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Targeting Interleukin-1 beta to Suppress Sympathoexcitation in Hypothalamic Paraventricular Nucleus in Dahl Salt-Sensitive Hypertensive Rats

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Abstract

Findings from our laboratory indicate that expressions of some proinflammatory cytokines such as tumor necrosis factor, interleukin-6 and oxidative stress responses are increased in the hypothalamic paraventricular nucleus (PVN) and contribute to the progression of salt-sensitive hypertension. In this study, we determined whether interleukin-1 beta (IL-1β) activation within the PVN contributes to sympathoexcitation during development of salt-dependent hypertension. Eight-week-old male Dahl salt-sensitive (S) rats received a high-salt diet (HS, 8 % NaCl) or a normal-salt diet (NS, 0.3 % NaCl) for 6 weeks, and all rats were treated with bilateral PVN injection of gevokizumab (IL-1β inhibitor, 1 μL of 10 μg) or vehicle once a week. The mean arterial pressure (MAP), heart rate (HR) and plasma norepinephrine (NE) were significantly increased in high-salt-fed rats. In addition, rats with high-salt diet had higher levels of NOX-2, NOX-4 [subunits of NAD (P) H oxidase], IL-1β, NLRP3 (NOD-like receptor family pyrin domain containing 3), Fra-LI (an indicator of chronic neuronal activation) and lower levels of IL-10 in the PVN than normal-diet rats. Bilateral PVN injection of gevokizumab decreased MAP, HR and NE, attenuated the levels of oxidative stress and restored the balance of cytokines. These findings suggest that IL-1β activation in the PVN plays a role in salt-sensitive hypertension.

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References

  1. Li, N., Luo, W., Juhong, Z., Yang, J., Wang, H., Zhou, L., & Chang, J. (2010). Associations between genetic variations in the FURIN gene and hypertension. BMC Medical Genetics, 11, 124.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Zhang, M., Qin, D. N., Suo, Y. P., Su, Q., Li, H. B., Miao, Y. W., et al. (2015). Endogenous hydrogen peroxide in the hypothalamic paraventricular nucleus regulates neurohormonal excitation in high salt-induced hypertension. Toxicology Letters, 235, 206–215.

    Article  PubMed  CAS  Google Scholar 

  3. Huang, B. S., Zheng, H., Tan, J., Patel, K. P., & Leenen, F. H. (2011). Regulation of hypothalamic renin-angiotensin system and oxidative stress by aldosterone. Experimental Physiology, 96, 1028–1038.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Kang, Y. M., Ma, Y., Zheng, J. P., Elks, C., Sriramula, S., Yang, Z. M., & Francis, J. (2009). Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension. Cardiovascular Research, 82, 503–512.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Yu, Y., Qin, J., Chen, D., Wang, H., & Wang, J. (2015). Chronic cardiovascular disease-associated gene network analysis in human umbilical vein endothelial cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cardiovascular Toxicology, 15, 157–171.

    Article  PubMed  CAS  Google Scholar 

  6. Janahmadi, Z., Nekooeian, A. A., Moaref, A. R., & Emamghoreishi, M. (2015). Oleuropein offers cardioprotection in rats with acute myocardial infarction. Cardiovascular Toxicology, 15, 61–68.

    Article  PubMed  CAS  Google Scholar 

  7. Nguyen, K. T., Deak, T., Will, M. J., Hansen, M. K., Hunsaker, B. N., Fleshner, M., et al. (2000). Timecourse and corticosterone sensitivity of the brain, pituitary, and serum interleukin-1beta protein response to acute stress. Brain Research, 859, 193–201.

    Article  PubMed  CAS  Google Scholar 

  8. Wei, S. G., Yu, Y., Zhang, Z. H., & Felder, R. B. (2015). Proinflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat. Hypertension, 65, 1126–1133.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Song, X. A., Jia, L. L., Cui, W., Zhang, M., Chen, W., Yuan, Z. Y., et al. (2014). Inhibition of TNF-alpha in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats. Toxicology and Applied Pharmacology, 281, 101–108.

