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Urolithin A shows anti-atherosclerotic activity via activation of class B scavenger receptor and activation of Nef2 signaling pathway

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Abstract

Background

This study investigates the therapeutic potential of urothelin A in attenuating atherosclerotic lesion in wistar rat models and explore the role of Scavenger receptor-class B type I (SR-BI) and activation of Nrf-2 singling pathway.

Methods

Wistar rats (n = 48) were feed with high cholesterol diet supplemented with Vitamin D3 and subjected to balloon injury of the aorta. Three days prior to the aortal injury, rats (n = 16) were administered urothelin A (3 mg/kg/d; po). Positive control were rats receiving high cholesterol diet and balloon injury of the aorta (n = 16). The sham group (n = 16) consisted of rats fed on basal diet. After twelve weeks blood was collected from all animals for estimation of lipid and angiotensin II (Ang II) levels along, subsequently all animals were sacrificed and morphologic analysis of the aorta was performed. Expression of SR-BI and phosphorylated extracellular signal regulated kinase 1/2 (p-ERK1/2) protein were evaluated by Western blot.

Results

After twelve weeks of treatment with urolithin A, there was a significant decrease in the plasma lipid and Ang II levels and improvement of aortic lesion compared with the sham group. There was an increased expression of SR-BI and inhibition of p-ERK1/2 (p < 0.05). The expression of SR-BI was inversely correlated with levels of Ang II.

Conclusion

From the results it can be safely concluded that administration of urolithin A attenuates atherosclerosis via upregulation of SR-BI expression and inhibition of p-ERK1/2 levels.

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References

  1. Bonaventura A., Montecucco F, Dallegri F. Cellular recruitment in myocardial ischaemia/reperfusion injury. Eur J Clin Invest 2016;46(6):590–601.

    Article  CAS  Google Scholar 

  2. Gong M, Wilson M, Kelly T, Su W, Dressman J, Kincer J, et al. HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner. J Clin Invest 2003;111(10):1579–87.

    Article  CAS  Google Scholar 

  3. Louwe MC, Lammers B, Frias MA, Foks AC, de Leeuw LR, Hildebrand RB, et al. Abca1 deficiency protects the heart against myocardial infarction-induced injury. Atherosclerosis 2016;251:159–63.

    Article  CAS  Google Scholar 

  4. Han J, Parsons M, Zhou X, Nicholson AC, Gotto AM, Hajjar DP. Functional interplay between the macrophage scavenger receptor class B type I and pitavastatin (NK-104). Circulation 2004;110(22):3472–9.

    Article  CAS  Google Scholar 

  5. Higuchi S, Ohtsu H, Suzuki H, Shirai H, Frank GD, Eguchi S. Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 2007;112(8):417–28.

    Article  CAS  Google Scholar 

  6. Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Felix AA, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med 2016.

  7. Kang I, Kim Y, Tomas-Barberan FA, Espin JC, Chung S. Urolithin A, C, and D, but not iso-urolithin A and urolithin B, attenuate triglyceride accumulation in human cultures of adipocytes and hepatocytes. Mol Nutr Food Res 2016;60(5):1129–38.

    Article  CAS  Google Scholar 

  8. Gonzalez-Sarrias A, Nunez-Sanchez MA, Garcia-Villalba R, Tomas-Barberan FA, Espin JC. Antiproliferative activity of the ellagic acid-derived gut microbiota isourolithin A and comparison with its urolithin A isomer: the role of cell metabolism. Eur J Nutr 2015.

  9. Zhang W, Chen JH, Aguilera-Barrantes I, Shiau CW, Sheng X, Wang LS, et al. Urolithin A suppresses the proliferation of endometrial cancer cells by mediating estrogen receptor-alpha-dependent gene expression. Mol Nutr Food Res 2016.

  10. Rohrl C, Stangl H. HDL endocytosis and resecretion. Biochim Biophys Acta 2013;1831(11):1626–33.

    Article  Google Scholar 

  11. Piwowarski JP, Kiss AK, Granica S, Moeslinger T. Urolithins, gut microbiota-derived metabolites of ellagitannins, inhibit LPS-induced inflammation in RAW 264.7 murine macrophages. Mol Nutr Food Res 2015;59(11):2168–77.

    Article  CAS  Google Scholar 

  12. Cho H, Jung H, Lee H, Yi HC, Kwak HK, Hwang KT. Chemopreventive activity of ellagitannins and their derivatives from black raspberry seeds on HT-29 colon cancer cells. Food Funct 2015;6(5):1675–83.

    Article  CAS  Google Scholar 

  13. Liu J, Wang H, Li J. Inflammation and inflammatory cells in myocardial infarction and reperfusion injury: a double-edged sword. Clin Med Insights Cardiol 2016;10:79–84.

