Chinese Journal of Integrative Medicine

, Volume 24, Issue 12, pp 897–904 | Cite as

Berberine-Promoted CXCR4 Expression Accelerates Endothelial Repair Capacity of Early Endothelial Progenitor Cells in Persons with Prehypertension

  • Yi-jia Shao
  • Jun Tao
  • Bing-bo Yu
  • Dan Meng
  • Xu-long Yang
  • Jia-pan Sun
  • Yan-xia Qiu
  • Xiao-yu ZhangEmail author
Original Article



To evaluate whether the berberine treatment can improve endothelial repair capacity of early endothelial progenitor cells (EPCs) from prehypertensive subjects through increasing CXC chemokine receptor 4 (CXCR4) signaling.


EPCs were isolated from prehypertensive and healthy subjects and cultured. In vivo reendothelialization capacity of EPCs from prehypertensive patients with or without in vitro berberine treatment was examined in a nude mouse model of carotid artery injury. The protein expressions of CXCR4/Janus kinase-2 (JAK-2) signaling of in vitro EPCs were detected by Western blot analysis.


CXCR4 signaling and alteration in migration and adhesion functions of EPCs were evaluated. Basal CXCR4 expression was significantly reduced in EPCs from prehypertensive patients compared with normal subjects (P<0.01). Also, the phosphorylation of JAK-2 of EPCs, a CXCR4 downstream signaling, was significantly decreased (P<0.01). Berberine promoted CXCR4/JAK-2 signaling expression of in vitro EPCs (P<0.01). Transplantation of EPCs pretreated with berberine markedly accelerated in vivo reendothelialization (P<0.01). The increased in vitro function and in vivo reendothelialization capacity of EPCs were inhibited by CXCR4 neutralizing antibody or pretreatment with JAK-2 inhibitor AG490, respectively (P<0.01).


Berberinemodified EPCs via up-regulation of CXCR4 signaling contributes to enhanced endothelial repair capacity in prehypertension, indicating that berberine may be used as a novel potential primary prevention means against prehypertension-related atherosclerotic cardiovascular disease.


