Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension.
Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension.
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DOI：
10.1186/s12974-015-0242-7
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发表时间：
2015-02-18
影响因子：
9.3
通讯作者：
Francis J
中科院分区：
文献类型：
--
作者：
Dange RB;Agarwal D;Teruyama R;Francis J
尽管已有多种降压药物问世，但高血压引起的发病率和死亡率仍在上升，提示有必要研究与其发病相关的新的信号转导途径。最近的证据表明，Toll样受体(TLR)4在包括高血压在内的多种炎症性疾病中起作用。大脑在各种形式的高血压的发生和发展中的作用已经得到了很好的证实，但大脑TLR4在高血压进展中的作用从未被探索过。因此，我们研究了室旁核(PVN；大脑中重要的心脏调节中心)中TLR4在人类高血压动物模型中的作用。我们假设，在PVN内阻断TLR4会导致高血压动物平均动脉压(MAP)、炎性细胞因子和交感神经驱动的降低。自发性高血压大鼠(SHR)和血压正常的Wistar京都(WKY)大鼠在PVN内分别给予TLR4受体阻断剂、病毒抑制肽(Viper)或对照多肽14天。用无线电遥测法连续记录MAP。分别检测致炎细胞因子(肿瘤坏死因子α、白介素1β)、抗炎性细胞因子IL 10、诱导型一氧化氮合酶、TLR4、核因子κB活性及血浆去甲肾上腺素和高迁移率族蛋白B的表达。高血压大鼠下丘脑室旁核TLR4水平显著升高。下丘脑室旁核抑制TLR4可降低自发性高血压大鼠的平均动脉压，改善心肌肥厚，降低自发性高血压大鼠的肿瘤坏死因子α、白介素1β、诱导型一氧化氮合酶和核因子κB活性，但对大鼠心肌肥厚无明显影响。这些结果与自发性高血压患者血浆NE和HMGB1水平降低以及IL-10水平升高有关。本研究表明，TLR4在PVN中的上调在高血压反应中起重要作用。我们的结果提供了机制证据，证明SHR的高血压反应至少部分是由PVN中的TLR4介导的，并且PVN中抑制TLR4可能通过减少交感神经活动来降低血压和改善炎症。
Despite the availability of several antihypertensive medications, the morbidity and mortality caused by hypertension is on the rise, suggesting the need for investigation of novel signaling pathways involved in its pathogenesis. Recent evidence suggests the role of toll-like receptor (TLR) 4 in various inflammatory diseases, including hypertension. The role of the brain in the initiation and progression of all forms of hypertension is well established, but the role of brain TLR4 in progression of hypertension has never been explored. Therefore, we investigated the role of TLR4 within the paraventricular nucleus (PVN; an important cardioregulatory center in the brain) in an animal model of human essential hypertension. We hypothesized that a TLR4 blockade within the PVN causes a reduction in mean arterial blood pressure (MAP), inflammatory cytokines and sympathetic drive in hypertensive animals. Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were administered either a specific TLR4 blocker, viral inhibitory peptide (VIPER), or control peptide in their PVN for 14 days. MAP was recorded continuously by radiotelemetry. PVN and blood were collected for the measurement of pro-inflammatory cytokines (Tumor Necrosis Factor (TNF)-α, interleukin (IL)-1β), anti-inflammatory cytokine IL-10, inducible nitric oxide synthase (iNOS), TLR4, nuclear factor (NF) κB activity and plasma norepinephrine (NE) and high mobility group box (HMGB)1 expression, respectively. Hypertensive rats exhibited significantly higher levels of TLR4 in the PVN. TLR4 inhibition within the PVN attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1β, iNOS levels, and NFκB activity in SHR but not in WKY rats. These results were associated with a reduction in plasma NE and HMGB1 levels and an increase in IL-10 levels in SHR. This study demonstrates that TLR4 upregulation in PVN plays an important role in hypertensive response. Our results provide mechanistic evidence that hypertensive response in SHR are mediated, at least in part, by TLR4 in the PVN and that inhibition of TLR4 within the PVN attenuates blood pressure and improves inflammation, possibly via reduction in sympathetic activity.
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影响因子：
5.7
作者：
Jennings, J. Richard;Zanstra, Ydwine
通讯作者：
Zanstra, Ydwine
影响因子：
--
作者：
Ji, Yuanyuan;Liu, Juntian;Liu, Na
通讯作者：
Liu, Na
影响因子：
12.3
作者：
Coban, Erkan;Nizam, Ilknur;Akar, Yusuf
通讯作者：
Akar, Yusuf
影响因子：
10.8
作者：
Dange, Rahul B.;Agarwal, Deepmala;Francis, Joseph
通讯作者：
Francis, Joseph
影响因子：
15.9
作者：
Frantz, S;Kobzik, L;Kelly, RA
通讯作者：
Kelly, RA