Central blockade of TLR4 improves cardiac function and attenuates myocardial inflammation in angiotensin II-induced hypertension
Central blockade of TLR4 improves cardiac function and attenuates myocardial inflammation in angiotensin II-induced hypertension
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DOI：
10.1093/cvr/cvu067
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发表时间：
2014-07-01
影响因子：
10.8
通讯作者：
Francis, Joseph
中科院分区：
文献类型：
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作者：
Dange, Rahul B.;Agarwal, Deepmala;Francis, Joseph
了解高血压发病机制中涉及的新信号通路对于制定有效的治疗策略至关重要。最近的证据表明toll样受体（TLR） 4在心血管疾病的发展中起作用。虽然脑与高血压的发病机制有关，但脑TLR4在高血压中的作用在很大程度上尚未被探索。因此，我们研究了脑TLR4在血管紧张素（Ang） ii诱导的高血压中的作用，以及中枢性TLR4阻断是否对高血压有心脏保护作用。雄性Sprague-Dawley大鼠经AngII灌胃14天，诱导高血压。大鼠脑室内分别给予特异性TLR4阻滞剂、病毒抑制肽（VIPER）或对照肽。分别用无线电遥测和超声心动图评估血压、心脏肥厚和功能。采集血和室旁核分别测定血浆去甲肾上腺素（NE）、肿瘤坏死因子- α (tnf - α)、白细胞介素(IL)-1 β和TLR4的表达。分析心脏的tnf - α、IL-1 β、诱导型一氧化氮合酶（iNOS）、核因子κ B （NF κ B）和肾素-血管紧张素系统（RAS）成分。与正常大鼠相比，高血压大鼠TLR4表达显著升高。中枢性阻断TLR4可延缓高血压大鼠的进展，改善心脏肥厚和功能。TLR4阻断显著降低高血压大鼠心肌tnf - α、IL-1 β、iNOS水平、NF κ B活性，并改变RAS成分。这些结果与经viper治疗的高血压大鼠循环NE水平降低有关。这些结果提供了机制证据，表明血管内皮素诱导的高血压效应至少部分是由脑TLR4介导的，而脑TLR4阻断可能通过下调心肌炎症分子和交感神经活性来减弱血管内皮素诱导的高血压反应。
Understanding the novel signalling pathways involved in the pathogenesis of hypertension is vital for the development of effective therapeutic strategies. Recent evidence suggests a role for Toll-like receptor (TLR) 4 in the development of cardiovascular diseases. Although brain has been implicated in the pathogenesis of hypertension, the role of brain TLR4 in hypertension is largely unexplored. Therefore, we investigated the role of brain TLR4 in angiotensin (Ang) II-induced hypertension and whether central TLR4 blockade has cardioprotective effects in hypertension.Hypertension was induced in male Sprague-Dawley rats by delivering AngII for 14 days. The rats were administered either specific TLR4 blocker, viral inhibitory peptide (VIPER), or control peptide, intracerebroventricularly. Blood pressure, and cardiac hypertrophy and function, was evaluated by radiotelemetry and echocardiography, respectively. Blood and paraventricular nucleus were collected for measurement of plasma norepinephrine (NE), tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, and TLR4 expression, respectively. Heart was analysed for TNF-alpha, IL-1 beta, inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF kappa B), and renin-angiotensin system (RAS) components. Hypertensive rats had dramatically increased TLR4 expression compared with normotensive rats. Central blockade of TLR4 delayed progression of hypertension and improved cardiac hypertrophy and function in hypertensive rats. TLR4 blockade significantly reduced myocardial TNF-alpha, IL-1 beta, iNOS levels, NF kappa B activity, and altered RAS components in hypertensive rats. These results were associated with reduced circulating NE levels in VIPER-treated hypertensive rats.These results provide mechanistic evidence that AngII-induced hypertensive effects are mediated, at least in part, by brain TLR4, and that brain TLR4 blockade attenuates AngII-induced hypertensive response, possibly via down-regulation of myocardial inflammatory molecules and sympathetic activity.