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Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension.
Int J Mol Sci. 2019 Aug 28; 20(17)IJ

Abstract

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.

Authors+Show Affiliations

Department of Physiology, Nanjing Medical University, Nanjing 211166, China.Department of Pathophysiology, Xuzhou Medical University, Xuzhou 221004, China.Department of Physiology, Nanjing Medical University, Nanjing 211166, China.Department of Physiology, Nanjing Medical University, Nanjing 211166, China.Department of Physiology, Nanjing Medical University, Nanjing 211166, China.Department of Physiology, Nanjing Medical University, Nanjing 211166, China.Department of Physiology, Nanjing Medical University, Nanjing 211166, China.Department of Physiology, Nanjing Medical University, Nanjing 211166, China.Department of Physiology, Nanjing Medical University, Nanjing 211166, China.Department of Physiology, Nanjing Medical University, Nanjing 211166, China.Department of Physiology, Nanjing Medical University, Nanjing 211166, China.Department of Physiology, Nanjing Medical University, Nanjing 211166, China. zhouyebo666@njmu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31466304

Citation

Kang, Ying, et al. "Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation Through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats With Hypertension." International Journal of Molecular Sciences, vol. 20, no. 17, 2019.
Kang Y, Ding L, Dai H, et al. Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension. Int J Mol Sci. 2019;20(17).
Kang, Y., Ding, L., Dai, H., Wang, F., Zhou, H., Gao, Q., Xiong, X., Zhang, F., Song, T., Yuan, Y., Zhu, G., & Zhou, Y. (2019). Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension. International Journal of Molecular Sciences, 20(17). https://doi.org/10.3390/ijms20174217
Kang Y, et al. Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation Through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats With Hypertension. Int J Mol Sci. 2019 Aug 28;20(17) PubMed PMID: 31466304.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension. AU - Kang,Ying, AU - Ding,Lei, AU - Dai,Hangbing, AU - Wang,Fangzheng, AU - Zhou,Hong, AU - Gao,Qing, AU - Xiong,Xiaoqing, AU - Zhang,Feng, AU - Song,Tianrun, AU - Yuan,Yan, AU - Zhu,Guoqing, AU - Zhou,Yebo, Y1 - 2019/08/28/ PY - 2019/07/23/received PY - 2019/08/19/revised PY - 2019/08/26/accepted PY - 2019/8/31/entrez PY - 2019/8/31/pubmed PY - 2020/1/21/medline KW - NADPH oxidase KW - angiotensin II KW - intermedin KW - obesity-related hypertension KW - paraventricular nucleus KW - sympathoexcitation JF - International journal of molecular sciences JO - Int J Mol Sci VL - 20 IS - 17 N2 - 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. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/31466304/Intermedin_in_Paraventricular_Nucleus_Attenuates_Ang_II_Induced_Sympathoexcitation_through_the_Inhibition_of_NADPH_Oxidase_Dependent_ROS_Generation_in_Obese_Rats_with_Hypertension_ L2 - https://www.mdpi.com/resolver?pii=ijms20174217 DB - PRIME DP - Unbound Medicine ER -