Skip to main content
Log in

Astaxanthin Ameliorates Blood Pressure in Salt-Induced Prehypertensive Rats Through ROS/MAPK/NF-κB Pathways in the Hypothalamic Paraventricular Nucleus

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Astaxanthin (AST) has a variety of biochemical effects, including anti-inflammatory, antioxidative, and antihypertensive functions. The aim of the present study was to determine whether AST ameliorates blood pressure in salt-induced prehypertensive rats by ROS/MAPK/NF-κB pathways in hypothalamic paraventricular nucleus.

To explore the central effects of AST on the development of blood pressure, prehypertensive rats were induced by a high-salt diet (HS, 8% NaCl) and its control groups were treated with normal-salt diet (NS, 0.3% NaCl). The Dahl salt-sensitive (S) rats with HS diet for 6 weeks received AST or vehicle by gastric perfusion for 6 weeks. Compared to those with NS diet, rats with HS diet exhibited increased mean arterial pressure (MAP) and heart rate (HR). These increases were associated with higher plasma level of norepinephrine (NE), interleukin 1β (IL-1β), and interleukin 6 (IL-6); elevated PVN level of reactive oxygen species (ROS), NOX2, and NOX4, that of IL-1β, IL-6, monocyte chemotactic protein 1 (MCP-1), tyrosine hydroxylase (TH), phosphorylation extracellular-signal-regulated kinase (p-ERK1/2), phosphorylation Jun N-terminal kinases (p-JNK), nuclear factor-kappa B (NF-κB) activity; and lower levels of IL-10, superoxide dismutase (SOD), and catalase (CAT) in the PVN. In addition, our data demonstrated that chronic AST treatment ameliorated these changes in the HS but not NS diet rats. These data suggested that AST could alleviate prehypertensive response in HS-induced prehypertension through ROS/MAPK/NF-κB pathways in the PVN.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Sueta, D., Koibuchi, N., Hasegawa, Y., Toyama, K., Uekawa, K., Katayama, T., Ma, M. J., Nakagawa, T., Waki, H., Maeda, M., Ogawa, H., & Kim-Mitsuyama, S. (2014). Blood pressure variability, impaired autonomic function and vascular senescence in aged spontaneously hypertensive rats are ameliorated by angiotensin blockade. Atherosclerosis, 236, 101–107.

    Article  CAS  PubMed  Google Scholar 

  2. Xu, M. L., Yu, X. J., Zhao, J. Q., Du, Y., Xia, W. J., Su, Q., Du, M. M., Yang, Q., Qi, J., Li, Y., Zhou, S. W., Zhu, G. Q., Li, H. B., & Kang, Y. M. (2020). Calcitriol ameliorated autonomic dysfunction and hypertension by down-regulating inflammation and oxidative stress in the paraventricular nucleus of SHR. Toxicology and Applied Pharmacology, 394, 114950.

    Article  CAS  PubMed  Google Scholar 

  3. Mittal, B. V., & Singh, A. K. (2010). Hypertension in the developing world: Challenges and opportunities. American Journal of Kidney Diseases, 55, 590–598.

    Article  PubMed  Google Scholar 

  4. Campbell, N. R. C., & Chen, G. M. (2010). Canadian efforts to prevent and control hypertension. Canadian Journal of Cardiology, 26, 14c–17c.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Grassi, G., & Ram, V. S. (2016). Evidence for a critical role of the sympathetic nervous system in hypertension. Journal of the American Society of Hypertension, 10, 457–466.

    Article  CAS  PubMed  Google Scholar 

  6. Thomas, P., & Dasgupta, I. (2015). The role of the kidney and the sympathetic nervous system in hypertension. Pediatric Nephrology(Berlin, Germany), 30, 549–560.

    Article  Google Scholar 

  7. Marciante, A. B., Wang, L. A., Little, J. T., & Cunningham, J. T. (2020). Caspase lesions of PVN-projecting MnPO neurons block the sustained component of CIH-induced hypertension in adult male rats. American Journal of Physiology-Heart and Circulatory, 318, H34–H48.

