TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular nucleus are involved in the effects of telmisartan in hypertension
TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular nucleus are involved in the effects of telmisartan in hypertension
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室旁核内的 TLR4/MyD88/NF-κB 信号传导和 PPAR-γ 参与替米沙坦治疗高血压的作用
DOI：
10.1016/j.taap.2016.06.014
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发表时间：
2016-08-15
影响因子：
3.8
通讯作者：
Kang, Yu-Ming
中科院分区：
文献类型：
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作者：
Li, Hong-Bao;Li, Xiang;Kang, Yu-Ming
本实验室等研究表明，血管紧张素II 1型受体(AT1-R)拮抗剂的主要治疗作用是降低血压和在心血管系统中发挥抗炎作用。在这项研究中，我们确定了下丘脑室旁核(PVN)内AT1-R拮抗剂替米沙坦是否通过TLR4/MyD88/NF-kappa B信号通路和PVN中的PPAR-伽马(PPAR-γ)来减轻高血压大鼠的高血压和下丘脑炎症。给自发性高血压大鼠(SHR)和血压正常的Wistar京都(WKY)大鼠双侧室旁核注射AT1-R拮抗剂替米沙坦(TEL，10 mU g/h)、氯沙坦(LOS，20 mU g/h)或PPAR-γ拮抗剂GW9662(GW，100 mU g/h)，或经渗透压微泵给药。尾袖夹闭法记录平均动脉压(MAP)。分别测定PVN组织和血中AT1-R、PPAR-γ、促炎性细胞因子(肿瘤坏死因子-α、白介素1-β、白介素6)、诱导型一氧化氮合酶(INOS)、TLR4、MyD88、核因子-kappaB(NF-kappa B)活性和血浆去甲肾上腺素(NE)水平。高血压大鼠下丘脑室旁核AT1-R水平显著升高，PPAR-γ水平显著降低。TEL可降低SHR大鼠MAP，改善心肌肥厚，降低TNF-α、IL-1β、IL-6、iNOS水平和血浆NE水平，但对WKY大鼠无明显影响。这些结果与高血压大鼠室旁核中TLR4、MyD88和NF-kappa B水平降低以及PPAR-γ水平升高有关。我们的研究结果提示，TLR4/MyD88/NF-kappa B信号通路和PVN内的PPAR-γ参与了替米沙坦的降压作用。(C)2016 Elsevier Inc.保留所有权利。
Previous findings from our laboratory and others indicate that the main therapeutic effect of angiotensin II type 1 receptor (AT1-R) antagonists is to decrease blood pressure and exert anti-inflammatory effects in the cardiovascular system. In this study, we determined whether AT1-R antagonist telmisartan within the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and hypothalamic inflammation via both the TLR4/MyD88/NF-kappa B signaling pathway and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in the PVN in hypertensive rats. Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated for 4 weeks through bilateral PVN infusion with the AT1-R antagonist telmisartan (TEL, 10 mu g/h), or losartan (LOS, 20 mu g/h), or the PPAR-gamma antagonist GW9662 (GW, 100 mu g/h), or vehicle via osmotic minipump. Mean arterial pressure (MAP) was recorded by a tail-cuff occlusion method. PVN tissue and blood were collected for the measurement of AT1-R, PPAR-gamma, pro-inflammatory cytokines (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6), inducible nitric oxide synthase (iNOS), TLR4, MyD88, nuclear factor-kappa B (NF kappa B) activity and plasma nor epinephrine (NE), respectively. Hypertensive rats exhibited significantly higher level of AT1-R and lower level of PPAR-gamma in the PVN. PVN treatment with TEL attenuated MAP, improved cardiac hypertrophy, reduced TNF-alpha, IL-1 beta, IL-6, iNOS levels, and plasma NE in SHR but not in WKY rats. These results were associated with reduced TLR4, MyD88 and NF-kappa B levels and increased PPAR-gamma level in the PVN of hypertensive rats. Our findings suggest that TLR4/MyD88/NF-kappa B signaling and PPAR-gamma within the PVN are involved in the beneficial effects of telmisartan in hypertension. (C) 2016 Elsevier Inc All rights reserved.