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Magnesium lithospermate B protects the endothelium from inflammation-induced dysfunction through activation of Nrf2 pathway

Acta Pharmacologica Sinica (2019) | Download Citation

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Abstract

Magnesium lithospermate B (MLB) is an active component of Salvia miltiorrhiza Radix, a traditional Chinese herb used in treating cardiovascular diseases. In this study, we investigated the protective effects of MLB against inflammation-induced endothelial dysfunction in vitro and in vivo, and the underlying mechanisms. Endothelial dysfunction was induced in human dermal microvascular endothelial cells (HMEC-1) in vitro by lipopolysaccharide (LPS, 1 μg/mL). We showed that pretreatment with MLB (10–100 μM) dose-dependently inhibited LPS-induced upregulation of inflammatory cytokines ICAM1, VCAM1, and TNFα, which contributed to reduced leukocytes adhesion and attenuation of endothelial hyperpermeability in HMEC-1 cells. SD rats were injected with LPS (10 mg/kg, ip) to induce endothelial dysfunction in vivo. We showed that pretreatment with MLB (25–100 mg/kg, ip) dose-dependently restored LPS-impaired endothelial-dependent vasodilation in superior mesenteric artery (SMA), attenuated leukocyte adhesion in mesenteric venules and decreased vascular leakage in the lungs. We further elucidated the mechanisms underlying the protective effects of MLB, and revealed that MLB pretreatment inhibited NF-κB activation through inhibition of IκBα degradation and subsequent phosphorylation of NF-κB p65 in vitro and in vivo. In HMEC-1 cells, MLB pretreatment activated the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. Knockdown of Nrf2 with siRNA abolished the inhibitory effects of MLB on IκBα degradation and ICAM1 up-regulation, which were mimicked by PKC inhibition (Gö6983) or PI3K/Akt inhibition (LY294002). In summary, our results demonstrate that MLB inhibits NF-κB activation through PKC- and PI3K/Akt-mediated Nrf2 activation in HMEC-1 cells and protects against LPS-induced endothelial dysfunction in murine model of acute inflammation.

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Acknowledgements

We thank Xiao-yu Zhou, Jing Zhao, Zi-ying Shen, and Wen-wei Xu for their technical assistance. We would also like to express our special gratitude and deep condolence for our mentor, Professor Yi-ping Wang, who passed away on 11 April 2018, for his tremendous mentoring and support all along.

Author contributions

FG, YPW, and LJX designed the experiments and wrote the manuscript; FG performed the experiments and the data analyses. JML, CX, HHL, and YLL participated in the data analyses of this manuscript. All authors have read, revised, and approved the submitted version of this manuscript.

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Affiliations

  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, 201203, China

    • Fei Gao
    • , Jiao-meng Li
    • , Cong Xi
    • , Hui-hui Li
    • , Ying-luo Liu
    • , Yi-ping Wang
    •  & Li-jiang Xuan
  2. School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China

    • Fei Gao
    • , Jiao-meng Li
    • , Cong Xi
    • , Hui-hui Li
    • , Ying-luo Liu
    • , Yi-ping Wang
    •  & Li-jiang Xuan

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The authors declare no competing interests.

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Correspondence to Li-jiang Xuan.

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https://doi.org/10.1038/s41401-018-0189-1