Toll-like receptor 4 inhibition reduces vascular inflammation in spontaneously hypertensive rats.
Toll-like receptor 4 inhibition reduces vascular inflammation in spontaneously hypertensive rats.
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DOI：
10.1016/j.lfs.2014.12.001
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发表时间：
2015-02-01
期刊：
影响因子：
6.1
通讯作者：
Carvalho MH
中科院分区：
文献类型：
--
作者：
Bomfim GF;Echem C;Martins CB;Costa TJ;Sartoretto SM;Dos Santos RA;Oliveira MA;Akamine EH;Fortes ZB;Tostes RC;Webb RC;Carvalho MH
高血压与循环细胞因子水平升高有关，最近的研究表明先天免疫会导致高血压。高血压刺激免疫反应的机制尚不清楚，但可能涉及激活免疫系统的新抗原的形成。 Toll 样受体 4 (TLR4) 是一种先天免疫受体，可结合多种外源（脂多糖）和内源配体。 TLR4 信号传导导致核因子 kappa B (NFκB) 的激活和炎症反应相关基因的转录。我们之前证明，TLR4 阻断可降低自发性高血压大鼠 (SHR) 的血压并增强血管收缩力。在这里，我们假设抑制 TLR4 通过 NFκB 信号通路改善血管炎症过程。 SHR 和 Wistar 大鼠用抗 TLR4 抗体（1 µg/天）或非特异性 IgG 治疗 15 天（腹腔注射）。与 IgG 治疗的 SHR 相比，抗 TLR4 治疗降低了 SHR 肠系膜阻力动脉中活性氧的产生和 IL-6 细胞因子的表达。抗 TLR4 治疗还消除了在 IgG 处理的 SHR 中观察到的血管对去甲肾上腺素反应性的增加，如前所述，并且 NFκB 的抑制仅在 IgG 处理的 SHR 中降低了去甲肾上腺素反应。用抗 TLR4 处理的 SHR 肠系膜动脉显示 TLR4 信号转导中的关键分子 MyD88 的表达减少，但 TRIF 的表达没有减少。与 IgG 处理的 SHR 相比，抗 TLR4 处理的 SHR 的动脉中 p38 和 NF-κB p65 的磷酸化降低。总之，这些结果表明 TLR4 通过 NFκB 信号通路在高血压和血管炎症过程中发挥关键作用。
Hypertension is associated with increased levels of circulating cytokines and recent studies have shown that innate immunity contributes to hypertension. The mechanisms which hypertension stimulates immune response remain unclear, but may involve formation of neoantigens that activate the immune system. Toll like receptor 4 (TLR4) is an innate immune receptor that binds a wide spectrum of exogenous (lipopolysaccharide) and endogenous ligands. TLR4 signaling leads to activation of nuclear factor kappa B (NFκB) and transcription of genes involved in inflammatory response. We previously demonstrated that TLR4 blockade reduces blood pressure and the augmented vascular contractility in spontaneously hypertensive rats (SHR). Here we hypothesized that inhibition of TLR4 ameliorates the vascular inflammatory process by a NFκB signaling pathway. SHR and Wistar rats were treated with anti-TLR4 antibody (1µg/day) or unspecific IgG for 15 days (i.p.). Anti-TLR4 treatment decreased production of reactive oxygen species and expression of IL-6 cytokine in mesenteric resistance arteries from SHR, when compared with IgG-treated SHR. Anti-TLR4 treatment also abolished the increased vascular reactivity to noradrenaline observed in IgG-treated SHR, as described before, and inhibition of NFκB decreased noradrenaline responses only in IgG-treated SHR. Mesenteric arteries from SHR treated with anti-TLR4 displayed decreased expression of MyD88, but not TRIF, key molecules in TLR4 signaling. Phosphorylation of p38 and NF-κB p65 were decreased in arteries from anti-TLR4-treated SHR versus IgG-treated SHR. Together, these results suggest that TLR4 is a key player in hypertension and vascular inflammatory process by a NFκB signaling pathway.