    Article  CAS  Google Scholar 

  8. Dos Santos, K. M., Moraes, D. J. A., da Silva, M. P., & Antunes, V. R. (2021). Exercise training rescues the electrical activity of liver-projecting DMNV neurones in response to oxytocin in spontaneously hypertensive rats. Journal of Neuroendocrinology, 33, e12977.

    Article  PubMed  CAS  Google Scholar 

  9. Shi, Z., Gan, X. B., Fan, Z. D., Zhang, F., Zhou, Y. B., Gao, X. Y., De, W., & Zhu, G. Q. (2011). Inflammatory cytokines in paraventricular nucleus modulate sympathetic activity and cardiac sympathetic afferent reflex in rats. Acta Physiologica, 203, 289–297.

    Article  CAS  PubMed  Google Scholar 

  10. 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  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cardinale, J. P., Sriramula, S., Mariappan, N., Agarwal, D., & Francis, J. (2012). Angiotensin II-induced hypertension is modulated by nuclear factor-kappa B in the paraventricular nucleus. Hypertension, 59, 113-U282.

    Article  CAS  PubMed  Google Scholar 

  12. McCartney, D. M., Byrne, D. G., & Turner, M. J. (2015). Dietary contributors to hypertension in adults reviewed. Irish Journal of Medical Science, 184, 81–90.

    Article  CAS  PubMed  Google Scholar 

  13. Zou, Z., Wang, M., Wang, Z., Aluko, R. E., & He, R. (2020). Antihypertensive and antioxidant activities of enzymatic wheat bran protein hydrolysates. Jounal of Food Biochemistry, 44, e13090.

    Google Scholar 

  14. Ambati, R. R., Phang, S. M., Ravi, S., & Aswathanarayana, R. G. (2014). Astaxanthin: Sources, extraction, stability, biological activities and its commercial applications-a review. Marine Drugs, 12, 128–152.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Galasso, C., Orefice, I., Pellone, P., Cirino, P., Miele, R., Ianora, A., Brunet, C. & Sansone, C. (2018). On the neuroprotective role of astaxanthin: new perspectives? Marine drugs, 16.

  16. Kumar, A., Dhaliwal, N., Dhaliwal, J., Dharavath, R. N., & Chopra, K. (2020). Astaxanthin attenuates oxidative stress and inflammatory responses in complete Freund-adjuvant-induced arthritis in rats. Pharmacological Reports, 72, 104–114.

    Article  CAS  PubMed  Google Scholar 

  17. Monroy-Ruiz, J., Sevilla, M. A., Carron, R., & Montero, M. J. (2011). Astaxanthin-enriched-diet reduces blood pressure and improves cardiovascular parameters in spontaneously hypertensive rats. Pharmacological Research, 63, 44–50.

    Article  CAS  PubMed  Google Scholar 

  18. Stewart, J. S., Lignell, A., Pettersson, A., Elfving, E., & Soni, M. G. (2008). Safety assessment of astaxanthin-rich microalgae biomass: Acute and subchronic toxicity studies in rats. Food and Chemical Toxicology, 46, 3030–3036.

    Article  CAS  PubMed  Google Scholar 

  19. Hatabu, T., Harada, T., Takao, Y., Thi, D. H., Yamasato, A., Horiuchi, T., Mochizuki, A., & Kondo, Y. (2020). Daily meal supplemented with astaxanthin-enriched yolk has mitigative effects against hypertension in spontaneously hypertensive rats. Biological &/and Pharmaceutical Bulletin, 43, 404–408.

    Article  CAS  Google Scholar 

  20. Zhou, L. P., Gao, M., Xiao, Z. M., Zhang, J., Li, X. M., & Wang, A. M. (2015). Protective effect of astaxanthin against multiple organ injury in a rat model of sepsis. Journal of Surgical Research, 195, 559–567.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang, X. S., Zhang, X., Wu, Q., Li, W., Wang, C. X., Xie, G. B., Zhou, X. M., Shi, J. X., & Zhou, M. L. (2014). Astaxanthin offers neuroprotection and reduces neuroinflammation in experimental subarachnoid hemorrhage. Journal of Surgical Research, 192, 206–213.

