Skip to main content
SpringerLink
Log in

Puerarin-7-O-glucuronide, a water-soluble puerarin metabolite, prevents angiotensin II-induced cardiomyocyte hypertrophy by reducing oxidative stress

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

This study aimed to investigate the anti-oxidant and anti-hypertrophic effects of puerarin-7-O-glucuronide, a water-soluble puerarin metabolite. The anti-oxidant effects of puerarin-7-O-glucuronide were assessed by measurement of intracellular superoxide levels, total superoxide dismutase (SOD) activity, total anti-oxidant capacity, and glutathione (GSH)/glutathione disulfide (GSSG) ratio in cultured neonatal rat cardiomyocytes (NRCMs) stimulated with the xanthine oxidase (XO)/xanthine (X) system or angiotensin II. The activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and expression of NADPH oxidase subunits p22phox and p47phox were determined. The anti-hypertrophic effects of puerarin-7-O-glucuronide in angiotensin II-challenged NRCMs were characterized by changes in cell morphology and expression of hypertrophic genes. In the pharmacokinetic study, the plasma concentration of puerarin-7-O-glucuronide was determined by rapid resolution–liquid chromatography–tandem mass spectrometry (RR-LC-MS/MS). Puerarin-7-O-glucuronide prevented XO/X-induced increase in intracellular superoxide production and decreases in total SOD activity, GSH/GSSG ratio, and total anti-oxidant capacity. Puerarin-7-O-glucuronide also reversed angiotensin II-induced increases in intracellular superoxide production and NADPH oxidase activity and decreases in total SOD activity. These anti-oxidant effects of puerarin-7-O-glucuronide were accompanied by downregulation of p22phox and p47phox. Furthermore, puerarin-7-O-glucuronide prevented angiotensin II-induced increases in cell surface area and perimeter, as well as changes in Nppa, Myh7, and Myh6. In the pharmacokinetic study, puerarin-7-O-glucuronide was cleared with a half-life of 0.94 h after intravenous administration. Puerarin could be detected in rat plasma, albeit in low concentration, as early as 5 min after intravenous administration of puerarin-7-O-glucuronide. These anti-oxidant and anti-hypertrophic properties of puerarin-7-O-glucuronide were similar to those of its parent compound puerarin. These results support the development of puerarin-7-O-glucuronide as a novel pharmaceutical agent for therapeutic application.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Adlercreutz H, Markkanen H, Watanabe S (1993) Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 342:1209–1210

    Article  CAS  PubMed  Google Scholar 

  • Day AJ, Bao Y, Morgan MR, Williamson G (2000) Conjugation position of quercetin glucuronides and effect on biological activity. Free Radic Biol Med 29:1234–1243

    Article  CAS  PubMed  Google Scholar 

  • De Giusti VC, Garciarena CD, Aiello EA (2009) Role of reactive oxygen species (ROS) in angiotensin II-induced stimulation of the cardiac Na+/HCO3 − cotransport. J Mol Cell Cardiol 47:716–722. doi:10.1016/j.yjmcc.2009.07.023

    Article  CAS  PubMed  Google Scholar 

  • Gang C, Qiang C, Xiangli C, Shifen P, Chong S, Lihong L (2015) Puerarin suppresses angiotensin II-induced cardiac hypertrophy by inhibiting NADPH oxidase activation and oxidative stress-triggered AP-1 signaling pathways journal of pharmacy & pharmaceutical sciences: a publication of the Canadian Society for Pharmaceutical Sciences. Societe canadienne des sciences pharmaceutiques 18:235–248

    Google Scholar 

  • Gao L et al (2009) Puerarin protects against ischemic brain injury in a rat model of transient focal ischemia. Neurol Res 31:402–406. doi:10.1179/174313209X444017

    Article  PubMed  Google Scholar 

  • Griendling KK, Sorescu D, Ushio-Fukai M (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 86:494–501

    Article  CAS  PubMed  Google Scholar 

  • Hou N et al (2010) Leptin induces hypertrophy through activating the peroxisome proliferator-activated receptor α pathway in cultured neonatal rat cardiomyocytes. Clin Exp Pharmacol Physiol 37:1087–1095

    Article  CAS  PubMed  Google Scholar 

  • Hsu FL, Liu IM, Kuo DH, Chen WC, Su HC, Cheng JT (2003) Antihyperglycemic effect of puerarin in streptozotocin-induced diabetic rats. J Nat Prod 66:788–792. doi:10.1021/np0203887