    Article  PubMed  CAS  Google Scholar 

  10. Cao, Y., Mu, J. J., Fang, Y., Yuan, Z. Y., & Liu, F. Q. (2013). Impact of high salt independent of blood pressure on PRMT/ADMA/DDAH pathway in the aorta of Dahl salt-sensitive rats. International Journal of Molecular Sciences, 14, 8062–8072.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Gan, Y., Xing, J., Jing, Z., Stetler, R. A., Zhang, F., Luo, Y., et al. (2012). Mutant erythropoietin without erythropoietic activity is neuroprotective against ischemic brain injury. Stroke; A Journal of Cerebral Circulation, 43, 3071–3077.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Kang, Y. M., Gao, F., Li, H. H., Cardinale, J. P., Elks, C., Zang, W. J., et al. (2011). NF-kappaB in the paraventricular nucleus modulates neurotransmitters and contributes to sympathoexcitation in heart failure. Basic Research in Cardiology, 106, 1087–1097.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Francis, J., MohanKumar, S. M., & MohanKumar, P. S. (2000). Correlations of norepinephrine release in the paraventricular nucleus with plasma corticosterone and leptin after systemic lipopolysaccharide: blockade by soluble IL-1 receptor. Brain Research, 867, 180–187.

    Article  PubMed  CAS  Google Scholar 

  14. Chen, A. D., Zhang, S. J., Yuan, N., Xu, Y., De, W., Gao, X. Y., & Zhu, G. Q. (2011). Angiotensin AT1 receptors in paraventricular nucleus contribute to sympathetic activation and enhanced cardiac sympathetic afferent reflex in renovascular hypertensive rats. Experimental Physiology, 96, 94–103.

    Article  PubMed  CAS  Google Scholar 

  15. Li, H. B., Qin, D. N., Ma, L., Miao, Y. W., Zhang, D. M., Lu, Y., et al. (2014). Chronic infusion of lisinopril into hypothalamic paraventricular nucleus modulates cytokines and attenuates oxidative stress in rostral ventrolateral medulla in hypertension. Toxicology and Applied Pharmacology, 279, 141–149.

    Article  PubMed  CAS  Google Scholar 

  16. Zhu, G. Q., Gao, L., Patel, K. P., Zucker, I. H., & Wang, W. (2004). ANG II in the paraventricular nucleus potentiates the cardiac sympathetic afferent reflex in rats with heart failure. Journal of Applied Physiology, 97, 1746–1754.

    Article  PubMed  CAS  Google Scholar 

  17. Su, Q., Qin, D. N., Wang, F. X., Ren, J., Li, H. B., Zhang, M., et al. (2014). Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system and proinflammatory cytokines in hypertension. Toxicology and Applied Pharmacology, 276, 115–120.

    Article  PubMed  CAS  Google Scholar 

  18. Kang, Y. M., He, R. L., Yang, L. M., Qin, D. N., Guggilam, A., Elks, C., et al. (2009). Brain tumour necrosis factor-alpha modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure. Cardiovascular Research, 83, 737–746.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. MohanKumar, S. M., MohanKumar, P. S., & Quadri, S. K. (1998). Specificity of interleukin-1beta-induced changes in monoamine concentrations in hypothalamic nuclei: blockade by interleukin-1 receptor antagonist. Brain Research Bulletin, 47, 29–34.

    Article  PubMed  CAS  Google Scholar 

  20. Kang, Y. M., Zhang, Z. H., Johnson, R. F., Yu, Y., Beltz, T., Johnson, A. K., et al. (2006). Novel effect of mineralocorticoid receptor antagonism to reduce proinflammatory cytokines and hypothalamic activation in rats with ischemia-induced heart failure. Circulation Research, 99, 758–766.

    Article  PubMed  CAS  Google Scholar 

  21. Sriramula, S., Cardinale, J. P., Lazartigues, E., & Francis, J. (2011). ACE2 overexpression in the paraventricular nucleus attenuates angiotensin II-induced hypertension. Cardiovascular Research, 92, 401–408.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Miller, F. J, Jr, Gutterman, D. D., Rios, C. D., Heistad, D. D., & Davidson, B. L. (1998). Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis. Circulation Research, 82, 1298–1305.

    Article  PubMed  CAS  Google Scholar 

  23. Sriramula, S., Cardinale, J. P., & Francis, J. (2013). Inhibition of TNF in the brain reverses alterations in RAS components and attenuates angiotensin II-induced hypertension. PLoS ONE, 8, e63847.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Yu, X. J., Zhang, D. M., Jia, L. L., Qi, J., Song, X. A., Tan, H., et al. (2015). Inhibition of NF-kappaB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress. Toxicology and Applied Pharmacology, 284, 315–322.

