Download PDF
Planta Med 2018; 84(15): 1094-1100
DOI: 10.1055/a-0601-7083
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Crataegus Special Extract WS 1442 Effects on eNOS and microRNA 155

Xinwen Wang
1   Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
,
Yan Liang
1   Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
2   The Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
,
Jian Shi
1   Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
,
Hao-jie Zhu
1   Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
,
Barry E. Bleske
3   Department of Pharmacy Practice & Administrative Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA
› Author Affiliations
Further Information

Publication History

received 29 December 2017
revised 23 March 2018

accepted 02 April 2018

Publication Date:
16 April 2018 (online)

    Permissions and Reprints

Abstract

Increased expression of microRNA 155 (miR-155) results in a decrease in endothelial nitric oxide synthase (eNOS) expression and impaired endothelial function. Factors that have been shown to increase expression of miR-155 may be mitigated by WS 1442, an extract of hawthorn leaves and flowers (Crataegus special extract) that contains a range of pharmacologically active substances including oligomeric proanthocyanidins and flavonoids. The purpose of this study is to determine the effect of WS 1442 on the expression of miR-155 and eNOS in the presence of tumor necrosis factor (TNF-α). Human umbilical vein endothelial cells (HUVECs) were studied after the exposure to TNF-α, with or without simvastatin (positive control) and WS 1442. The expression levels of eNOS, phosphorylated eNOS, and miR-155 in the different HUVEC treatment groups were determined by western blot and quantitative real-time polymerase chain reaction, respectively. To evaluate the effect of WS 1442 on the eNOS activity, the medium and intracellular nitrate/nitrite (NO) concentrations were also analyzed using a colorimetric Griess assay kit. The results demonstrated that TNF-α upregulated miR-155 expression and decreased eNOS expression and NO concentrations. WS 1442 also increased miR-155 expression and decreased eNOS expression but, unlike TNF-α, increased phosphorylated eNOS expression and NO concentrations. Surprisingly, WS 1442 increased miR-155 expression; however, WS 1442 mitigated the overall negative effect of miR-155 on decreasing eNOS expression by increasing expression of phosphorylated eNOS and resulting in an increase in NO concentrations. In the setting where miR-155 may be expressed, WS 1442 may offer vascular protection by increasing the expression of phosphorylated eNOS.

Key words

Crataegus species - hawthorn - nitric oxide - miR-155 - eNOS - cardiovascular - TNF-α - Rosaceae
 