    Article  CAS  PubMed  Google Scholar 

  22. Yu, X. J., Zhao, Y. N., Hou, Y. K., Li, H. B., Xia, W. J., Gao, H. L., Liu, K. L., Su, Q., Yang, H. Y., Liang, B., Chen, W. S., Cui, W., Li, Y., Zhu, G. Q., Yang, Z. M., & Kang, Y. M. (2019). Chronic intracerebroventricular infusion of metformin inhibits salt-sensitive hypertension via attenuation of oxidative stress and neurohormonal excitation in rat paraventricular nucleus. Neuroscience Bulletin, 35, 57–66.

    Article  CAS  PubMed  Google Scholar 

  23. Palkovits, M. (1973). Isolated removal of hypothalamic or other brain nuclei of the rat. Brain Research, 59, 449–450.

    Article  CAS  PubMed  Google Scholar 

  24. Chen, Y. M., Yu, X. J., Liu, K. L., Gao, H. L., Li, Y., Sun, T. Z., Shi, X. L., Li, H. B., Zhu, G. Q., Qi, J., & Kang, Y. M. (2020). Inhibition of hypothalamic inhibitor kappa b kinase beta/nuclear transcription factor kappa b pathway attenuates metabolism and cardiac dysfunction in type 2 diabetic rats. Neuroendocrinology, 110, 899–913.

    Article  CAS  PubMed  Google Scholar 

  25. Sueta, D., Koibuchi, N., Hasegawa, Y., Toyama, K., Uekawa, K., Katayama, T., Ma, M., Nakagawa, T., Waki, H., Maeda, M., Ogawa, H., & Kim-Mitsuyama, S. (2014). Blood pressure variability, impaired autonomic function and vascular senescence in aged spontaneously hypertensive rats are ameliorated by angiotensin blockade. Atherosclerosis, 236, 101–107.

    Article  CAS  PubMed  Google Scholar 

  26. Li, H. B., Li, X., Huo, C. J., Su, Q., Guo, J., Yuan, Z. Y., Zhu, G. Q., Shi, X. L., Liu, J. J., & Kang, Y. M. (2016). TLR4/MyD88/NF-kappa B signaling and PPAR-gamma within the paraventricular nucleus are involved in the effects of telmisartan in hypertension. Toxicology and Applied Pharmacology, 305, 93–102.

    Article  CAS  PubMed  Google Scholar 

  27. Li, H. B., Yang, T., Richards, E. M., Pepine, C. J., & Raizada, M. K. (2020). Maternal treatment with captopril persistently alters gut-brain communication and attenuates hypertension of male offspring. Hypertension, 75, 1315–1324.

    Article  CAS  PubMed  Google Scholar 

  28. Sharma, R. K., Oliveira, A. C., Kim, S., Rigatto, K., Zubcevic, J., Rathinasabapathy, A., Kumar, A., Lebowitz, J. J., Khoshbouei, H., Lobaton, G., Aquino, V., Richards, E. M., Katovich, M. J., Shenoy, V., & Raizada, M. K. (2018). Involvement of neuroinflammation in the pathogenesis of monocrotaline-induced pulmonary hypertension. Hypertension, 71, 1156–1163.

    Article  CAS  PubMed  Google Scholar 

  29. Li, Y., Yu, X. J., Xiao, T., Chi, H. L., Zhu, G. Q., & Kang, Y. M. (2021). Nrf1 knock-down in the hypothalamic paraventricular nucleus alleviates hypertension through intervention of superoxide production-removal balance and mitochondrial function. Cardiovascular Toxicology, 21, 472–489.

    Article  PubMed  CAS  Google Scholar 

  30. Xia, W. J., Xu, M. L., Yu, X. J., Du, M. M., Li, X. H., Yang, T., Li, L., Li, Y., Kang, K. B., Su, Q., Xu, J. X., Shi, X. L., Wang, X. M., Li, H. B., & Kang, Y. M. (2021). Antihypertensive effects of exercise involve reshaping of gut microbiota and improvement of gut-brain axis in spontaneously hypertensive rat. Gut Microbes, 13, 1–24.

