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


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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  1. 1.

    Gutterman DD, Chabowski DS, Kadlec AO, Durand MJ, Freed JK, Ait-Aissa K, et al. The human microcirculation: regulation of flow and beyond. Circ Res. 2016;118:157–72.

  2. 2.

    Ellis CG, Jagger J, Sharpe M. The microcirculation as a functional system. Crit Care. 2005;9(Suppl 4):S3–8.

  3. 3.

    Abularrage CJ, Sidawy AN, Aidinian G, Singh N, Weiswasser JM, Arora S. Evaluation of the microcirculation in vascular disease. J Vasc Surg. 2005;42:574–81.

  4. 4.

    Serne EH, de Jongh RT, Eringa EC, IJzerman RG, Stehouwer CD. Microvascular dysfunction: a potential pathophysiological role in the metabolic syndrome. Hypertension. 2007;50:204–11.

  5. 5.

    De Boer MP, Meijer RI, Wijnstok NJ, Jonk AM, Houben AJ, Stehouwer CD, et al. Microvascular dysfunction: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension. Microcirculation. 2012;19:5–18.

  6. 6.

    Crea F, Camici PG, Bairey Merz CN. Coronary microvascular dysfunction: an update. Eur Heart J. 2014;35:1101–11.

  7. 7.

    Task Force M, Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949–3003.

  8. 8.

    Li ZM, Xu SW, Liu PQ. Salvia miltiorrhizaBurge (Danshen): a golden herbal medicine in cardiovascular therapeutics. Acta Pharmacol Sin. 2018;39:802–24.

  9. 9.

    Wang J, Xiong X, Feng B. Cardiovascular effects of salvianolic acid B. Evid Based Complement Alternat Med. 2013;2013:247948.

  10. 10.

    Chen YJ, Lo YH, Chen YT, Lai NW, Lin NH, Chung TY, et al. Magnesium lithospermate B improves metabolic changes in high-fat diet-fed rats with metabolic syndrome. J Funct Foods. 2015;14:163–73.

  11. 11.

    Tzen JT, Jinn TR, Chen YC, Li FY, Cheng FC, Shi LS, et al. Magnesium lithospermate B possesses inhibitory activity on Na+,K+-ATPase and neuroprotective effects against ischemic stroke. Acta Pharmacol Sin. 2007;28:609–15.

  12. 12.

    Chang CZ, Wu SC, Kwan AL. Magnesium lithospermate B, an active extract of Salvia miltiorrhiza, mediates sGC/cGMP/PKG translocation in experimental vasospasm. Biomed Res Int. 2014;2014:272101.

  13. 13.

    Kim SH, Kim SH, Choi M, Lee Y, Kim YO, Ahn DS, et al. Natural therapeutic magnesium lithospermate B potently protects the endothelium from hyperglycaemia-induced dysfunction. Cardiovasc Res. 2010;87:713–22.

  14. 14.

    Wu XJ, Wang YP, Wei W, Sun WK, Xu YM, Xuan LJ. Free radical scavenging and inhibition of lipid peroxidation by magnesium lithospermate B. Acta Pharmacol Sin. 2000;21:855.

  15. 15.

    Li XF, Wang YP. Depside salts from Salvia miltiorrhiza improve myocardial microperfusion in rats using laser Doppler flowmetry. Acta Pharmacol Sin. 2007;28:789–95.

  16. 16.

    ZY Zhen, Guo YC, Zhang ZG, Yan L, Ge PJ, Jin HM. Experimental Study on microthrombi and myocardial injuries. Microvasc Res. 1996;51:99–107.

  17. 17.

    Palmer RM, Ferrige AG, Moncada S. Niric oxide release accounts for the biological activity for endothelium-derived relaxing factor. Nature. 1987;327:524–6.

  18. 18.

    Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al. Regulation of endothelium derivednitric oxide production by the protein kinase Akt. Nature. 1999;399:597–601.

  19. 19.

    Bernier SG, Haldar S, Michel T. Bradykinin-regulated interactions of the mitogen-activated protein kinase pathway with the endothelial nitric-oxide synthase. J Biol Chem. 2000;275:8.

  20. 20.

    Wu WY, Wang YP. Pharmacological actions and therapeutic applications of Salvia miltiorrhiza depside salt and its active components. Acta Pharmacol Sin. 2012;33:1119–30.

  21. 21.

    Liu CL, Xie LX, Li M, Durairajan SS, Goto S, Huang JD. Salvianolic acid B inhibits hydrogen peroxide-induced endothelial cell apoptosis through regulating PI3K/Akt signaling. PLoS ONE. 2007;2:e1321.

  22. 22.

    Chen YH, Lin SJ, Ku HH, Chen YL. Salvianolic acid B attenuates VCAM-1 and ICAM-1 expression in TNF-α-treated human aortic endothelial cells. J Cell Biochem. 2001;82:512–21.

  23. 23.

    Zhang HF, Chen XQ, Hu GY, Wang YP. Magnesium lithospermate B dilates mesenteric arteries by activating BKCa currents and contracts arteries by inhibiting Kv currents. Acta Pharmacol Sin. 2010;31:665–70.

  24. 24.

    Clough GF. Role of nitric oxide in the regulation of microvascular perfusion in human skin in vivo. J Physiol. 1999;516.2:549–57.

  25. 25.

    Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmcol Rev. 1991;43:109–34.

  26. 26.

    Quyyumi AA, Dakak N, Andrews NP, Husain S, Arora S, Gilligan DM, et al. Nitric oxide activity in the human coronary circulation Impact of risk factors for coronary atherosclerosis. J Clin Invest. 1995;95:1747–55.

  27. 27.

    Kukreja RC, Xi L. eNOS phosphorylation: a pivotal molecular switch in vasodilation and cardioprotection? J Mol Cell Cardiol. 2007;42:280–2.

  28. 28.

    Fleming I. Molecular mechanisms underlying the activation of eNOS. Pflug Arch. 2010;459:793–806.

  29. 29.

    Quan W, Wu B, Bai Y, Zhang X, Yin J, Xi M, et al. Magnesium lithospermate B improves myocardial function and prevents simulated ischemia/reperfusion injury-induced H9c2 cardiomyocytes apoptosis through Akt-dependent pathway. J Ethnopharmacol. 2014;151:714–21.

  30. 30.

    Cao ZQ, Quan W, Hou SX, Guo C, Ma SB, Zhang W, et al. The natural therapeutic magnesium lithospermate B potently provides neuroprotective effects on cerebral ischemia/reperfusion injury in rats. J Ethnopharmacol. 2015;162:191–8.

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