Abstract
6-Gingerol, a pungent ingredient of ginger, has been reported to possess anti-inflammatory and antioxidant activities, but the effect of 6-gingerol on pressure overload-induced cardiac remodeling remains inconclusive. In this study, we investigated the effect of 6-gingerol on cardiac remodeling in in vivo and in vitro models, and to clarify the underlying mechanisms. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 6-gingerol (20 mg/kg, ig) three times a week (1 week in advance and continued until the end of the experiment). Four weeks after TAC surgery, the mice were subjected to echocardiography, and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes and cardiac fibroblasts were used to validate the protective effects of 6-gingerol in response to phenylephrine (PE) and transforming growth factor-β (TGF-β) challenge. We showed that 6-gingerol administration protected against pressure overload-induced cardiac hypertrophy, fibrosis, inflammation, and dysfunction in TAC mice. In the in vitro study, we showed that treatment with 6-gingerol (20 μM) blocked PE-induced-cardiomyocyte hypertrophy and TGF-β-induced cardiac fibroblast activation. Furthermore, 6-gingerol treatment significantly decreased mitogen-activated protein kinase p38 (p38) phosphorylation in response to pressure overload in vivo and extracellular stimuli in vitro, which was upregulated in the absence of 6-gingerol treatment. Moreover, transfection with mitogen-activated protein kinase kinase 6 expressing adenoviruses (Ad-MKK6), which specifically activated p38, abolished the protective effects of 6-gingerol in both in vitro and in vivo models. In conclusion, 6-gingerol improves cardiac function and alleviates cardiac remodeling induced by pressure overload in a p38-dependent manner. The present study demonstrates that 6-gingerol is a promising agent for the intervention of pathological cardiac remodeling.
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References
Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling-concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an international forum on cardiac remodeling. J Am Coll Cardiol. 2000;35:569–82.
Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 2001;81:807–69.
Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther. 2009;123:255–78.
Suetomi T, Willeford A, Brand CS, Cho Y, Ross RS, Miyamoto S, et al. Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca2+/calmodulin-dependent protein kinase II δ signaling in cardiomyocytes are essential for adverse cardiac remodeling. Circulation. 2018;138:2530–44.
Zhang Y, Bauersachs J, Langer HF. Immune mechanisms in heart failure. Eur J Heart Fail. 2017;19:1379–89.
Laroumanie F, Douin-Echinard V, Pozzo J, Lairez O, Tortosa F, Vinel C, et al. CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload. Circulation. 2014;129:2111–24.
Nevers T, Salvador AM, Grodecki-Pena A, Knapp A, Velázquez F, Aronovitz M, et al. Left ventricular T-cell recruitment contributes to the pathogenesis of heart failure. Circ Heart Fail. 2015;8:776–87.
Molkentin JD, Dorn GW. Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu Rev Physiol. 2001;63:391–426.
Tenhunen O, Rysä J, Ilves M, Soini Y, Ruskoaho H, Leskinen H. Identification of cell cycle regulatory and inflammatory genes as predominant targets of p38 mitogen-activated protein kinase in the heart. Circ Res. 2006;99:485–93.
Westermann D, Rutschow S, Van Linthout S, Linderer A, Bücker-Gärtner C, Sobirey M, et al. Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Diabetologia. 2006;49:2507–13.
Zhang D, Gaussin V, Taffet GE, Belaguli NS, Yamada M, Schwartz RJ, et al. TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nat Med. 2000;6:556–63.
Lee JH, Kim YG, Choi P, Ham J, Park JG, Lee J. Antibiofilm and antivirulence activities of 6-gingerol and 6-shogaol against candida albicans due to hyphal inhibition. Front Cell Infect Microbiol. 2018;8:299.
Song S, Dang M, Kumar M. Anti-inflammatory and renal protective effect of gingerol in high-fat diet/streptozotocin-induced diabetic rats via inflammatory mechanism. Inflammopharmacology. 2019;27:1243–54.
Kim SO, Kundu JK, Shin YK, Park JH, Cho MH, Kim TY, et al. [6]-Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase and NF-κB in phorbol ester-stimulated mouse skin. Oncogene. 2005;24:2558–67.