    Article  PubMed  CAS  Google Scholar 

  31. Kuo, M.H., Lee, H.F., Tu, Y.F., Lin, L.H., Cheng, Y.Y., & Lee, H.T. (2019). Astaxanthin ameliorates ischemic-hypoxic-induced neurotrophin receptor p75 upregulation in the endothelial cells of neonatal mouse brains. International Journal of Molecular Sciences, 20.

  32. Grimmig, B., Kim, S. H., Nash, K., Bickford, P. C., & Douglas Shytle, R. (2017). Neuroprotective mechanisms of astaxanthin: A potential therapeutic role in preserving cognitive function in age and neurodegeneration. Geroscience, 39, 19–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Allison, M. A., Aragaki, A. K., Ray, R. M., Margolis, K. L., Beresford, S. A., Kuller, L., Jo O’Sullivan, M., Wassertheil-Smoller, S., & Van Horn, L. (2016). A randomized trial of a low-fat diet intervention on blood pressure and hypertension: Tertiary analysis of the whi dietary modification trial. American Journal of Hypertension, 29, 959–968.

    Article  CAS  PubMed  Google Scholar 

  34. Tian, H., Kang, Y. M., Gao, H. L., Shi, X. L., Fu, L. Y., Li, Y., Jia, X. Y., Liu, K. L., Qi, J., Li, H. O., Chen, Y. I., Chen, W. S., Cui, W., Zhu, G. Q., & Yu, X. J. (2019). Chronic infusion of berberine into the hypothalamic paraventricular nucleus attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway. Phytomedicine, 52, 216–224.

    Article  CAS  PubMed  Google Scholar 

  35. Su, Q., Qin, D. N., Wang, F. X., Ren, J., Li, H. B., Zhang, M., Yang, Q., Miao, Y. W., Yu, X. J., Qi, J., Zhu, Z. M., Zhu, G. Q., & Kang, Y. M. (2014). Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system and proinflammatory cytokines in hypertension. Toxicol Appl Pharm, 276, 115–120.

    Article  CAS  Google Scholar 

  36. Tan, X., Jiao, P. L., Wang, Y. K., Wu, Z. T., Zeng, X. R., Li, M. L., & Wang, W. Z. (2017). The phosphoinositide-3 kinase signaling is involved in neuroinflammation in hypertensive rats. CNS Neuroscience & Therapeutics, 23, 350–359.

    Article  CAS  Google Scholar 

  37. Yu, X. J., Zhang, D. M., Jia, L. L., Qi, J., Song, X. A., Tan, H., Cui, W., Chen, W., Zhu, G. Q., Qin, D. N., & Kang, Y. M. (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  CAS  PubMed  Google Scholar 

  38. Visioli, F., & Artaria, C. (2017). Astaxanthin in cardiovascular health and disease: Mechanisms of action, therapeutic merits, and knowledge gaps. Food & Function, 8, 39–63.

    Article  CAS  Google Scholar 

  39. Stefanadi, E., Tousoulis, D., Androulakis, E. S., Papageorgiou, N., Charakida, M., Siasos, G., Tsioufis, C., & Stefanadis, C. (2010). Inflammatory markers in essential hypertension: Potential clinical implications. Current Vascular Pharmacology, 8, 509–516.

    Article  CAS  PubMed  Google Scholar 

  40. Wang, M.L., Kang, Y.M., Li, X.G., Su, Q., Li, H.B., Liu, K.L., Fu, L.Y., Saahene, R.O., Li, Y., Tan, H., Yu, X.J. (2018). Central blockade of NLRP3 reduces blood pressure via regulating inflammation microenvironment and neurohormonal excitation in salt-induced prehypertensive rats. Journal of Neuroinflammation, 15.

