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Apigenin Improves Hypertension and Cardiac Hypertrophy Through Modulating NADPH Oxidase-Dependent ROS Generation and Cytokines in Hypothalamic Paraventricular Nucleus

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Abstract

Apigenin, identified as 4′, 5, 7-trihydroxyflavone, is a natural flavonoid compound that has many interesting pharmacological activities and nutraceutical potential including anti-inflammatory and antioxidant functions. Chronic, low-grade inflammation and oxidative stress are involved in both the initiation and progression of hypertension and hypertension-induced cardiac hypertrophy. However, whether or not apigenin improves hypertension and cardiac hypertrophy through modulating NADPH oxidase-dependent reactive oxygen species (ROS) generation and inflammation in hypothalamic paraventricular nucleus (PVN) has not been reported. This study aimed to investigate the effects of apigenin on hypertension in spontaneously hypertensive rats (SHRs) and its possible central mechanism of action. SHRs and Wistar-Kyoto (WKY) rats were randomly assigned and treated with bilateral PVN infusion of apigenin or vehicle (artificial cerebrospinal fluid) via osmotic minipumps (20 μg/h) for 4 weeks. The results showed that after PVN infusion of apigenin, the mean arterial pressure (MAP), heart rate, plasma norepinephrine (NE), Beta 1 receptor in kidneys, level of phosphorylation of PKA in the ventricular tissue and cardiac hypertrophy, perivascular fibrosis, heart level of oxidative stress, PVN levels of oxidative stress, interleukin 1β (IL-1β), interleukin 6 (IL-6), iNOS, monocyte chemotactic protein 1 (MCP-1), tyrosine hydroxylase (TH), NOX2 and NOX4 were attenuated and PVN levels of interleukin 10 (IL-10), superoxide dismutase 1 (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67) were increased. These results revealed that apigenin improves hypertension and cardiac hypertrophy in SHRs which are associated with the down-regulation of NADPH oxidase-dependent ROS generation and inflammation in the PVN.

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Acknowledgements

This work was funded by National Natural Science Foundation of China (Nos. 81770426, 82070439, 82070440), the Fundamental Research Funds for the Central Universities (Nos. PY3A044, xjh012019059, xzd012019035), China Postdoctoral Science Foundation (No. 2019M663750), and Natural Science Basic Research Program of Shaanxi (Nos. 2021JQ-068, 2020JM-079, 2019JQ-605).

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    1. Key Laboratory of Environment and Genes Related To Diseases of Education Ministry of China, Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Xi’an, 710061, China

      Hong-Li Gao, Xiao-Jing Yu, Han-Bo Hu, Qian-Wen Yang, Kai-Li Liu, Yan-Mei Chen, Yan Zhang, Dong-Dong Zhang, Hua Tian, Jie Qi & Yu-Ming Kang

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

      Guo-Qing Zhu

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    Contributions

    YM-K, J-Q and HL-G designed the study. HL-G, J-Q, HB-H, QW-Y, KL-L and YM-C performed all experiments. HL-G, Y–Z and DD-Z performed the data analysis and drafted the manuscript. YM-K, GQ-Z and H-T revised the manuscript. All authors reviewed the final manuscript.

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    Correspondence to Jie Qi or Yu-Ming Kang.

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    Hong-Li Gao and Xiao-Jing Yu contributed equally to this study.

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    Gao, HL., Yu, XJ., Hu, HB. et al. Apigenin Improves Hypertension and Cardiac Hypertrophy Through Modulating NADPH Oxidase-Dependent ROS Generation and Cytokines in Hypothalamic Paraventricular Nucleus. Cardiovasc Toxicol 21, 721–736 (2021). https://doi.org/10.1007/s12012-021-09662-1

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