    Article  CAS  PubMed  Google Scholar 

  • Ishizawa K et al (2009) Quercetin glucuronide inhibits cell migration and proliferation by platelet-derived growth factor in vascular smooth muscle cells. J Pharmacol Sci 109:257–264

    Article  CAS  PubMed  Google Scholar 

  • Jalil JE, Perez A, Ocaranza MP, Bargetto J, Galaz A, Lavandero S (2005) Increased aortic NADPH oxidase activity in rats with genetically high angiotensin-converting enzyme levels. Hypertension 46:1362–1367. doi:10.1161/01.HYP.0000188980.57312.63

    Article  CAS  PubMed  Google Scholar 

  • Kim J, Kim KM, Kim CS, Sohn E, Lee YM, Jo K, Kim JS (2012) Puerarin inhibits the retinal pericyte apoptosis induced by advanced glycation end products in vitro and in vivo by inhibiting NADPH oxidase-related oxidative stress. Free Radic Biol Med 53:357–365. doi:10.1016/j.freeradbiomed.2012.04.030

    Article  CAS  PubMed  Google Scholar 

  • Li H, Dong L, Liu Y, Wang G, Qiao Y (2014) Biopharmaceutics classification of puerarin and comparison of perfusion approaches in rats. Int J Pharm 466:133–138. doi:10.1016/j.ijpharm.2014.03.014

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Pan WS, Chen SL, Xu HX, Yang DJ, Chan ASC (2006) Pharmacokinetic, tissue distribution, and excretion of puerarin and puerarin-phospholipid complex in rats. Drug Dev Ind Pharm 32:413–422. doi:10.1080/03639040600559123

    Article  CAS  PubMed  Google Scholar 

  • Luo CF et al (2012) UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for puerarin metabolism in human liver microsomes. Arch Toxicol 86:1681–1690. doi:10.1007/s00204-012-0874-7

    Article  CAS  PubMed  Google Scholar 

  • Luo CF, Yuan M, Chen MS, Liu SM, Huang BY, Liu XW, Zhu L (2011a) Determination of puerarin in rat plasma by rapid resolution liquid chromatography tandem mass spectrometry in positive ionization mode. J Chromatogr B Analyt Technol Biomed Life Sci 879:1497–1501

    Article  CAS  PubMed  Google Scholar 

  • Luo CF, Yuan M, Chen MS, Liu SM, Ji H (2010) Metabolites of puerarin identified by liquid chromatography tandem mass spectrometry: similar metabolic profiles in liver and intestine of rats. J Chromatogr B Analyt Technol Biomed Life Sci 878:363–370. doi:10.1016/j.jchromb.2009.12.002

    Article  CAS  PubMed  Google Scholar 

  • Luo CF et al (2011b) Pharmacokinetics, tissue distribution and relative bioavailability of puerarin solid lipid nanoparticles following oral administration. Int J Pharm 410:138–144

    Article  CAS  PubMed  Google Scholar 

  • Luo CF, Yuan M, Chen MS, Liu SM, Zhu L, Liu XW (2009) Determination of puerarin in rat plasma by HPLC with fluorescence detection and its application to pharmacokinetic studies. Lat Am J Pharm 28:351–357

    CAS  Google Scholar 

  • Morand C, Crespy V, Manach C, Besson C, Demigné C, Rémésy C (1998) Plasma metabolites of quercetin and their antioxidant properties. Am J Phys 275:R212–R219

    CAS  Google Scholar 

  • Polizio AH, Balestrasse KB, Yannarelli GG, Noriega GO, Gorzalczany S, Taira C, Tomaro ML (2008) Angiotensin II regulates cardiac hypertrophy via oxidative stress but not antioxidant enzyme activities in experimental renovascular hypertension. Hypertension research : official journal of the Japanese Society of Hypertension 31:325–334. doi:10.1291/hypres.31.325

    Article  CAS  Google Scholar 

  • Prasain JK, Peng N, Moore R, Arabshahi A, Barnes S, Wyss JM (2009) Tissue distribution of puerarin and its conjugated metabolites in rats assessed by liquid chromatography-tandem mass spectrometry. Phytomedicine 16:65–71. doi:10.1016/j.phymed.2008.09.004

    Article  CAS  PubMed  Google Scholar 

  • Proteggente AR, Basu-Modak S, Kuhnle G, Gordon MJ, Youdim K, Tyrrell R, Rice-Evans CA (2003) Hesperetin glucuronide, a photoprotective agent arising from flavonoid metabolism in human skin fibroblasts. Photochem Photobiol 78:256–261