  41. Wang, M. L., Yu, X. J., Li, X. G., Pang, D. Z., Su, Q., Saahene, R. O., Li, H. B., Mao, X. Y., Liu, K. L., Fu, L. Y., Li, Y., Zhu, G. Q., & Kang, Y. M. (2018). Blockade of TLR4 within the paraventricular nucleus attenuates blood pressure by regulating ros and inflammatory cytokines in prehypertensive rats. American Journal of Hypertension, 31, 1013–1023.

    Article  PubMed  CAS  Google Scholar 

  42. Suzuki, Y., Ohgami, K., Shiratori, K., Jin, X. H., Ilieva, I., Koyama, Y., Yazawa, K., Yoshida, K., Kase, S., & Ohno, S. (2006). Suppressive effects of astaxanthin against rat endotoxin-induced uveitis by inhibiting the NF-kappaB signaling pathway. Experimental Eye Research, 82, 275–281.

    Article  CAS  PubMed  Google Scholar 

  43. Speranza, L., Pesce, M., Patruno, A., Franceschelli, S., de Lutiis, M. A., Grilli, A., & Felaco, M. (2012). Astaxanthin treatment reduced oxidative induced pro-inflammatory cytokines secretion in U937: SHP-1 as a novel biological target. Marine Drugs, 10, 890–899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li, J., Wang, F., Xia, Y., Dai, W., Chen, K., Li, S., Liu, T., Zheng, Y., Wang, J., Lu, W., Zhou, Y., Yin, Q., Lu, J., Zhou, Y., & Guo, C. (2015). Astaxanthin pretreatment attenuates hepatic ischemia reperfusion-induced apoptosis and autophagy via the ROS/MAPK pathway in mice. Marine Drugs, 13, 3368–3387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang, X., Guo, A.L., Pang, Y.P., Cheng, X.J., Xu, T., Li, X.R., Liu, J., Zhang, Y.Y., & Liu, Y. (2019). Astaxanthin attenuates environmental tobacco smoke-induced cognitive deficits: a critical role of p38 MAPK. Marine Drugs, 17.

  46. Gao, H. L., Yu, X. J., Liu, K. L., Shi, X. L., Qi, J., Chen, Y. M., Zhang, Y., Bai, J., Yi, Q. Y., Feng, Z. P., Chen, W. S., Cui, W., Liu, J. J., Zhu, G. Q., & Kang, Y. M. (2017). PVN blockade of p44/42 mapk pathway attenuates salt-induced hypertension through modulating neurotransmitters and attenuating oxidative stress. Scientific Reports, 7, 43038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhao, Y. N., Li, J. M., Chen, C. X., Zhang, P., & Li, S. X. (2015). Hypertension-mediated enhancement of JNK activation in association with endoplasmic reticulum stress in rat model hippocampus with cerebral ischemia-reperfusion. Genetics and Molecular Research : GMR, 14, 10980–10990.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (Nos. 81770426, 82070439, 82070440), the Fundamental Research Funds for the Central Universities (Nos. PY3A044, xjh012019059), China Postdoctoral Science Foundation (Nos. 2019M663750, 2020M683440), and Natural Science Basic Research Program of Shaanxi (Nos. 2021JQ-068, 2020JM-079, 2019JQ-605).

Author information

Authors and Affiliations

Authors

Contributions

YK, HG, and XY designed the study. HG, WC, LY, and KL performed all experiments. HG and NJ also performed the data analysis and drafted the manuscript. YZ, YL, DZ, JY, and DZ participated in data analysis. YL, DZ, HT, and NZ critically revised the manuscript. All authors reviewed the final manuscript.

Corresponding authors

Correspondence to Nian-Ping Zhang or Yu-Ming Kang.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest with respect to the research, authorship, and/or publication of this article.

Additional information

Handling Editor: Kurt J. Varner.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, HL., Yu, XJ., Zhang, Y. et al. Astaxanthin Ameliorates Blood Pressure in Salt-Induced Prehypertensive Rats Through ROS/MAPK/NF-κB Pathways in the Hypothalamic Paraventricular Nucleus. Cardiovasc Toxicol 21, 1045–1057 (2021). https://doi.org/10.1007/s12012-021-09695-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-021-09695-6

Keywords

Navigation