延髓头侧腹外侧神经元自噬通量阻断
DOI：
10.1186/s12974-017-0942-2
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发表时间：
2017-08-23
影响因子：
9.3
通讯作者：
Xia C
中科院分区：
文献类型：
--
作者：
Du D;Hu L;Wu J;Wu Q;Cheng W;Guo Y;Guan R;Wang Y;Chen X;Yan X;Zhu D;Wang J;Zhang S;Guo Y;Xia C
背景神经炎症在中枢神经系统未损伤的自主神经核中发挥高血压作用，但其机制仍不清楚。本研究旨在探讨神经炎症对延髓头侧腹外侧（RVLM）神经元自噬的影响，该部位存在维持血管舒缩张力的交感前运动神经元。方法采用足部电击应激源和噪声干预诱导大鼠应激性高血压（SIH）。测量收缩压 (SBP) 和 SAP 频谱低频 (LF) 分量的功率密度，以反映交感血管舒缩活动。通过免疫印迹和免疫染色测量 RVLM 中小胶质细胞的活化和促炎细胞因子 (PIC (IL-1β、TNF-α)) 的表达。分别通过自噬标记物（LC3 和 p62）表达和透射电子显微镜（TEM）图像检查自噬和自噬液泡（AV）。通过转染至 RVLM 的 RFP-GFP-串联荧光 LC3 (tf-LC3) 载体评估自噬通量。使用高效液相色谱 (HPLC) 和电化学检测技术测量谷氨酸、γ 氨基丁酸 (GABA) 的组织水平和去甲肾上腺素 (NE) 的血浆水平。分析小脑延髓池注射小胶质细胞激活抑制剂米诺环素对上述参数的影响。结果SIH大鼠SBP升高，血浆NE伴随SBP谱LF成分升高。 SIH 大鼠中小胶质细胞活化和 PICs 表达增加。 TEM 证明应激导致 SIH 大鼠 RVLM 中 AV 的积累。除了 Tf-LC3 测定之外，LC3-II 和 p62 水平同时升高表明 SIH 大鼠自噬通量受损。相反，米诺环素促进自噬流并诱导降压作用，同时减弱小胶质细胞的激活并减少 SIH 大鼠 RVLM 中的 PIC。此外，SIH大鼠的RVLM中谷氨酸含量较高，GABA含量较低，而米诺环素则减弱了SIH大鼠GABA的减少和谷氨酸的增加。结论总的来说，我们的结论是，神经炎症可能会损害SIH后RVLM神经元的自噬通量并诱导神经兴奋性毒性，这参与了SIH的发生。
BackgroundNeuroinflammation plays hypertensive roles in the uninjured autonomic nuclei of the central nervous system, while its mechanisms remain unclear. The present study is to investigate the effect of neuroinflammation on autophagy in the neurons of the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of vasomotor tone reside.MethodsStress-induced hypertension(SIH) was induced by electric foot-shock stressors with noise interventions in rats. Systolic blood pressure (SBP) and the power density of the low frequency (LF) component of the SAP spectrum were measured to reflect sympathetic vasomotor activity. Microglia activation and pro-inflammatory cytokines (PICs (IL-1β, TNF-α)) expression in the RVLM were measured by immunoblotting and immunostaining. Autophagy and autophagic vacuoles (AVs) were examined by autophagic marker (LC3 and p62) expression and transmission electron microscopy (TEM) image, respectively. Autophagy flux was evaluated by RFP-GFP-tandem fluorescent LC3 (tf-LC3) vectors transfected into the RVLM. Tissue levels of glutamate, gamma aminobutyric acid (GABA), and plasma levels of norepinephrine (NE) were measured by using high-performance liquid chromatography (HPLC) with electrochemical detection. The effects of the cisterna magna infused minocycline, a microglia activation inhibitor, on the abovementioned parameters were analyzed.ResultsSIH rats showed increased SBP, plasma NE accompanied by an increase in LF component of the SBP spectrum. Microglia activation and PICs expression was increased in SIH rats. TEM demonstrated that stress led to the accumulation of AVs in the RVLM of SIH rats. In addition to the Tf-LC3 assay, the concurrent increased level of LC3-II and p62 suggested the impairment of autophagic flux in SIH rats. To the contrary, minocycline facilitated autophagic flux and induced a hypotensive effect with attenuated microglia activation and decreased PICs in the RVLM of SIH rats. Furthermore, SIH rats showed higher levels of glutamate and lower level of GABA in the RVLM, while minocycline attenuated the decrease in GABA and the increase in glutamate of SIH rats.ConclusionsCollectively, we concluded that the neuroinflammation might impair autophagic flux and induced neural excitotoxicity in the RVLM neurons following SIH, which is involved in the development of SIH.
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