Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec 3.
doi: 10.1111/bph.17402. Online ahead of print.

Targeting acetylated high mobility group box 1 protein (HMGB1) and toll-like receptor (TLR4) interaction to alleviate hypertension and neuroinflammation in fructose-fed rats

Yu-Te Lin  1   2   3 , Chiu-Yi Ho  4 , Gwo-Ching Sun  5 , Tzyy-Yue Wong  6 , Michael Hsiao  7   8 , Ching-Jiunn Tseng  3   4   9 , Pei-Wen Cheng  3   4
Affiliations

Targeting acetylated high mobility group box 1 protein (HMGB1) and toll-like receptor (TLR4) interaction to alleviate hypertension and neuroinflammation in fructose-fed rats

Yu-Te Lin et al. Br J Pharmacol. .

Abstract

Background and purpose: Our previous study reported that fructose intake increased systemic blood pressure and reduced nitric oxide (NO) in the nucleus tractus solitarius (NTS) due to oxidative stress and neuroinflammation. However, it remains unclear how reactive oxygen species (ROS) reduce NO and how this process impacts neuroinflammation in the NTS. This study aimed at investigating the effect of ROS on acetylation of high mobility group box 1 protein (HMGB1) in the NTS of fructose-induced hypertensive rats.

Experimental approach: Male Wistar-Kyoto (WKY) rats were fed with 10% fructose water to elevate blood pressure. Thereafter, CLI-095 and glycyrrhizic acid (GA) treatments were delivered for up to 2 weeks (1 mg·12 μL-1·day-1, by intracerebroventricular injection) to reduce the negative effects of toll-like receptor 4 (TLR4) and HMGB1 activation.

Key results: Two weeks of CLI-095 and GA treatment reduced systemic blood pressure and significantly preserved neuronal and endothelial nitric oxide synthase (nNOS and eNOS) availability against the inflammatory insults of fructose consumption. Both CLI-095 and GA halted the interaction of acetylated HMGB1 and TLR4. Two weeks of CLI-095 and GA treatment markedly reduced NTS inflammation (pro-inflammatory cytokines and microglial activation) and lowered serum norepinephrine levels.

Conclusion and implications: Our data reveal novel pharmacological properties for CLI-095 and GA, which improved blood pressure and inflammatory conditions by decreasing the interaction of acetylated HMGB1 with TLR4. These findings challenge the commonly accepted dogma that essential hypertension is specifically mediated by neuroinflammation due to acetylated HMGB1 coupling to TLR4.

Keywords: HMGB1; TLR4; acetylation; hypertension; neuroinflammation; nucleus tractus solitarius.

PubMed Disclaimer

References

REFERENCES

    1. Abo El‐Magd, N. F., El‐Mesery, M., El‐Karef, A., & El‐Shishtawy, M. M. (2018). Glycyrrhizin ameliorates high fat diet‐induced obesity in rats by activating NrF2 pathway. Life Sciences, 193, 159–170. https://doi.org/10.1016/j.lfs.2017.11.005
    1. Acosta, J. I., Mayer, L., Talboom, J. S., Tsang, C. W., Smith, C. J., Enders, C. K., & Bimonte‐Nelson, H. A. (2009). Transitional versus surgical menopause in a rodent model: Etiology of ovarian hormone loss impacts memory and the acetylcholine system. Endocrinology, 150(9), 4248–4259. https://doi.org/10.1210/en.2008-1802
    1. Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Amarosi, L., & Verri, T. (2023). The concise guide to PHARMACOLOGY 2023/24: Transporters. British Journal of Pharmacology, 180(Suppl 2), S374–S469. https://doi.org/10.1111/bph.16182
    1. Alexander, S. P. H., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Buneman, O. P., Faccenda, E., Harding, S. D., Spedding, M., Cidlowski, J. A., & Zolghadri, Y. (2023). The concise guide to PHARMACOLOGY 2023/24: Introduction and other protein targets. British Journal of Pharmacology, 180(Suppl 2), S1–S22. https://doi.org/10.1111/bph.16176
    1. Biancardi, V. C., Bomfim, G. F., Reis, W. L., Al‐Gassimi, S., & Nunes, K. P. (2017). The interplay between angiotensin II, TLR4 and hypertension. Pharmacological Research, 120, 88–96. https://doi.org/10.1016/j.phrs.2017.03.017

LinkOut - more resources