Does p-coumaric acid improve cardiac injury following LPS-induced lung inflammation through miRNA-146a activity?

Document Type : Original Research Article


1 Department of Physiology, Physiology Research Center, Faculty of Medicine,Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Physiology Research Center and Department of Physiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

3 Department of Physiology, Physiology Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

4 Cellular and Molecular Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.


Objective: In cardiovascular diseases, inflammatory response plays an important role and affects heart function. As a flavonoid compound, p-coumaric acid (pCA), commonly exists in many fruits and vegetables and has a therapeutic effect on inflammatory diseases due to its anti-inflammatory properties. The purpose of the present study was to investigate pCA anti-inflammatory effect and the miRNAs (miRs) signaling pathway involved in cardiac inflammation following lipopolysaccharide-induced acute lung injury (ALI).
Material and Methods: Thirty-two Sprague-Dawley male rats were divided into 4 groups: control (received saline for 10 days, i.p.), LPS (received saline for 10 days+5 mg/kg LPS on day 8, intratracheally), pCA (received pCA 100 mg/kg for 10 days, ip), and LPS+pCA (received LPS+pCA). The level of IL-1β, IL-18 in heart tissue and IL-1β in bronchoalveolar lavage fluid (BALF) was determined by ELISA kits. Also the level of lactate dehydrogenase (LDH) in heart tissue and myeloperoxidase (MPO) in lung tissue were measured, and pCA effect on miR- 146a in heart tissue was analyzed.
Results: Data showed that 100 mg/kg of pCA significantly suppressed LDH activity (p<0.05), IL-18 (p<0.05) and IL-1β (p<0.01) level in heart tissue. Also, in BAL, IL-1β and MPO levels were significantly reduced (p<0.001). Finally, pCA modulated activation of miR-146a (p<0.05) in LPS -induced cardiac injury.
Conclusion: These findings indicated that LPS causes cardiac dysfunction and pre-treatment with pCA, as an anti-inflammatory agent, improved cardiac inflammation through modulation of miR-146a, and reducing cytokines and LDH activity.


