Intermedin in Paraventricular Nucleus Attenuates Sympathoexcitation and Decreases TLR4-Mediated Sympathetic Activation via Adrenomedullin Receptors in Rats with Obesity-Related Hypertension
Intermedin in Paraventricular Nucleus Attenuates Sympathoexcitation and Decreases TLR4-Mediated Sympathetic Activation via Adrenomedullin Receptors in Rats with Obesity-Related Hypertension
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室旁核中的 Intermedin 通过肾上腺髓质素受体减弱肥胖相关高血压大鼠的交感神经兴奋并减少 TLR4 介导的交感神经激活
DOI：
10.1007/s12264-018-0292-9
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Ye-bo Zhou
中科院分区：
文献类型：
--
作者：
Jing Sun;Xing-sheng Ren;Ying Kang;Hang-bing Dai;Lei Ding;Ning Tong;Guo-qing Zhu;Ye-bo Zhou
中间体/肾上腺髓质素-2（IMD/AM 2）是降钙素基因相关肽/AM家族的成员，在心血管系统的保护中起重要作用。然而，它在肥胖相关高血压中增强交感兴奋的作用尚不清楚。在这项研究中，我们研究了IMD在室旁核（PVN）的下丘脑交感神经活动（SNA）的影响，脂多糖（LPS）诱导的交感神经激活肥胖相关的高血压（OH）大鼠高脂饮食诱导12周。急性实验在麻醉下进行。交感神经流出量的动态变化以肾SNA和平均动脉压（MAP）的变化来评价。雄性大鼠喂食对照饮食（12%千卡脂肪）或高脂肪饮食（42%千卡脂肪）12周以诱导OH。结果显示，OH大鼠室旁核IMD蛋白表达下调，Toll样受体4（TLR 4）和血浆去甲肾上腺素（NE，提示交感神经功能亢进）水平升高，收缩压升高。LPS（0.5 µg/50 nL）诱导的OH大鼠肾SNA和MAP增强大于肥胖或对照大鼠。双侧PVN微量注射IMD（50 pmol）引起OH大鼠肾SNA和MAP比对照组大鼠更大的下降，并抑制LPS诱导的交感神经激活，而这些在OH大鼠中被有效地阻止了AM受体拮抗剂AM 22 -52预处理。PVN中的丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK）抑制剂U 0126部分逆转了LPS诱导的SNA增强。然而，PVN中的IMD降低了LPS诱导的ERK激活，这也被AM 22 -52有效地阻止。慢性IMD给药导致OH大鼠血浆NE水平和血压显著降低。IMD还能降低PVN内TLR 4蛋白表达和ERK活性，减轻LPS诱导的交感神经过度兴奋。这些结果表明，IMD在PVN减弱SNA和高血压，并降低ERK激活参与LPS诱导的增强SNA在OH大鼠，这是由AM受体介导的。
Intermedin/adrenomedullin-2 (IMD/AM2), a member of the calcitonin gene-related peptide/AM family, plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in obesity-related hypertension is unknown. In this study, we investigated the effects of IMD in the paraventricular nucleus (PVN) of the hypothalamus on sympathetic nerve activity (SNA), and lipopolysaccharide (LPS)-induced sympathetic activation in obesity-related hypertensive (OH) rats induced by a high-fat diet for 12 weeks. Acute experiments were performed under anesthesia. The dynamic alterations of sympathetic outflow were evaluated as changes in renal SNA and mean arterial pressure (MAP) in response to specific drugs. Male rats were fed a control diet (12% kcal as fat) or a high-fat diet (42% kcal as fat) for 12 weeks to induce OH. The results showed that IMD protein in the PVN was downregulated, but Toll-like receptor 4 (TLR4) and plasma norepinephrine (NE, indicating sympathetic hyperactivity) levels, and systolic blood pressure were increased in OH rats. LPS (0.5 µg/50 nL)-induced enhancement of renal SNA and MAP was greater in OH rats than in obese or control rats. Bilateral PVN microinjection of IMD (50 pmol) caused greater decreases in renal SNA and MAP in OH rats than in control rats, and inhibited LPS-induced sympathetic activation, and these were effectively prevented in OH rats by pretreatment with the AM receptor antagonist AM22-52. The mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) inhibitor U0126 in the PVN partially reversed the LPS-induced enhancement of SNA. However, IMD in the PVN decreased the LPS-induced ERK activation, which was also effectively prevented by AM22-52. Chronic IMD administration resulted in significant reductions in the plasma NE level and blood pressure in OH rats. Moreover, IMD lowered the TLR4 protein expression and ERK activation in the PVN, and decreased the LPS-induced sympathetic overactivity. These results indicate that IMD in the PVN attenuates SNA and hypertension, and decreases the ERK activation implicated in the LPS-induced enhancement of SNA in OH rats, and this is mediated by AM receptors.
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影响因子：
3.7
作者：
Gan XB;Sun HJ;Chen D;Zhang LL;Zhou H;Chen LY;Zhou YB
通讯作者：
Zhou YB
影响因子：
9.3
作者：
Wang ML;Kang YM;Li XG;Su Q;Li HB;Liu KL;Fu LY;Saahene RO;Li Y;Tan H;Yu XJ
通讯作者：
Yu XJ
影响因子：
4.9
作者：
Zhang ZH;Yu Y;Wei SG;Felder RB
通讯作者：
Felder RB
影响因子：
--
作者：
Beckhauser TF;Francis-Oliveira J;De Pasquale R
通讯作者：
De Pasquale R
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
影响因子：
3.8
作者：
Li, Hong-Bao;Li, Xiang;Kang, Yu-Ming
通讯作者：
Kang, Yu-Ming