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Magnesium lithospermate B ameliorates microcirculation perfusion in rats by promoting vascular NO production via activating the PI3K/AKT pathway

Abstract

Microcirculation morphologically refers to the blood flow in vessels of less than 150 μm in diameter, including arterioles, capillaries and venules, which provides nutrients and removes metabolic byproducts within tissues. Microcirculation dysfunction is involved in the pathological progress of many diseases, such as obesity, hypertension, and insulin resistance. In this study we investigated the effects of magnesium lithospermate B (MLB), an active compound of the traditional Chinese medicine Slavia miltiorrhiza, on the microcirculation dysfunction in rats and the underlying molecular mechanisms. The effects of MLB on microcirculation were assessed in vivo by measuring the hindlimb blood perfusion in dextran-induced microcirculation dysfunction rats and mesentery blood flow in anesthetized rats. We demonstrated that administration of MLB restored the impaired rat hindlimb blood flow and promoted the mesenteric micoperfusion in vivo. We further revealed in these two animal models that MLB treatment significantly increased the production of total nitrite in vascular tissues (mesentery, aorta, and heart), which was confirmed in human microvascular endothelial cells (HMEC-1) treated with MLB in vitro. Moreover, we showed that MLB treatment significantly increased the phosphorylation of endothelium nitric oxide synthase (eNOS) via inducing AKT phosphorylation in vivo and in vitro. Co-administration of the eNOS inhibitor L-NAME (20 mg/kg) abolished the protective effects of MLB against dextran-induced microcirculation dysfunction in rats, whereas pretreatment with PI3K inhibitor LY294002 (10 μM) prevented eNOS activation in MLB-treated HMEC-1 cells. Our results suggest that MLB can restore the microcirculation dysfunction via activating eNOS, and in turn enhancing the vascular nitric oxide production, which is medicated by MLB-caused activation of the PI3K/AKT pathway.

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Acknowledgements

We thank Prof Yi-ping Wang for the experimental design and financial support and for his considerate supervision and invaluable suggestions to students, which will benefit us for the rest of our lives. His sudden passing grieves us, and his contributions can only be appreciated in the acknowledgements section according to the authorship regulations of ICMJE. We thank Min Huang for the language editing and Jing Zhao, Zi-ying Shen, Wen-wei Xu, Liang Hu, Fei Gao, Cong Xi, Hui-hui Li, and Jiao-meng Li for their technical assistance.

Author contributions

YLL and XYZ designed the study; LJX provided the MLB and supervised this study; YLL and XYZ performed the experiments; YLL wrote the manuscript. All of the authors have read, revised. and approved the submitted version of the manuscript.

Author information

Correspondence to Li-jiang Xuan.

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Keywords

  • traditional Chinese medicine
  • Salvia miltiorrhiza
  • magnesium lithospermate B
  • microcirculation dysfunction
  • NO
  • endothelium nitric oxide synthase
  • PI3K/AKT pathway
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