prehypertension berberine endothelial progenitor cells reendothelialization CXC chemokine receptor 4 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eight Joint National Committee (JNC 8). JAMA 2014;311:507–520.CrossRefPubMedGoogle Scholar
  2. 2.
    Ishikawa Y, Ishikawa J, Ishikawa S, Kario K, Kajii E. Progression from prehypertension to hypertension and risk of cardiovascular disease. J Epidemiol 2017;27:8–13.CrossRefPubMedGoogle Scholar
  3. 3.
    Thiyagarajan R, Pal P, Pal GK, Subramanian SK, Bobby Z, Das AK, et al. Cardiovagal modulation, oxidative stress, and cardiovascular risk factors in prehypertensive subjects: crosssectional study. Am J Hypertens 2013;26:850–857.CrossRefPubMedGoogle Scholar
  4. 4.
    Weil BR, Stauffer BL, Greiner JJ, DeSouza CA. Prehypertension is associated with impaired nitric oxide-mediated endotheliumdependent vasodilation in sedentary adults. Am J Hypertens 2011;24:976–981.CrossRefPubMedGoogle Scholar
  5. 5.
    Di Stefano R, Barsotti MC, Felice F, Vlachopoulos C, Balbarini A. Endothelial progenitor cells in prehypertension. Curr Pharm Des 2011;17:3002–3019.CrossRefPubMedGoogle Scholar
  6. 6.
    Rigato M, Avogaro A, Fadini GP. Levels of circulating progenitor cells, cardiovascular outcomes and death: A meta-analysis of prospective observational studies. Circ Res 2016;118:1930–1939.CrossRefPubMedGoogle Scholar
  7. 7.
    Foteinos G, Hu Y, Xiao Q, Metzler B, Xu Q. Rapid endothelial turnover in atherosclerosis-prone areas coincides with stem cell repair in apolipoprotein E-deficient mice. Circulation 2008;117:1856–1863.CrossRefPubMedGoogle Scholar
  8. 8.
    Moreno PR, Sanz J, Fuster V. Promoting mechanisms of vascular health: circulating progenitor cells, angiogenesis, and reverse cholesterol transport. J Am Coll Cardiol 2009;53:2315–2323.CrossRefPubMedGoogle Scholar
  9. 9.
    Giannotti G, Doerries C, Mocharla PS, Mueller MF, Bahlmann FH, Horvàth T, et al. Impaired endothelial repair capacity of early endothelial progenitor cells in prehypertension: Relation to endothelial dysfunction. Hypertension 2010;55:1389–1397.CrossRefPubMedGoogle Scholar
  10. 10.
    Affuso F, Mercurio V, Fazio V, Fazio S. Cardiovascular and metabolic effects of berberine. World J Cardiol 2010;2:71–77.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Derosa G, Maffioli P, Cicero AF. Berberine on metabolic and cardiovascular risk factors: an analysis from preclinical evidences to clinical trials. Expert Opin Biol Ther 2012;12:1113–1124.CrossRefPubMedGoogle Scholar
  12. 12.
    Ma YG, Liang L, Zhang YB, Wang BF, Bai YG, Dai ZJ, et al. Berberine reduced blood pressure and improved vasodilation in diabetic rats. J Mol Endocrinol 2017;59:191–204.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhang M, Wang CM, Li J, Meng ZJ, Wei SN, Li J, et al. Berberine protects against palmitate-induced endothelial dysfunction: Involvements of up-regulation of AMPK and eNOS and downregulation of NOX4. Mediators Inflamm 2013;2013:260464.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Wang Y, Huang Y, Lam KS, Li Y, Wong WT, Ye H, et al. Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphateactivated protein kinase and endothelial nitric oxide synthase. Cardiovasc Res 2009;82:484–492.CrossRefPubMedGoogle Scholar
  15. 15.
    Xu MG, Wang JM, Chen L, Wang Y, Yang Z, Tao J. Berberineinduced mobilization of circulating endothelial progenitor cells improves human small artery elasticity. J Hum Hypertens 2008;22:389–393.CrossRefPubMedGoogle Scholar
  16. 16.
    Xu MG, Wang JM, Chen L, Wang Y, Yang Z, Tao J. Berberineinduced upregulation of circulating endothelial progenitor cells is related to nitric oxide production in healthy subjects. Cardiology 2009;112:279–286.CrossRefPubMedGoogle Scholar
  17. 17.
    Cheng F, Wang Y, Li J, Su C, Wu F, Xia WH, et al. Berberine improves endothelial function by reducing endothelial microparticles-mediated oxidative stress in humans. Int J Cardiol 2013;167:936–942.CrossRefPubMedGoogle Scholar
  18. 18.
    Sainz J, Sata M. CXCR4, a key modulator of vascular progenitor cells. Arterioscler Thromb Vasc Biol 2007;27:263–265.CrossRefPubMedGoogle Scholar
  19. 19.
    Chen L, Wu F, Xia WH, Zhang YY, Xu SY, Cheng F, et al. CXCR4 gene transfer contributes to in vivo reendothelialization capacity of endothelial progenitor cells. Cardiovasc Res 2010;88:462–470.CrossRefPubMedGoogle Scholar
  20. 20.
    Xia WH, Li J, Su C, Yang Z, Chen L, Wu F, et al. Physical exercise attenuates age-associated reduction in endothelium-reparative capacity of endothelial progenitor cells by increasing CXCR4/JAK-2 signaling in healthy men. Aging Cell 2012;11:111–119.CrossRefPubMedGoogle Scholar
  21. 21.
    Liu X, Zhang GX, Zhang XY, Xia WH, Yang Z, Su C, et al. Lacidipine improves endothelial repair capacity of endothelial progenitor cells from patients with essential hypertension. Int J Cardiol 2013;168:3317–3326.CrossRefPubMedGoogle Scholar
  22. 22.
    MacEneaney OJ, DeSouza CA, Weil BR, Kushner EJ, Van Guilder GP, Mestek ML, et al. Prehypertension and endothelial progenitor cell function. J Hum Hypertens 2011;25:57–62.CrossRefPubMedGoogle Scholar
  23. 23.
    Cheng M, Huang K, Zhou J, Yan D, Tang YL, Zhao TC, et al. A critical role of Src family kinase in SDF-1/CXCR4-mediated bone-marrow progenitor cell recruitment to the ischemic heart. J Mol Cell Cardiol 2015;81:49–53.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Liu L, Liu J, Huang Z, Yu X, Zhang X, Dou D, et al. Berberine improves endothelial function by inhibiting endoplasmic reticulum stress in the carotid arteries of spontaneously hypertensive rats. Biochem Biophys Res Commun 2015;458:796–801.CrossRefPubMedGoogle Scholar
  25. 25.
    Lv X, Yu X, Wang H, Yan Y, Wang Y, Lu D, et al. Berberine inhibits norepinephrine-induced apoptosis in neonatal rat cardiomyocytes via inhibiting ROS-TNF-a-caspase signaling pathway. Chin J Integr Med 2013;19:424–431.CrossRefPubMedGoogle Scholar
  26. 26.
    Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, et al. Feasibility of treating prehypertension with an angiotensinreceptor blocker. N Engl J Med 2006;354:1685–1697.CrossRefPubMedGoogle Scholar
  27. 27.
    Wang ZW, Chen Z, Zhang LF, Wang X, Hao G, Zhang ZG, et al. Status of hypertension in China: Results from the China hypertension survey, 2012–2015. Circulation 2018;137:2344–2356.CrossRefPubMedGoogle Scholar
  28. 28.
    Minami Y, Nakajima T, Ikutomi M, Morita T, Komuro I, Sata M, et al. Angiogenic potential of early and late outgrowth endothelial progenitor cells is dependent on the time of emergence. Int J Cardiol 2015;186:305–314.CrossRefPubMedGoogle Scholar

Copyright information

© Chinese Association of the Integration of Traditional and Western Medicine 2018

Authors and Affiliations

  • Yi-jia Shao
    • 1
  • Jun Tao
    • 1
  • Bing-bo Yu
    • 1
  • Dan Meng
    • 1
  • Xu-long Yang
    • 1
  • Jia-pan Sun
    • 1
  • Yan-xia Qiu
    • 1
  • Xiao-yu Zhang
    • 1
    Email author
  1. 1.Department of Hypertension and Vascular Disease, the First Affiliated Hospital of Sun Yat-Sen University, Key Laboratory on Assisted CirculationMinistry of HealthGuangzhouChina

Personalised recommendations