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Interaction Between AT1 Receptor and NF-κB in Hypothalamic Paraventricular Nucleus Contributes to Oxidative Stress and Sympathoexcitation by Modulating Neurotransmitters in Heart Failure

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Abstract

Angiotensin II type 1 receptor (AT1-R) and nuclear factor-kappaB (NF-κB) in the paraventricular nucleus (PVN) play important roles in heart failure (HF); however, the central mechanisms by which AT1-R and NF-κB contribute to sympathoexcitation in HF are yet unclear. In this study, we determined whether interaction between AT1-R and NF-κB in the PVN modulates neurotransmitters and contributes to NAD(P)H oxidase-dependent oxidative stress and sympathoexcitation in HF. Rats were implanted with bilateral PVN cannulae and subjected to coronary artery ligation or sham surgery (SHAM). Subsequently, animals were treated for 4 weeks through bilateral PVN infusion with either vehicle or losartan (LOS, 10 μg/h), an AT1-R antagonist; or pyrrolidine dithiocarbamate (PDTC, 5 μg/h), a NF-κB inhibitor via osmotic minipump. Myocardial infarction (MI) rats had higher levels of glutamate (Glu), norepinephrine (NE) and NF-κB p65 activity, lower levels of gamma-aminobutyric acid (GABA), and more positive neurons for phosphorylated IKKβ and gp91phox (a subunit of NAD(P)H oxidase) in the PVN when compared to SHAM rats. MI rats also had higher levels of renal sympathetic nerve activity (RSNA) and plasma proinflammatory cytokines (PICs), NE and epinephrine. PVN infusions of LOS or PDTC attenuated the decreases in GABA and the increases in gp91phox, NF-κB activity, Glu and NE, in the PVN of HF rats. PVN infusions of LOS or PDTC also attenuated the increases in RSNA and plasma PICs, NE and epinephrine in MI rats. These findings suggest that interaction between AT1 receptor and NF-κB in the PVN contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure.

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Acknowledgments

This study was supported by National Basic Research Program of China (No. 2012CB517805), National Natural Science Foundation of China (Nos. 81170248, 81070199, 31171095) and Research Fund for the Doctoral Program of Higher Education of China (No. 20101417110002).

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Authors and Affiliations

  1. Department of Physiology and Pathophysiology, Xi’an Jiaotong University Cardiovascular Research Center, Xi’an Jiaotong University School of Medicine, Xi’an, 710061, China

    Xiao-Jing Yu, Jie Qi, Qing Yang, Qiu-Yue Yi & Yu-Ming Kang

  2. Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, The Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, 400042, China

    Zhiming Zhu

  3. Department of Obstetrics and Gynecology, Shanxi Provincial People’s Hospital, Taiyuan, 030012, China

    Yu-Ping Suo

  4. Department of Pathology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China

    Hui-Hua Li

  5. Department of Physiology, Dalian Medical University, Dalian, 116044, China

    Dong-Mei Zhang

  6. Department of Physiology, Nanjing Medical University, Nanjing, 210029, China

    Guo-Qing Zhu

  7. Department of Heart Failure Care Unit, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, 100037, China

    Jian Zhang

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  1. Xiao-Jing Yu
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  10. Zhiming Zhu
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Correspondence to Yu-Ming Kang.

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Xiao-Jing Yu and Yu-Ping Suo have contributed equally to this study.

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Yu, XJ., Suo, YP., Qi, J. et al. Interaction Between AT1 Receptor and NF-κB in Hypothalamic Paraventricular Nucleus Contributes to Oxidative Stress and Sympathoexcitation by Modulating Neurotransmitters in Heart Failure. Cardiovasc Toxicol 13, 381–390 (2013). https://doi.org/10.1007/s12012-013-9219-x

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