year 20, Issue 78 (5-2021)                   J. Med. Plants 2021, 20(78): 1-13 | Back to browse issues page

Research code: 29339


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Asadi F, Razmi A, Ghazizadeh F, Shafiei M. Protective effect of ellagic acid against angiotensin II-induced cardiomyocyte hypertrophy in H9c2 myocardial cells: Role of calcineurin/NFAT pathway. J. Med. Plants. 2021; 20 (78) :1-13
URL: http://jmp.ir/article-1-2951-en.html
1- Department of Pharmacology and Toxicology, School of Pharmacy, Lorestan University of Medical Sciences, Khoramabad, Iran.
2- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
3- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
4- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran , shafiei.m@iums.ac.ir
Abstract:   (554 Views)
Background: Ellagic acid, a major ellagitannin found in pomegranate extract, might be an attractive natural and safe bioactive compound for prevention of cardiac hypertrophy in many pathological conditions that are associated with elevated circulating angiotensin II (Ang II). Ang II stimulates multiple signal transduction pathways involved in hypertrophy including calcineurin/nuclear factor of activated T cell (NFAT). Objective: The present study aimed to explore the possible anti-hypertrophic activity of ellagic acid against Ang II-induced cardiomyocyte hypertrophy and the role of calcineurin/ NFAT signaling pathway in this action. Methods: H9c2 myocardial cells were treated with different concentrations of ellagic acid one hour before exposure to Ang II. Biological markers of cardiac hypertrophy including changes in cell size and protein content, and atrial natriuretic peptide (ANP) protein expression were assessed using light microscopy, Bradford method and western blotting, respectively. The effects of ellagic acid on the protein expression of calcineurin and nuclear localization of NFATc4 were also investigated using western blotting and immunofluorescence assay, respectively. Results: The results showed that pretreatment with ellagic acid could efficiently prevent Ang II-induced hypertrophic response which was associated with changes in hypertrophy-related biomarkers including increase in cell size and protein content, and ANP overexpression. Moreover, ellagic acid inhibited Ang II-induced calcineurin up-regulation and nuclear localization of NFATc4. Conclusion: In summary, our findings showed that ellagic acid effectively inhibited Ang II-induced cardiomyocyte hypertrophy. This is the first report demonstrating the role of calcineurin/NFAT pathway inhibition in this protective effects. Future in vivo studies are required to elucidate if ellagic acid could ameliorate cardiac hypertrophy and its transition to heart failure.
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Type of Study: Research | Subject: Pharmacognosy & Pharmaceutics
Received: 2020/10/17 | Accepted: 2021/02/13 | Published: 2021/06/1