    Article  CAS  PubMed  Google Scholar 

  • Quan DQ, Xu GX, Wu XG (2007) Studies on preparation and absolute bioavailability of a self-emulsifying system containing puerarin. Chem Pharm Bull (Tokyo) 55:800–803

    Article  CAS  Google Scholar 

  • Simpson P, Savion S (1982) Differentiation of rat myocytes in single cell cultures with and without proliferating nonmyocardial cells. Cross-striations, ultrastructure, and chronotropic response to isoproterenol Circ Res 50:101–116

    CAS  PubMed  Google Scholar 

  • Song XP, Chen PP, Chai XS (1988) Effects of puerarin on blood pressure and plasma renin activity in spontaneously hypertensive rats. Acta Pharmacol Sin 9:55–58

    CAS  Google Scholar 

  • Tu L, Yi Y, Wu W, Hu F, Hu K, Feng J (2013) Effects of particle size on the pharmacokinetics of puerarin nanocrystals and microcrystals after oral administration to rat. Int J Pharm 458:135–140. doi:10.1016/j.ijpharm.2013.10.001

    Article  CAS  PubMed  Google Scholar 

  • Yan LP, Chan SW, Chan ASC, Chen SL, Ma XJ, Xu HX (2006) Puerarin decreases serum total cholesterol and enhances thoracic aorta endothelial nitric oxide synthase expression in diet-induced hypercholesterolemic rats. Life Sci 79:324–330. doi:10.1016/j.lfs.2006.01.016

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Chen S, Shen Y, Yang D, Liu X, Sun-Chi AC, Xu H (2006) Puerarin induces angiogenesis in myocardium of rat with myocardial infarction. Biol Pharm Bull 29:945–950

    Article  CAS  PubMed  Google Scholar 

  • Zhou YX, Zhang H, Peng C (2014) Puerarin: a review of pharmacological effects. Phytother Res 28:961–975. doi:10.1002/ptr.5083

    Article  CAS  PubMed  Google Scholar 

  • Zhu LH et al (2010) Puerarin attenuates high-glucose-and diabetes-induced vascular smooth muscle cell proliferation by blocking PKCbeta2/Rac1-dependent signaling. Free Radic Biol Med 48:471–482. doi:10.1016/j.freeradbiomed.2009.10.040

    Article  CAS  PubMed  Google Scholar 

Download references

Authors’ contributions

NH, CFL, and MSC formulated the original ideas and working hypothesis and designed the research study; NH, BC, CWO, and CFL performed the detailed experiments; CFL and MSC supervised the experiments; ZHZ, SML, LGX, and JDL participated in assessment of oxidative stress; XWL and MY participated in puerarin-7-O-glucuronide preparation and pharmacokinetic studies; CFL and NH prepared the manuscript; and MSC provided revisions and submission considerations. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China

    Ning Hou, Xia-Wen Liu, Mu Yuan & Jian-Dong Luo

  2. Changsha Central Hospital, 161 Shaoshannan Road, Changsha, 410018, China

    Bin Cai

  3. Department of Cardiology, Guangdong Provincial Center of Biomedical Engineering for Cardiovascular Disease, Zhujiang Hospital of Southern Medical University, 253 Gongye Avenue, Guangzhou, 510280, China

    Cai-Wen Ou & Min-Sheng Chen

  4. Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou, 510260, China

    Zhen-Hui Zhang, Gan-Jian Zhao, Shi-Ming Liu, Long-Gen Xiong & Cheng-Feng Luo

Authors
  1. Ning Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bin Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cai-Wen Ou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhen-Hui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xia-Wen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mu Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gan-Jian Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shi-Ming Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Long-Gen Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jian-Dong Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Cheng-Feng Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Min-Sheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Cheng-Feng Luo or Min-Sheng Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Sources of funding

This work was supported by the National Natural Science Foundation of China (grant numbers 81,374,009, U1501222, 81,402,928), and Guangzhou Education Bureau (grant number 2012C090).

Additional information

Ning Hou, Bin Cai, and Cai-Wen Ou contributed equally to this work.

Electronic supplementary material

ESM 1

(DOCX 5134 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hou, N., Cai, B., Ou, CW. et al. Puerarin-7-O-glucuronide, a water-soluble puerarin metabolite, prevents angiotensin II-induced cardiomyocyte hypertrophy by reducing oxidative stress. Naunyn-Schmiedeberg's Arch Pharmacol 390, 535–545 (2017). https://doi.org/10.1007/s00210-017-1353-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-017-1353-8

Keywords

Search

Navigation