Li Y, Xu B, Xu M, Chen D, Xiong Y, Lian M, et al. 6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-κB signalling. Pharmacol Res. 2017;119:137–48.
Chen YL, Zhuang XD, Xu ZW, Lu LH, Guo HL, Wu WK, et al. Higenamine combined with [6]-gingerol suppresses doxorubicin-triggered oxidative stress and apoptosis in cardiomyocytes via upregulation of PI3K/Akt pathway. Evid Based Complement Altern Med. 2013;2013:970490.
Wen J, Zhang L, Wang J, Wang J, Wang L, Wang R, et al. Therapeutic effects of higenamine combined with [6]-gingerol on chronic heart failure induced by doxorubicin via ameliorating mitochondrial function. J Cell Mol Med. 2020;24:4036–50.
Jeong CH, Bode AM, Pugliese A, Cho YY, Kim HG, Shim JH, et al. [6]-Gingerol suppresses colon cancer growth by targeting leukotriene A4 hydrolase. Cancer Res. 2009;69:5584–91.
Ju SA, Park SM, Lee YS, Bae JH, Yu R, An WG, et al. Administration of 6-gingerol greatly enhances the number of tumor-infiltrating lymphocytes in murine tumors. Int J Cancer. 2012;130:2618–28.
Jain M, Singh A, Singh V, Maurya P, Barthwal MK. Gingerol inhibits serum-induced vascular smooth muscle cell proliferation and injury-induced neointimal hyperplasia by suppressing p38 MAPK activation. J Cardiovasc Pharmacol Ther. 2016;21:187–200.
Wen J, Wang J, Li P, Wang R, Wang J, Zhou X, et al. Protective effects of higenamine combined with [6]-gingerol against doxorubicin-induced mitochondrial dysfunction and toxicity in H9c2 cells and potential mechanisms. Biomed Pharmacother. 2019;115:108881.
Weng LQ, Zhang WB, Ye Y, Yin PP, Yuan J, Wang XX, et al. Aliskiren ameliorates pressure overload-induced heart hypertrophy and fibrosis in mice. Acta Pharmacol Sin. 2014;35:1005–14.
Ji YX, Zhang P, Zhang XJ, Zhao YC, Deng KQ, Jiang X, et al. The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling. Nat Commun. 2016;7:11267.
Deng KQ, Wang A, Ji YX, Zhang XJ, Fang J, Zhang Y, et al. Suppressor of IKKÉ› is an essential negative regulator of pathological cardiac hypertrophy. Nat Commun. 2016;7:11432.
Sun M, Opavsky MA, Stewart DJ, Rabinovitch M, Dawood F, Wen WH, et al. Temporal response and localization of integrins β1 and β3 in the heart after myocardial infarction: regulation by cytokines. Circulation. 2003;107:1046–52.
Roberts AB, Roche NS, Winokur TS, Burmester JK, Sporn MB. Role of transforming growth factor-β in maintenance of function of cultured neonatal cardiac myocytes. Autocrine action and reversal of damaging effects of interleukin-1. J Clin Invest. 1992;90:2056–62.
Wu QQ, Xiao Y, Duan MX, Yuan Y, Jiang XH, Yang Z, et al. Aucubin protects against pressure overload-induced cardiac remodelling via the β3 -adrenoceptor-neuronal NOS cascades. Br J Pharmacol. 2018;175:1548–66.
Li N, Zhou H, Ma ZG, Zhu JX, Liu C, Song P, et al. Geniposide alleviates isoproterenol-induced cardiac fibrosis partially via SIRT1 activation in vivo and in vitro. Front Pharmacol. 2018;9:854.
Algandaby MM, El-Halawany AM, Abdallah HM, Alahdal AM, Nagy AA, Ashour OM, et al. Gingerol protects against experimental liver fibrosis in rats via suppression of pro-inflammatory and profibrogenic mediators. Naunyn Schmiedebergs Arch Pharmacol. 2016;389:419–28.
Hamid T, Guo SZ, Kingery JR, Xiang X, Dawn B, Prabhu SD. Cardiomyocyte NF-κB p65 promotes adverse remodelling, apoptosis, and endoplasmic reticulum stress in heart failure. Cardiovasc Res. 2011;89:129–38.
