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Carbon Monoxide Attenuates High Salt-Induced Hypertension While Reducing Pro-inflammatory Cytokines and Oxidative Stress in the Paraventricular Nucleus

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Abstract

Carbon monoxide (CO) presents anti-inflammatory and antioxidant activities as a new gaseous neuromessenger produced by heme oxygenase-1 (HO-1) in the body. High salt-induced hypertension is relevant to the levels of pro-inflammatory cytokines (PICs) and oxidative stress in the hypothalamic paraventricular nucleus (PVN). We explored whether CO in PVN can attenuate high salt-induced hypertension by regulating PICs or oxidative stress. Male Dahl Salt-Sensitive rats were fed high-salt (8% NaCl) or normal-salt (0.3% NaCl) diet for 4 weeks. CORM-2, ZnPP IX, or vehicle was microinjected into bilateral PVN for 6 weeks. High-salt diet increased the levels of MAP, plasma norepinephrine (NE), reactive oxygen species (ROS), and the expressions of COX2, IL-1β, IL-6, NOX2, and NOX4 significantly in PVN (p < 0.05), but decreased the expressions of HO-1 and Cu/Zn-SOD in PVN (p < 0.05). Salt increased sympathetic activity as measured by circulating norepinephrine, and increased the ratio of basal RSNA to max RSNA, in part by decreasing max RSNA. PVN microinjection of CORM-2 decreased the levels of MAP, NE, RSNA, ROS and the expressions of COX2, IL-1β, IL-6, NOX2, NOX4 significantly in PVN of hypertensive rat (p < 0.05), but increased the expressions of HO-1 and Cu/Zn-SOD significantly (p < 0.05), which were all opposite to the effects of ZnPP IX microinjected in PVN (p < 0.05). We concluded that exogenous or endogenous CO attenuates high salt-induced hypertension by regulating PICs and oxidative stress in PVN.

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Acknowledgements

We thank Xin-ai Song for technical assistance. This work was supported by National Natural Science Foundation of China (Grant Numbers 81770426, 91439120, 81600330, 81600333), China Postdoctoral Science Foundation (Nos. 2016M590957, 2016M602835), Shaanxi Postdoctoral Science Foundation (Nos. 2016BSHEDZZ89, 2016BSHEDZZ91), and the Foundation of Jiamusi University (Grant Number Sq2014-001).

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  1. Dong-Dong Zhang and Yan-Feng Liang have contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi’an Jiaotong University, Xi’an, 710061, China

    Dong-Dong Zhang, Yan-Feng Liang, Jie Qi, Xiao-Jing Yu, Hong-Li Gao, Kai-Li Liu, Yan-Mei Chen, Guo-Rui Xin, Li-Yan Fu & Yu-Ming Kang

  2. Department of Endocrinology and Metabolism, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, China

    Wei Cui

  3. Department of Anatomy, School of Basic Medical Sciences, Jiamusi University, Jiamusi, 154007, China

    Dong-Dong Zhang

  4. Department of Pathophysiology, School of Basic Medical Sciences, Jiamusi University, Jiamusi, 154007, China

    Yan-Feng Liang

  5. Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA

    Kai B. Kang

  6. Department of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, China

    Xiao-Lian Shi

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Contributions

YK, XY, and DZ designed the study. DZ, YL, JQ, HG, KL, YC, XS, GX, and LF performed all experiments. DZ and YL also performed data analysis and drafted the manuscript. YK, WC, JQ, and KK critically revised the manuscript. All authors reviewed the final manuscript.

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Correspondence to Jie Qi, Yu-Ming Kang or Wei Cui.

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Zhang, DD., Liang, YF., Qi, J. et al. Carbon Monoxide Attenuates High Salt-Induced Hypertension While Reducing Pro-inflammatory Cytokines and Oxidative Stress in the Paraventricular Nucleus. Cardiovasc Toxicol 19, 451–464 (2019). https://doi.org/10.1007/s12012-019-09517-w

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