  • References

  • 1 Bartel DP. MicroRNAs: target recognition and regulatory function. Cell 2009; 136: 215-233
    CrossrefPubMedGoogle Scholar
  • 2 Condorelli G, Latronico MVG, Cavarretta E. microRNAs in cardiovascular diseases. J Am Coll Cardiol 2014; 63: 2177-2187
    CrossrefPubMedGoogle Scholar
  • 3 Sun X, Belkin N, Feinberg MW. Endothelial microRNAs and atherosclerosis. Curr Atheroscier Rep 2013; 15: 372-379
    PubMedGoogle Scholar
  • 4 Lee KS, Kim J, Kwak SN, Lee KS, Lee DK, Ha KS, Won MH, Jeoung D, Lee H, Kwon YG, Kim YM. Functional role of NF-κB in expression of human endothelial nitric oxide synthase. Biochem Biophys Res Commun 2014; 448: 101-107
    CrossrefPubMedGoogle Scholar
  • 5 Sun HX, Zeng DY, Li RT, Pang RP, Yang H, Hu YL, Zhang Q, Jiang Y, Huang LY, Tang YB, Yan GJ, Zhou JG. Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase. Hypertension 2012; 60: 1407-1414
    CrossrefPubMedGoogle Scholar
  • 6 Flemming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol 2002; 284: R1-R12
    PubMedGoogle Scholar
  • 7 McCoy CE, Sheedy FJ, Qualls JE, Doyle SL, Quinn SR, Murray PJ, OʼNeill LA. IL-10 inhibits miR-155 induction by toll-like receptors. J Biol Chem 2010; 285: 20492-20498
    CrossrefPubMedGoogle Scholar
  • 8 Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Hooks JJ, Redmond M. Inflammatory cytokines regulate microRNA-155 expression in human retinal pigment epithelial cells activating JAK/STAT pathway. Biochem Biophys Res Commun 2010; 402: 390-395
    CrossrefPubMedGoogle Scholar
  • 9 Elango C, Devaraj SN. Immunomodulatory effect of hawthorn extract in an experimental stroke model. J Neuroinflammation 2010; 7: 97
    CrossrefPubMedGoogle Scholar
  • 10 Li C, Wang MH. Anti-inflammatory effect of the water fraction from hawthorn fruit on LPS-stimulated RAW 264.7 cells. Nutr Res Pract 2011; 5: 101-106
    CrossrefPubMedGoogle Scholar
  • 11 Dalli E, Milara J, Cortijo J, Morcillo EJ, Cosín-Sales J, Sotillo JF. Hawthorn extract inhibits human isolated neutrophil functions. Pharmacol Res 2008; 57: 445-450
    CrossrefPubMedGoogle Scholar
  • 12 Fu JH, Zheng YQ, Li P, Li XZ, Shang XH, Liu JX. Hawthorn leaves flavonoids decreases inflammation related to acute myocardial ischemia/reperfusion in anesthetized dogs. Chin J Integr Med 2013; 19: 582-588
    CrossrefPubMedGoogle Scholar
  • 13 Zhang DL, Zhang YT, Yin JJ, Zhao BL. Oral administration of Crataegus flavonoids protects against ischemia/reperfusion brain damage in gerbils. J Neurochem 2004; 90: 211-219
    CrossrefPubMedGoogle Scholar
  • 14 Ye XL, Huang WW, Chen Z, Li XG, Li P, Lan P, Wang L, Gao Y, Zhao ZQ, Chen X. Synergetic effect and structure-activity relationship of 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors from Crataegus pinnatifida Bge. J Argric Food Chem 2010; 58: 3132-3138
    PubMedGoogle Scholar
  • 15 Indra MR, Karyono S, Ratnawati R, Malik SG. Quercetin suppresses inflammation by reducing ERK1/2 phosphorylation and NF kappa B activation in leptin-induced human umbilical vein endothelial cells (HUVECs). BMC Res Notes 2013; 6: 275
    CrossrefPubMedGoogle Scholar
  • 16 Sikder K, Kesh SB, Das N, Manna K, Dey S. The high antioxidative power of quercetin (aglycone flavonoid) and its glycone (rutin) avert high cholesterol diet induced hepatotoxicity and inflammation in Swiss albino mice. Food Funct 2014; 5: 1294-1303
    CrossrefPubMedGoogle Scholar
  • 17 Yan L, Zhang JD, Wang B, Lv YJ, Jiang H, Liu GL, Qiao Y, Ren M, Guo XF. Quercetin inhibits left ventricular hypertrophy in spontaneously hypertensive rats and inhibits angiotensin II-induced H9C2 cells hypertrophy by enhancing PPAR-γ expression and suppressing AP-1 activity. PLoS One 2013; 8: e72548
    CrossrefPubMedGoogle Scholar
  • 18 Vazquez-Prieto MA, Bettaieb A, Haj FG, Fraga CG, Oteiza PI. (−)-Epicatechin prevents TNFα-induced activation of signaling cascades involved in inflammation and insulin sensitivity in 3T3-L1 adipocytes. Arch Biochem Biophys 2012; 527: 113-118
    CrossrefPubMedGoogle Scholar
  • 19 Khoi PN, Park JS, Kim JH, Xia Y, Kim NH, Kim KK, Jung YD. (−)-Epigallocatechin-3-gallate blocks nicotine-induced matrix metalloproteinase-9 expression and invasiveness via suppression of NF-κB and AP-1 in endothelial cells. Int J Oncol 2013; 43: 868-876
    CrossrefPubMedGoogle Scholar
  • 20 Ku SK, Kwak S, Kwon OJ, Bae JS. Hyperoside inhibits high-glucose-induced vascular inflammation in-vitro and in-vivo . Inflammation 2014; 37: 1389-1400
