Skip to main content
SpringerLink
Log in

Icariin regulates PRMT/ADMA/DDAH pathway to improve endothelial function

  • Original research article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

Oxidative stress may affect PRMT/ADMA/DDAH (protein arginine methyltransferases/asymmetric dimethylarginine/dimethylarginine dimethylaminohydrolase) pathway to impair endothelial dysfunction. The present study was carried out to test the effect of icariin on endothelial function and the mechanisms responsible for this.

Methods

Eighty mice at 12 weeks of age were separated randomly into four groups (n = 20): C57BL/6J control, untreated apolipoprotein E-deficient (ApoE−/−), two groups of icariin-treated (10 or 30 mg/kg body wt/day, intragastrically) ApoE−/−. Primary human umbilical vein endothelial cells (HUVECs) were randomly divided into 7 groups: control group, vehicle of icariin (10 μmol/L) group, icariin (10 μmol/L) group, lysophosphatidylcholine (LPC) (10 μg/mL) group, LPC plus icariin (1 μmol/L) group, LPC plus icariin (3 μmol/L) group, and LPC plus icariin (10 μmol/L) group.

Results

In ApoE−/− mice and primary HUVECs, icariin treatment decreased reactive oxygen species production, PRMT I expression, ADMA level, half-maximum effective concentration of ApoE−/− mice aortic rings. Icariin increased DDAH II expression, DDAH activity, maximal relaxation value and endothelium-dependent vasorelaxation in aortic rings from ApoE−/− mice (p < 0.05 or p < 0.01).

Conclusions

The present results suggest that icariin regulates PRMT/ADMA/DDAH pathway to improve endothelial function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Dzau VJ, Gnecchi M, Pachori AS, Morello F, Melo LG. Therapeutic potential of endothelial progenitor cells in cardiovascular diseases. Hypertension 2005;46:7–18.

    Article  CAS  Google Scholar 

  2. Vasilev V, Matrozova J, Elenkova A, Vandeva S, Kirilov G, Zacharieva S. Asymmetric dimethylarginine (ADMA) and soluble vascular cell adhesion molecule 1(sVCAM-1) as circulating markers for endothelial dysfunction in patients with pheochromocytoma. Exp Clin Endocrinol Diabetes 2013;121: 551–5.

    Article  CAS  Google Scholar 

  3. Wadham C, Mangoni AA. Dimethylarginine dimethylaminohydrolase regulation: a novel therapeutic target in cardiovascular disease. Expert Opin Drug Metab Toxicol 2009;5:303–519.

    Article  CAS  Google Scholar 

  4. Bai F, Makino T, Ono T, Mizukami H. Anti-hypertensive effects of shichimotsukokato in 5/6 nephrectomized Wistar rats mediated by the DDAH-ADMA-NO pathway. J Nat Med 2012;66:583–90.

    Article  Google Scholar 

  5. Raptis V, Georgianos PI, Sarafidis PA, Sioulis A, Makedou K, Makedou A, et al. Elevated asymmetric dimethylarginine is associated with oxidant stress aggravation in patients with early stage autosomal dominant polycystic kidney disease. Kidney Blood Press Res 2013;38:72–82.

    Article  CAS  Google Scholar 

  6. Pan Y, Kong L, Xia X, Zhang W, Xia Z, Jiang F. Antidepressant-like effect of icariin and its possible mechanism in mice. Pharmacol Biochem Behav 2005;82:686–94.

    Article  CAS  Google Scholar 

  7. Xu HB, Huang ZQ. Vasorelaxant effects of icariin on isolated canine coronary artery. J Cardiovasc Pharmacol 2007;49:207–13.

    Article  CAS  Google Scholar 

  8. Wang YK, Huang ZQ. Protective effects of icariin on human umbilical vein endothelial cell injury induced by H2O2 in vitro. Pharmacol Res 2005;52:174– 82.

    Article  CAS  Google Scholar 

  9. Shindel AW, Xin ZC, Lin G, Fandel TM, Huang YC, Banie L, et al. Erectogenic and neurotrophic effects of icariin, a purified extract of horny goat weed (Epimedium spp.) in vitro and in vivo. J Sex Med 2010;7:1518–28.