References
1. Selvetella G and Lembo G. Mechanisms of cardiac hypertrophy. J. Card Fail. 2005; 1: 263-273. [DOI:10.1016/j.hfc.2005.03.006]
2. Molkentin JD. Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc. Res. 2004; 63: 467-475. [DOI:10.1016/j.cardiores.2004.01.021]
3. Frey N and Olson E. Cardiac hypertrophy: the good, the bad, and the ugly. Annu. Rev. Plant Biol. 2003; 65: 45-79. [DOI:10.1146/annurev.physiol.65.092101.142243]
4. Watkins SJ, Borthwick GM and Arthur HM. The H9C2 cell line and primary neonatal cardiomyocyte cells show similar hypertrophic responses in vitro. In Vitro Cell. Dev. Biol. Anim. 2011; 47: 125-131. [DOI:10.1007/s11626-010-9368-1]
5. Hogan PG, Chen L, Nardone J and Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003; 17(18): 2205-2232. [DOI:10.1101/gad.1102703]
6. Wilkins BJ and Molkentin JD. Calcineurin and cardiac hypertrophy: where have we been? Where are we going? J. Physiol. 2002; 541: 1-8. [DOI:10.1113/jphysiol.2002.017129]
7. Huang B, He Y and Li S. The RCAN1.4-calcineurin/NFAT signaling pathway is essential for hypoxic adaption of intervertebral discs. Exp. Mol. Med. 2020; 52: 865-875. [DOI:10.1038/s12276-020-0441-x]
8. Creamer T.P. Calcineurin. Cell Commun. Signal. 2020; 18: 137. [DOI:10.1186/s12964-020-00636-4]
9. Grunwell JR, Stephenson ST, Mohammad AF. Differential type I interferon response and primary airway neutrophil extracellular trap release in children with acute respiratory distress syndrome. Sci. Rep. 2020; 10: 19049. [DOI:10.1038/s41598-020-76122-1]
10. Nakata T, Toyoshima Y, Yagi T, Katsumata H, Tokita R, Minami S. Growth hormone increases regulator of calcineurin 1-4 (Rcan1-4) mRNA through c-JUN in rat liver. PLoS ONE 2020; 15(6): e0235270. [DOI:10.1371/journal.pone.0235270]
11. Wilkins BJ and Molkentin JD. Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. Biochem. Biophys. Res. Commun. 2004; 322: 1178-1191. [DOI:10.1016/j.bbrc.2004.07.121]
12. Rangrez AY, Borlepawar A and Schmiedel N. The E3 ubiquitin ligase HectD3 attenuates cardiac hypertrophy and inflammation in mice. Commun. Biol. 2020; 3: 562 [DOI:10.1038/s42003-020-01289-2]
13. Taigen T, De Windt LJ, Lim HW and Molkentin JD. Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Proc. Natl. Acad. Sci. U.S.A. 2000; 97(3): 1196-1201. [DOI:10.1073/pnas.97.3.1196]
14. Landete J M. Updated knowledge about polyphenols: functions, bioavailability, metabolism, and health. Crit. Rev. Food Sci. Nutr. 2012; 52(10): 936-948. [DOI:10.1080/10408398.2010.513779]
15. Asgary S, Sahebkar A, Afshani MR, Keshvari M, Haghjooyjavanmard S and Rafieian‐Kopaei M. Clinical evaluation of blood pressure lowering, endothelial function improving, hypolipidemic and anti‐inflammatory effects of pomegranate juice in hypertensive subjects. Phytother. Res. 2014; 28: 193-199. [DOI:10.1002/ptr.4977]
16. Shayganni E, Bahmani M, Asgary S and Rafieian-Kopaei, M. Inflammaging and cardiovascular disease: Management by medicinal plants. Phytomedicine 2016; 23: 1119-1126. [DOI:10.1016/j.phymed.2015.11.004]
17. Rouhi-Boroujeni H, Heidarian E, Rouhi-Boroujeni H, Deris F and Rafieian-Kopaei, M. Medicinal plants with multiple effects on cardiovascular diseases: a systematic review. Curr. Pharm. Des. 2017; 23: 999-1015. [DOI:10.2174/1381612822666161021160524]
18. Shaygannia E, Bahmani M, Zamanzad B, and Rafieian-Kopaei MA. Review study on Punica granatum L. Evid. Based Complement. Alternat. Med. 2016; 21: 221-227. [DOI:10.1177/2156587215598039]
19. Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG and Heber D. In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J. Nutr. Biochem. 2005; 16: 360-367. [DOI:10.1016/j.jnutbio.2005.01.006]
20. Kannan MM and Quine SD. Ellagic acid inhibits cardiac arrhythmias, hypertrophy and hyperlipidaemia during myocardial infarction in rats. Metabolism 2013; 62: 52-61. [DOI:10.1016/j.metabol.2012.06.003]
21. Rojanathammanee L, Puig KL and Combs CK. Pomegranate polyphenols and extract inhibit nuclear factor of activated T-cell activity and microglial activation in vitro and in a transgenic mouse model of Alzheimer disease. J. Nutr. 2013; 143: 597-605. [DOI:10.3945/jn.112.169516]
22. Asadi F, Razmi A, De hpour AR and Shafiei M. Tropisetron inhibits high glucose‐induced calcineurin/NFAT hypertrophic pathway in H9c2 myocardial cells. J. Physiol. Pharmacol. 2016; 68: 485-493. [DOI:10.1111/jphp.12522]
23. Kjær A and Hesse B. Heart failure and neuroendocrine activation: diagnostic, prognostic and therapeutic perspectives. Clin Physiol. 2001; 21: 661-672. [DOI:10.1046/j.1365-2281.2001.00371.x]
24. Lim HW, De Windt LJ, Mante J, Kimball TR, Witt SA, Sussman MA and Molkentin JD. Reversal of cardiac hypertrophy in transgenic disease models by calcineurin inhibition. J Mol Cell Cardiol. 2000a; 32: 697-709. [DOI:10.1006/jmcc.2000.1113]
25. Lim HW, De Windt, LJ, Steinberg L, Taigen T, Witt SA, Kimball TR and Molkentin, JD. Calcineurin expression, activation, and function in cardiac pressure-overload hypertrophy. Circulation 2000b; 101: 2431-2437. [DOI:10.1161/01.CIR.101.20.2431]
26. Sieber M and Baumgrass R. Novel inhibitors of the calcineurin/NFATc hub-alternatives to CsA and FK506? J. Cell Commun. Signal. 2009; 7: 25. [DOI:10.1186/1478-811X-7-25]
27. Lee SI, Kim BS, Kim KS, Lee S, Shin KS and Lim JS. Immune-suppressive activity of punicalagin via inhibition of NFAT activation. Biochem. Biophys. Res. Commun. 2008; 371:799-803. [DOI:10.1016/j.bbrc.2008.04.150]
28. Larrosa M, Tomás-Barberán FA and Espín JC. The dietary hydrolysable tannin punicalagin releases ellagic acid that induces apoptosis in human colon adenocarcinoma Caco-2 cells by using the mitochondrial pathway. J. Nutr. Biochem. 2006; 17(9): 611-625. [DOI:10.1016/j.jnutbio.2005.09.004]
29. Seeram NP, Lee R and Heber D. Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Clin. Chim. Acta. 2004; 348: 63-68. [DOI:10.1016/j.cccn.2004.04.029]
30. Kehat I and Molkentin JD. Molecular pathways underlying cardiac remodeling during pathophysiological stimulation. Circulation. 2010; 122: 2727-2735. [DOI:10.1161/CIRCULATIONAHA.110.942268]
31. Naesens M, Kuypers DR and Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin. J. Am. Soc. Nephrol. 2009; 4: 481-508. [DOI:10.2215/CJN.04800908]
32. Losso JN, Bansode RR, Trappey II, Bawadi HA and Truax R. In vitro anti-proliferative activities of ellagic acid. J. Nutr. Biochem. 2004; 15: 672-678. [DOI:10.1016/j.jnutbio.2004.06.004]
33. Tasaki M, Umemura T, Maeda M, Ishii Y, Okamura T, Inoue T, Kuroiwa Y, Hirose M and Nishikawa A. Safety assessment of ellagic acid, a food additive, in a subchronic toxicity study using F344 rats. Food Chem. Toxicol. 2008; 46: 1119-1124. [DOI:10.1016/j.fct.2007.10.043]

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