    Article  CAS  Google Scholar 

  14. Tomas-Barberan FA, Gonzalez-Sarrias A, Garcia-Villalba R, Nunez-Sanchez MA, Selma MV, Garcia-Conesa MT, et al. Urolithins, the rescue of ‘old’ metabolites to understand a ‘new’ concept: metabotypes as a nexus between phenolic metabolism, microbiota dysbiosis and host health status. Mol Nutr Food Res 2016.

  15. Nunez-Sanchez MA, Karmokar A, Gonzalez-Sarrias A, Garcia-Villalba R, Tomas-Barberan FA, Garcia-Conesa MT, et al. In vivo relevant mixed urolithins and ellagic acid inhibit phenotypic and molecular colon cancer stem cell features: a new potentiality for ellagitannin metabolites against cancer. Food Chem Toxicol 2016;92:8–16.

    Article  CAS  Google Scholar 

  16. Mele L, Mena P, Piemontese A, Marino V, Lopez-Gutierrez N, Bernini F, et al. Antiatherogenic effects of ellagic acid and urolithins in vitro. Arch Biochem Biophys 2016;599:42–50.

    Article  CAS  Google Scholar 

  17. Giorgio C, Mena P, Del RD, Brighenti F, Barocelli E, Hassan-Mohamed I, et al. The ellagitannin colonic metabolite urolithin D selectively inhibits EphA2 phosphorylation in prostate cancer cells. Mol Nutr Food Res 2015;59(11):2155–67.

    Article  CAS  Google Scholar 

  18. Gonzalez-Barrio R, Truchado P, Ito H, Espin JC, Tomas-Barberan FA. UV and MS identification of urolithins and nasutins, the bioavailable metabolites of ellagitannins and ellagic acid in different mammals. J Agric Food Chem 2011;59(4):1152–62.

    Article  CAS  Google Scholar 

  19. Dellafiora L, Mena P, Cozzini P, Brighenti F, Del RD. Modelling the possible bioactivity of ellagitannin-derived metabolites. In silico tools to evaluate their potential xenoestrogenic behavior. Food Funct 2013;4(10):1442–51.

    Article  CAS  Google Scholar 

  20. Trigatti B, Rigotti A, Krieger M. The role of the high-density lipoprotein receptor SR-BI in cholesterol metabolism. Curr Opin Lipidol 2000;11(2):123–31.

    Article  CAS  Google Scholar 

  21. Gonzalez-Sarrias A, Gimenez-Bastida JA, Nunez-Sanchez MA, Larrosa M, Garcia-Conesa MT, Tomas-Barberan FA, et al. Phase-II metabolism limits the antiproliferative activity of urolithins in human colon cancer cells. Eur J Nutr 2014;53(3):853–64.

    Article  CAS  Google Scholar 

  22. Abe I, Kashiwagi Y, Noguchi H, Tanaka T, Ikeshiro Y, Kashiwada Y. Ellagitannins and hexahydroxydiphenoyl esters as inhibitors of vertebrate squalene epoxidase. J Nat Prod 2001;64(8):1010–4.

    Article  CAS  Google Scholar 

  23. Zhang Y, Da Silva JR, Reilly M, Billheimer JT, Rothblat GH, Rader DJ. Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo. J Clin Invest 2005;115(10):2870–4.

    Article  CAS  Google Scholar 

  24. Al-Jarallah A, Trigatti BL. A role for the scavenger receptor, class B type I in high density lipoprotein dependent activation of cellular signaling pathways. Biochim Biophys Acta 2010;1801(12):1239–48.

    Article  CAS  Google Scholar 

  25. Sanchez-Gonzalez C, Ciudad CJ, Noe V, Izquierdo-Pulido M. Walnut polyphenol metabolites, urolithins A and B, inhibit the expression of the prostate-specific antigen and the androgen receptor in prostate cancer cells. Food Funct 2014;5(11):2922–30.

    Article  CAS  Google Scholar 

  26. Gimenez-Bastida JA, Gonzalez-Sarrias A, Larrosa M, Tomas-Barberan F, Espin JC, Garcia-Conesa MT. Ellagitannin metabolites, urolithin A glucuronide and its aglycone urolithin A, ameliorate TNF-alpha-induced inflammation and associated molecular markers in human aortic endothelial cells. Mol Nutr Food Res 2012;56(5):784–96.

    Article  CAS  Google Scholar 

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  1. These author contributed equally to this work

Authors and Affiliations

  1. Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Soochow University, Suzhou, China

    Guang-Hao Cui, Wei-Qian Chen & Zhen-Ya Shen

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  1. Guang-Hao Cui
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  2. Wei-Qian Chen
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Correspondence to Zhen-Ya Shen.

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Cui, GH., Chen, WQ. & Shen, ZY. Urolithin A shows anti-atherosclerotic activity via activation of class B scavenger receptor and activation of Nef2 signaling pathway. Pharmacol. Rep 70, 519–524 (2018). https://doi.org/10.1016/j.pharep.2017.04.020

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  • DOI: https://doi.org/10.1016/j.pharep.2017.04.020

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