    Article  PubMed  CAS  Google Scholar 

  25. Kang, Y. M., Zhang, Z. H., Xue, B., Weiss, R. M., & Felder, R. B. (2008). Inhibition of brain proinflammatory cytokine synthesis reduces hypothalamic excitation in rats with ischemia-induced heart failure. American journal of physiology. Heart and Circulatory Physiology, 295, H227–H236.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Qi, J., Zhang, D. M., Suo, Y. P., Song, X. A., Yu, X. J., Elks, C., et al. (2013). Renin-angiotensin system modulates neurotransmitters in the paraventricular nucleus and contributes to angiotensin II-induced hypertensive response. Cardiovascular Toxicology, 13, 48–54.

    Article  PubMed  CAS  Google Scholar 

  27. Yu, X. J., Suo, Y. P., Qi, J., Yang, Q., Li, H. H., Zhang, D. M., et al. (2013). Interaction between AT1 receptor and NF-kappaB in hypothalamic paraventricular nucleus contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure. Cardiovascular Toxicology, 13, 381–390.

    Article  PubMed  CAS  Google Scholar 

  28. Leenen, F. H., & Yuan, B. (2001). Prevention of hypertension by irbesartan in Dahl S rats relates to central angiotensin II type 1 receptor blockade. Hypertension, 37, 981–984.

    Article  PubMed  CAS  Google Scholar 

  29. Kang, Y. M., Zhang, D. M., Yu, X. J., Yang, Q., Qi, J., Su, Q., et al. (2014). Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines. Toxicology and Applied Pharmacology, 274, 436–444.

    Article  PubMed  CAS  Google Scholar 

  30. Shi, P., Diez-Freire, C., Jun, J. Y., Qi, Y., Katovich, M. J., Li, Q., et al. (2010). Brain microglial cytokines in neurogenic hypertension. Hypertension, 56, 297–303.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Leemans, J. C., Cassel, S. L., & Sutterwala, F. S. (2011). Sensing damage by the NLRP3 inflammasome. Immunological Reviews, 243, 152–162.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Kang, Y. M., Zhang, A. Q., Zhao, X. F., Cardinale, J. P., Elks, C., Cao, X. M., et al. (2011). Paraventricular nucleus corticotrophin releasing hormone contributes to sympathoexcitation via interaction with neurotransmitters in heart failure. Basic Research in Cardiology, 106, 473–483.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Mohamed, I. N., Hafez, S. S., Fairaq, A., Ergul, A., Imig, J. D., & El-Remessy, A. B. (2014). Thioredoxin-interacting protein is required for endothelial NLRP3 inflammasome activation and cell death in a rat model of high-fat diet. Diabetologia, 57, 413–423.

    Article  PubMed  CAS  Google Scholar 

  34. Luzardo, L., Noboa, O. and Boggia, J. (2015). Mechanisms of Salt-Sensitive Hypertension. Current hypertension reviews.

  35. Trinchieri, G., & Sher, A. (2007). Cooperation of Toll-like receptor signals in innate immune defence. Nature Reviews Immunology, 7, 179–190.

    Article  PubMed  CAS  Google Scholar 

  36. Zheng, F., Xing, S., Gong, Z., & Xing, Q. (2013). NLRP3 inflammasomes show high expression in aorta of patients with atherosclerosis. Heart, Lung and Circulation, 22, 746–750.

    Article  PubMed  Google Scholar 

  37. Tschopp, J., Martinon, F., & Burns, K. (2003). NALPs: a novel protein family involved in inflammation. Nature Reviews Molecular Cell Biology, 4, 95–104.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by National Basic Research Program of China (No. 2012CB517805) and National Natural Science Foundation of China (Nos. 91439120, 81370356 and 81170248). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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    Authors and Affiliations

    1. Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an Jiaotong University Cardiovascular Research Center, Xi’an, 710061, China

      Jie Qi, Xiu-Fang Zhao, Xiao-Jing Yu, Qiu-Yue Yi, Hong Tan, Xiao-Yan Fan, Hong-Li Gao, Li-Ying Yue, Zhi-Peng Feng & Yu-Ming Kang

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

      Xiao-Lian Shi

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

      Hong Tan

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    Qi, J., Zhao, XF., Yu, XJ. et al. Targeting Interleukin-1 beta to Suppress Sympathoexcitation in Hypothalamic Paraventricular Nucleus in Dahl Salt-Sensitive Hypertensive Rats. Cardiovasc Toxicol 16, 298–306 (2016). https://doi.org/10.1007/s12012-015-9338-7

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