    CrossrefPubMedGoogle Scholar
  • 21 Brixius K, Willms S, Napp A, Tossios P, Ladage D, Bloch W, Mehlhorn U, Schwinger RH. Crataegus special extract WS 1442 induces an endothelium-dependent, NO-mediated vasorelaxation via eNOS-phosphorylation at serine 1177. Cardiovasc Drugs Ther 2006; 20: 177-184
    CrossrefPubMedGoogle Scholar
  • 22 Anselm E, Socorro VFM, Dal-Ros S, Schott C, Bronner C, Schini-Kerth VB. Crataegus special extract WS 1442 causes endothelium-dependent relaxation via a redox-sensitive Src- and Akt-dependent activation of endothelial NO synthase but not via activation of estrogen receptors. J Cardiovasc Pharmacol 2009; 53: 253-260
    CrossrefPubMedGoogle Scholar
  • 23 Koch E, Malek FA. Standardized extracts from hawthorn leaves and flowers in the treatment of cardiovascular disorders – preclinical and clinical studies. Planta Med 2011; 77: 1123-1128
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Suarez Y, Wang C, Manes TD, Prober JS. TNF-induced microRNAs regulate TNF-induced expression of E-selectin and intercellular adhesion molecule-1 on human endothelial cells: feedback control of inflammation. J Immunol 2010; 184: 21-25
    CrossrefPubMedGoogle Scholar
  • 25 Alonso J, Sanchez de Miguel M, Monton S, Casado A, Lopez-Farre A. Endothelial cytosolic proteins bind to the 3′ untranslated region of endothelial nitric oxide synthase mRNA: regulation by tumor necrosis factor alpha. Mol Cell Biol 1997; 17: 5719-5726
    CrossrefPubMedGoogle Scholar
  • 26 Anslem E, Chataigneau M, Ndiaye M, Chataigneau T, Schini-Kerth VB. Grape juice causes endothelium-dependent relaxation via a redox-sensitive Src- and Akt-dependent activation of eNOS. Cardiovasc Res 2007; 73: 404-413
    CrossrefPubMedGoogle Scholar
  • 27 Ndiaye M, Chataigneau T, Andriantsitohaina R, Stoclet JC, Schini-Kerth VB. Red wine polyphenols cause endothelium-dependent EDHF-mediated relaxations in porcine coronary arteries via a redox-sensitive mechanism. Biophys Res Commun 2003; 310: 371-377
    CrossrefPubMedGoogle Scholar
  • 28 Sen CK, Packer L. Antioxidant and redox regulation of gene transcription. FASEB J 1996; 10: 709-720
    CrossrefPubMedGoogle Scholar
  • 29 Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-κB transcription factor and HIV-1. EMBO J 1991; 10: 2247-2258
    CrossrefPubMedGoogle Scholar
  • 30 Dornas WC, Cardoso LM, Silva M, Machado NL, Chianca jr. DA, Alzamora AC, Lima WG, Lagente V, Silva ME. Oxidative stress causes hypertension and activation of nuclear factor-κB after high fructose and salt treatments. Sci Rep 2017; 7: 46051
    CrossrefPubMedGoogle Scholar
  • 31 Idris-Khodja N, Auger C, Koch E, Schini-Kerth VB. Crataegus special extract WS 1442 prevents aging-related endothelial dysfunction. Phytomedicine 2012; 19: 699-706
    CrossrefPubMedGoogle Scholar
  • 32 Rieckeheer E, Schwinger RHG, Block W, Brixius K. Hawthorn special extract WS 1142 increases red blood cell NO-formation without altering red blood cell deformability. Phytomedicine 2011; 19: 20-24
    CrossrefPubMedGoogle Scholar
  • 33 Dood KP, Frey AD, Geisbuhler TP. The effect of hawthorn extract on coronary flow. J Evid Based Complementary Altern Med 2013; 18: 257-267
    CrossrefPubMedGoogle Scholar
  • 34 Hwang HS, Bleske BE, Ghannam MMJ, Converso K, Russell MW, Hunter JC, Boluyt MO. Effects of hawthorn on cardiac remodeling and left ventricular dysfunction after 1 month of pressure overload-induced cardiac hypertrophy in rats. Cardiovasc Drugs Ther 2008; 22: 19-28
    CrossrefPubMedGoogle Scholar
  • 35 Hwang HS, Boluyt MO, Converso K, Russell MW, Ghannam MMJ, Bleske BE. Effects of hawthorn on the progression of heart failure in an aortic constriction model. Pharmacotherapy 2009; 29: 639-648
    CrossrefPubMedGoogle Scholar
  • 36 Holubarsch CJ, Colucci WS, Meinertz T, Gaus W, Tendera M. The efficacy and safety of Crataegus extract WS 1442 in patients with heart failure: the SPICE trial. Eur J Heart Fail 2008; 10: 1255-1263
    CrossrefPubMedGoogle Scholar
  • 37 Vanin AF, Bevers LM, Slama-Schwok A, van Faassen EE. Nitric oxide synthase reduces nitrite to NO under anoxia. Cell Mol Life Sci 2007; 64: 96-103
    CrossrefPubMedGoogle Scholar
  • 38 Chen XN, Xu J, Feng Z, Fan M, Han JY, Yang Z. Simvastatin combined with nifedipine enhances endothelial cell protection by inhibiting ROS generation and activating Akt phosphorylation. Acta Pharmacol Sin 2010; 31: 813-820
    CrossrefPubMedGoogle Scholar