    Article  CAS  Google Scholar 

  10. Chen J, Kuhlencordt P, Urano F, Ichinose H, Astern J, Huang PL. Effects of chronic treatment with L-arginine on atherosclerosis in apoE knockout and apoE/inducible NO synthase double-knockout mice. Arterioscler Thromb Vasc Biol 2003;23:97–103.

    Article  Google Scholar 

  11. Hermenegildo C, Oviedo PJ, García-Pérez MA, Tarín JJ, Cano A. Effects of phytoestrogens genistein and daidzein on prostacyclin production by human endothelial cells. J Pharmacol Exp Ther 2005;315:722–8.

    Article  CAS  Google Scholar 

  12. Setsukinai K, Urano Y, Kakinuma K, Majima HJ, Nagano T. Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species. J Biol Chem 2003;278:3170–5.

    Article  CAS  Google Scholar 

  13. Ford RJ, Graham DA, Denniss SG, Quadrilatero J, Rush JW. Glutathione depletion in vivo enhances contraction and attenuates endothelium-dependent relaxation of isolateral aorta. Free Radic Biol Med 2006;40:670–8.

    Article  CAS  Google Scholar 

  14. Monsalve E, Oviedo PJ, García-Pérez MA, Tarín JJ, Cano A, Hermenegildo C. Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells. Cardiovasc Res 2007;73:66–72.

    Article  CAS  Google Scholar 

  15. Jacobi J, Maas R, Cardounel AJ, Arend M, Pope AJ, Cordasic N, et al. Dimethylarginine dimethylaminohydrolase overexpression ameliorates atherosclerosis in apolipoprotein E-deficient mice by lowering asymmetric dimethylarginine. Am J Pathol 2010;176:2559–3270.

    Article  CAS  Google Scholar 

  16. Limbourg FP, Huang Z, Plumier JC, Simoncini T, Fujioka M, Tuckermann J, et al. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J Clin Invest 2002;110:1729–38.

    Article  CAS  Google Scholar 

  17. Zou L, Zhang H, Du C, Liu X, Zhu S, Zhang W, et al. Correlation of SRSF1 and PRMT1 expression with clinical status of pediatric acute lymphoblastic leukemia. J Hematol Oncol 2012;5:42.

    Article  CAS  Google Scholar 

  18. Jacobi J, Maas R, Cordasic N, Koch K, Schmieder RE, Böger RH, et al. Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice. Am J Physiol Heart Circ Physiol 2008;294:H1058–66.

    Article  Google Scholar 

  19. Choi D, Oh KJ, Han HS, Yoon YS, Jung CY, Kim ST, et al. Protein arginine methyltransferase 1 regulates hepatic glucose production in a FoxO1-dependent manner. Hepatology 2012;56:1546–56.

    Article  CAS  Google Scholar 

  20. Ayling LJ1, Whitley GS, Aplin JD, Cartwright JE. Dimethylarginine dimethylaminohydrolase (DDAH) regulates trophoblast invasion and motility through effects on nitric oxide. Hum Reprod 2006;21:2530–7.

    Article  CAS  Google Scholar 

  21. Fu YF, Xiong Y, Guo ZA. Reduction of endogenous asymmetric dimethylarginine contributes to the effect of captopril on endothelial dysfunction induced by homocysteine in rats. Eur J Pharmacol 2005;508:167–75.

    Article  CAS  Google Scholar 

  22. Scalera F, Kielstein JT, Martens-Lobenhoffer J, Postel SC, Täger M, Bode-Böger SM. Erythropoietin increases asymmetric dimethylarginine in endothelial cells: role of dimethylarginine dimethylaminohydrolase. J Am Soc Nephrol 2005;16:892–8.

    Article  CAS  Google Scholar 

  23. Chen BM, Xia LW, Zhao RQ. Determination of N(G),N(G)-dimethylarginine in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1997;692:467–71.

    Article  CAS  Google Scholar 

  24. Kaul S, Coin B, Hedayiti A, Yano J, Cercek B, Chyu KY, et al. Rapid reversal of endothelial dysfunction in hypercholesterolemic apolipoprotein E-null mice by recombinant apolipoprotein A-I(Milano)-phospholipid complex. J Am Coll Cardiol 2004;44:1311–9.

    Article  CAS  Google Scholar 

  25. Cable DG, Celotto AC, Evora PR, Schaff HV. Asymmetric dimethylarginine endogenous inhibition of nitric oxide synthase causes differential vasculature effects. Med Sci Monit 2009;15:BR248–53.