Main Subjects

Abraham E. 2003. Neutrophils and acute lung injury. Crit Care Med, 31: S195-S199.
Akbari G, Mard SA, Dianat M, Mansouri E. 2017. The hepatoprotective and microRNAs downregulatory effects of crocin following hepatic ischemia-reperfusioninjury in rats. Oxid Med Cell Longev, 2017.
Arabaci B, Gulcin I, Alwasel S. 2014. Capsaicin: a potent inhibitor of carbonic anhydrase isoenzymes. Molecules, 19: 10103-10114.
Arango D, Diosa‐Toro M, Rojas‐Hernandez LS, Cooperstone JL, Schwartz SJ, Mo X, Jiang J, Schmittgen TD, Doseff AI. 2015. Dietary apigenin reduces LPS‐induced expression of miR‐155 restoring immune balance during inflammation. Mol Nutr Food Res, 59: 763-772.
Baltimore D, Boldin MP, O'connell RM, Rao DS, Taganov KD. 2008. MicroRNAs: new regulators of immune cell development and function. Nat Immunol, 9: 839-845.
Baumgarten G, Knuefermann P, Nozaki N, Sivasubramanian N, Mann DL, Vallejo JG. 2001. In Vivo Expression of Proinflammatory mediators in the adult heart after endotoxin administration: the role of toll-like receptor–4. J Infect Dis, 183: 1617-1624.
Buechner J, Henriksen JR, Haug bh, Tømte E. Flaegstad T, Einvik C. 2011. Inhibition of mir-21, which is up-regulated during MYCN knockdown-mediated differentiation, does not prevent differentiation of neuroblastoma cells. Differentiation, 81: 25-34.
Bursal E, Köksal E, Gulcin İ, Bilsel G, Gören AC. 2013. Antioxidant activity and polyphenol content of cherry stem (Cerasus avium L.) determined by LC–MS/MS. Food Res Int, 51: 66-74.
Çakmakci S, Topdas EF, Kalin P, Han H, Sekerci P, Köse L, Gulcin I .2015. Antioxidant capacity and functionality of oleaster (E laeagnus angustifolia L.) flour and crust in a new kind of fruity ice cream. Int J Food Sci Technol, 50: 472-481.
Deng W, Deng Y, Deng J, Wang DX, Zhang T. 2015. Losartan attenuated lipopolysaccharide-induced lung injury by suppression of lectin-like oxidized low-density lipoprotein receptor-1. Int J Clin Exp Pathol, 8:15670-15676.
Gulcin I, Bursal E, Sehitoglu MH, Bilsel M, Gorena C. 2010. Polyphenol contents and antioxidant activity of lyophilized aqueous extract of propolis from Erzurum, Turkey Food Chem Toxicol, 48: 2227-2238.
He Y, Sun X, Huang C, Long XR, Lin X, Zhang L, Lv X, Li J. 2014.  MiR-146a regulates IL-6 production in lipopolysaccharide-induced RAW264. 7 macrophage cells by inhibiting Notch1. Inflammation, 37: 71-82.
Henson PM. 2005. Dampening inflammation. Nat Immunol, 6: 1179-1181.
Innocenti A, Sarıkaya SB, Gulcin I, Supuran C. T. 2010. Carbonic anhydrase inhibitors. Inhibition of mammalian isoforms I–XIV with a series of natural product polyphenols and phenolic acids. Bioorg Med Chem, 18:2159-2164.
Kim VN. 2005. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol, 6: 376-385.
Lee K, Kim J, Baik EJ, Ryu JH, Lee S. 2015. Isobavachalcone attenuates lipopolysaccharide-induced ICAM-1 expression in brain endothelial cells through blockadeof toll-like receptor 4 signaling pathways. Eur J Pharmacol, 754: 11-18.
Lee S, Kim HB, Hwang ES, Kim ES, Kim S, Jeon D, Song C, Lee S, Chung MC, Maeng S. 2018. Antidepressant-like effects of p-coumaric acid on LPS-induced depressive and inflammatory changes in rats. Exp Neurol, 27: 189-199.
Nadeau-Vallee M, Chin PY, Belarbi L, Brien ME, Pundir S, Berryer MH, Beaudry-Richard A, Madaan A, Sharkey DJ, Lupien-Meilleur A. 2017. Antenatal suppression of IL-1 protects against inflammation-induced fetal injury and improves neonatal and developmental outcomes in mice. J Immunol, 198: 2047-2062.
Oglesby IK, Mcelvaney NG, Greene CM. 2010. MicroRNAs in inflammatory lung disease-master regulators or target practice? Respir Med, 11: 148.
Ono K, Kuwabara Y, Han J. 2011. MicroRNAs and cardiovascular diseases. FEBS J, 278: 1619-1633.
Pragasam SJ, Venkatesan V, Rasool M. 2013. Immunomodulatory and anti-inflammatory effect of p-coumaric acid, a common dietary polyphenol on experimental inflammation in rats. Inflammation, 36:169-176.
Rahman I, Adcoc I. 2006. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J, 28: 219-242.
Rocha VZ, Libby P. 2009. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol, 6: 399-409.
Rodriguez-Gonzalez R, Martin-Barrasa J, Ramos-Nuez A, Canas-Pedrosa AM Martinez-Saavedra MT, Garcia-Bello MA, Lopez-Aguilar J, Baluja A, Alvarez J, Slutsky AS. 2014. Multiple system organ response induced by hyperoxia in a clinically relevant animal model of sepsis. Shock, 42: 148-153.
Rudiger A, Singer M. 2007. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med, 35: 1599-1608.
Ruggiero T, Trabucchi M, De Santa F, Zupo S, Harfe BD, Mcmanus MT, Rosenfeld MG, Briata P, Gherzi R. 2009. LPS induces KH-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages. FASEB J, 23: 2898-2908.
Saba R, Sorensen DL, Booth SA. 2014. MicroRNA-146a: a dominant, negative regulator of the innate immune response. Front Immunol, 5: 578.
Tohma HS, Gulcin I. 2010. Antioxidant and radical scavenging activity of aerial parts and roots of Turkish liquorice (Glycyrrhiza glabra L.). Int J Food Prop, 13: 657-671.
Topal M, Gulcin I. 2014. Rosmarinic acid: a potent carbonic anhydrase isoenzymes inhibitor. Turk J Chem, 38: 894-902.
Tsai SC, Liang YH, Chiang JH, Liu FC, Lin WH, Chang SJ, Lin WY, Wu CH, Weng JR. 2012. Anti-inflammatory effects of Calophyllum inophyllum L. in RAW264. 7 cells. Oncol Rep, 28:1096-1102.
Wu J, Yan Z, Schwartz DE, Yu J, Malik AB, Hu G. 2013. Activation of NLRP3 inflammasome in alveolar macrophages contributes to mechanical stretch-induced lung inflammation and injury. J Immunol, 190: 3590-3599.
Yoon JH, Youn K, Ho CT, Karwe MV, Jeong WS, Jun M. 2014. p-Coumaric acid and ursolic acid from Corni fructus attenuated β-amyloid25–35-induced toxicity through regulation of the NF-κB signaling pathway in PC12 cells. J Agric Food Chem, 62: 4911-4916.