Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension
Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension
复制标题
室旁核中的 Intermedin 通过抑制肥胖高血压大鼠 NADPH 氧化酶依赖性 ROS 生成来减弱 Ang II 诱导的交感兴奋
DOI：
10.3390/ijms20174217
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发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Zhou, Yebo
中科院分区：
文献类型：
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作者：
Kang, Ying;Ding, Lei;Zhou, Yebo
血管紧张素II（Ang II）诱导室旁核（PVN）活性氧（ROS）增加在高血压（OH）交感神经兴奋中起重要作用。中间肽（IMD）是一种生物活性肽，在防治心血管疾病方面具有广泛的临床应用前景。本研究旨在验证PVN中的IMD可以抑制由Ang II引起的ROS的产生以减轻肥胖相关高血压（OH）大鼠的交感神经活动（SNA）和血压（BP）的假设。使用雄性Sprague-Dawley大鼠（160-180 g）通过喂食高脂肪饮食（42% kcal脂肪）12周来诱导OH。以肾交感神经活动（RSNA）和平均动脉压（MAP）对某些化学物质反应的变化来评价交感神经流出量的动态变化。结果显示，与对照组相比，OH大鼠血管紧张素Ⅱ 1型受体（AT 1 R）、降钙素受体样受体（CRLR）、受体活性修饰蛋白2（RAMP 2）和RAMP 3的蛋白表达均明显增加，而IMD明显降低。脑室旁核内注射IMD不仅能降低OH大鼠SNA、NADPH氧化酶活性和ROS水平，还能降低Ang Ⅱ引起的交感神经兴奋，增加NADPH氧化酶活性、ROS水平和丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）活性。肾上腺髓质素（AM）受体拮抗剂AM 22 -52预处理可阻断上述作用。AT 1 R拮抗剂lorsatan、超氧阴离子清除剂Tempol和NADPH氧化酶抑制剂apocynin（Apo）预处理OH大鼠，可明显减弱Ang Ⅱ引起的SNA增强作用。PVN中的ERK激活抑制剂U 0126逆转了Ang II诱导的SNA增强，并且PVN中的Apo和IMD预处理降低了Ang II诱导的ERK激活。PVN中的慢性IMD给药导致OH大鼠的基础SNA和BP显著降低。此外，IMD降低NADPH氧化酶活性和ROS水平的PVN;减少AT 1 R和NADPH氧化酶亚基NOX 2和NOX 4的蛋白表达，以及ERK激活的PVN;并降低Ang II水平诱导的交感神经过度激活。这些结果表明，IMD通过室旁核中的AM受体减弱SNA和高血压，并通过抑制NADPH氧化酶活性和ERK激活来降低Ang II诱导的SNA增强。
Increased reactive oxygen species (ROS) induced by angiotensin II (Ang II) in the paraventricular nucleus (PVN) play a critical role in sympathetic overdrive in hypertension (OH). Intermedin (IMD), a bioactive peptide, has extensive clinically prospects in preventing and treating cardiovascular diseases. The study was designed to test the hypothesis that IMD in the PVN can inhibit the generation of ROS caused by Ang II for attenuating sympathetic nerve activity (SNA) and blood pressure (BP) in rats with obesity-related hypertension (OH). Male Sprague-Dawley rats (160–180 g) were used to induce OH by feeding of a high-fat diet (42% kcal as fat) for 12 weeks. The dynamic changes of sympathetic outflow were evaluated as the alterations of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to certain chemicals. The results showed that the protein expressions of Ang II type 1 receptor (AT1R), calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 2 (RAMP2) and RAMP3 were markedly increased, but IMD was much lower in OH rats when compared to control rats. IMD itself microinjection into PVN not only lowered SNA, NADPH oxidase activity and ROS level, but also decreased Ang II-caused sympathetic overdrive, and increased NADPH oxidase activity, ROS levels and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activation in OH rats. However, those effects were mostly blocked by the adrenomedullin (AM) receptor antagonist AM22-52 pretreatment. The enhancement of SNA caused by Ang II can be significantly attenuated by the pretreatment of AT1R antagonist lorsatan, superoxide scavenger Tempol and NADPH oxidase inhibitor apocynin (Apo) in OH rats. ERK activation inhibitor U0126 in the PVN reversed Ang II-induced enhancement of SNA, and Apo and IMD pretreatment in the PVN decreased Ang II-induced ERK activation. Chronic IMD administration in the PVN resulted in significant reductions in basal SNA and BP in OH rats. Moreover, IMD lowered NADPH oxidase activity and ROS level in the PVN; reduced the protein expressions of AT1R and NADPH oxidase subunits NOX2 and NOX4, and ERK activation in the PVN; and decreased Ang II levels-inducing sympathetic overactivation. These results indicated that IMD via AM receptors in the PVN attenuates SNA and hypertension, and decreases Ang II-induced enhancement of SNA through the inhibition of NADPH oxidase activity and ERK activation.