    Google Scholar 

  26. Han HS, Choi D, Choi S, Koo SH. Roles of protein arginine methyltransferases in the control of glucose metabolism. Endocrinol Metab (Seoul) 2014;29:435–40.

    Article  Google Scholar 

  27. Leiper JM, Santa Maria J, Chubb A, MacAllister RJ, Charles IG, Whitley GS, et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 1999;343:209–14.

    Article  CAS  Google Scholar 

  28. Jacobi J, Sydow K, von Degenfeld G, Zhang Y, Dayoub H, Wang B, et al. Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis. Circulation 2010;111:1431–8.

    Article  Google Scholar 

  29. Savoia C, Ebrahimian T, Lemarié CA, Paradis P, Iglarz M, Amiri F, et al. Countervailing vascular effects of rosiglitazone in high cardiovascular risk mice: role of oxidative stress and PRMT-1. Clin Sci (Lond) 2010;118:583–92.

    Article  CAS  Google Scholar 

  30. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 1999;99:3092–5.

    Article  CAS  Google Scholar 

  31. Stühlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 2001;104:2569–75.

    Article  Google Scholar 

  32. Achan V, Tran CT, Arrigoni F, Whitley GS, Leiper JM, Vallance P. all-trans-Retinoic acid increases nitric oxide synthesis by endothelial cells: a role for the induction of dimethylarginine dimethylaminohydrolase. Circ Res 2002;90:764–9.

    Article  CAS  Google Scholar 

  33. Xiao HB, Lu XY, Li YJ, Xu JP, Sun ZL. Effect of 3,4,5,6-tetrahydroxyxanthone on erythrocyte deformability in apolipoprotein E-deficient mice. J Asian Nat Prod Res 2009;11:643–51.

    Article  CAS  Google Scholar 

  34. Zhao F, Tang YZ, Liu ZQ. Protective effect of icariin on DNA against radical-induced oxidative damage. J Pharm Pharmacol 2007;59:1729–32.

    Article  CAS  Google Scholar 

  35. Song YH, Li BS, Chen XM, Cai H. Ethanol extract from Epimedium brevicornum attenuates left ventricular dysfunction and cardiac remodeling through down-regulating matrix metalloproteinase-2 and -9 activity and myocardial apoptosis in rats with congestive heart failure. Int J Mol Med 2008;21:117– 24.

    CAS  PubMed  Google Scholar 

  36. Zhu DY, Lou YJ. Icariin-mediated expression of cardiac genes and modulation of nitric oxide signaling pathway during differentiation of mouse embryonic stem cells into cardiomyocytes in vitro. Acta Pharmacol Sin 2006;27:311–20.

    Article  CAS  Google Scholar 

  37. Jia SJ, Jiang DJ, Hu CP, Zhang XH, Deng HW, Li YJ. Lysophosphatidylcholine-induced elevation of asymmetric dimethylarginine level by the NADPH oxidase pathway in endothelial cells. Vascul Pharmacol 2006;44:143–8.

    Article  CAS  Google Scholar 

  38. Hu X, Atzler D, Xu X, Zhang P, Guo H, Lu Z, et al. Dimethylarginine dimethylaminohydrolase-1 is the critical enzyme for degrading the cardiovascular risk factor asymmetrical dimethylarginine. Arterioscler Thromb Vasc Biol 2011;31:1540–6.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. College of Veterinary Medicine, Hunan Agricultural University, Changsha, China

    Hong-Bo Xiao & Zi-Kui Liu

  2. Hunan Collaborative Innovation Center for Utilization of Botanical Functional Ingredients, Changsha, China

    Xiang-Yang Lu

  3. The Third Hospital of Changsha, Changsha, China

    Chun-Na Deng

  4. Department of Basic Medicine, Xiangnan University, Chenzhou, China

    Zhi-Feng Luo

Authors
  1. Hong-Bo Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zi-Kui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiang-Yang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun-Na Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhi-Feng Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hong-Bo Xiao.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiao, HB., Liu, ZK., Lu, XY. et al. Icariin regulates PRMT/ADMA/DDAH pathway to improve endothelial function. Pharmacol. Rep 67, 1147–1154 (2015). https://doi.org/10.1016/j.pharep.2015.04.017

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2015.04.017

Keywords

Search

Navigation