Wu QQ, Xiao Y, Yuan Y, Ma ZG, Liao HH, Liu C, et al. Mechanisms contributing to cardiac remodelling. Clin Sci. 2017;131:2319–45.
Han X, Liu P, Liu M, Wei Z, Fan S, Wang X, et al. [6]-Gingerol ameliorates ISO-induced myocardial fibrosis by reducing oxidative stress, inflammation, and apoptosis through inhibition of TLR4/MAPKs/NF-κB pathway. Mol Nutr Food Res. 2020;64:e2000003.
Kang C, Kang M, Han Y, Zhang T, Quan W, Gao J. 6-Gingerols (6G) reduces hypoxia-induced PC-12 cells apoptosis and autophagy through regulation of miR-103/BNIP3. Artif Cells Nanomed Biotechnol. 2019;47:1653–61.
Zechner D, Thuerauf DJ, Hanford DS, McDonough PM, Glembotski CC. A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression. J Cell Biol. 1997;139:115–27.
Clerk A, Michael A, Sugden PH. Stimulation of the p38 mitogen-activated protein kinase pathway in neonatal rat ventricular myocytes by the G protein-coupled receptor agonists, endothelin-1 and phenylephrine: a role in cardiac myocyte hypertrophy? J Cell Biol. 1998;142:523–35.
Liao P, Georgakopoulos D, Kovacs A, Zheng M, Lerner D, Pu H, et al. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proc Natl Acad Sci USA. 2001;98:12283–8.
Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: the fibroblast awakens. Circ Res. 2016;118:1021–40.
Khalil H, Kanisicak O, Prasad V, Correll RN, Fu X, Schips T, et al. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest. 2017;127:3770–83.
Divakaran V, Adrogue J, Ishiyama M, Entman ML, Haudek S, Sivasubramanian N, et al. Adaptive and maladptive effects of SMAD3 signaling in the adult heart after hemodynamic pressure overloading. Circ Heart Fail. 2009;2:633–42.
Davis J, Burr AR, Davis GF, Birnbaumer L, Molkentin JD. A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev Cell. 2012;23:705–15.
Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature. 2003;425:577–84.
Li Y, Li Z, Zhang C, Li P, Wu Y, Wang C, et al. Cardiac fibroblast-specific activating transcription factor 3 protects against heart failure by suppressing MAP2K3-p38 signaling. Circulation. 2017;135:2041–57.
Meyer-Ter-Vehn T, Gebhardt S, Sebald W, Buttmann M, Grehn F, Schlunck G, et al. p38 inhibitors prevent TGF-β-induced myofibroblast transdifferentiation in human tenon fibroblasts. Invest Ophthalmol Vis Sci. 2006;47:1500–9.
Molkentin JD, Bugg D, Ghearing N, Dorn LE, Kim P, Sargent MA, et al. Fibroblast-specific genetic manipulation of p38 mitogen-activated protein kinase in vivo reveals its central regulatory role in fibrosis. Circulation. 2017;136:549–61.
Furukawa F, Matsuzaki K, Mori S, Tahashi Y, Yoshida K, Sugano Y, et al. p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts. Hepatology. 2003;38:879–89.
Li M, Georgakopoulos D, Lu G, Hester L, Kass DA, Hasday J, et al. p38 MAP kinase mediates inflammatory cytokine induction in cardiomyocytes and extracellular matrix remodeling in heart. Circulation. 2005;111:2494–502.
Zhao QD, Viswanadhapalli S, Williams P, Shi Q, Tan C, Yi X, et al. NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways. Circulation. 2015;131:643–55.
Liu Q, Chen Y, Auger-Messier M, Molkentin JD. Interaction between NFκB and NFAT coordinates cardiac hypertrophy and pathological remodeling. Circ Res. 2012;110:1077–86.
Vanden Berghe W, Plaisance S, Boone E, De Bosscher K, Schmitz ML, Fiers W, et al. p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-κB p65 transactivation mediated by tumor necrosis factor. J Biol Chem. 1998;273:3285–90.
Liang F, Gardner DG. Mechanical strain activates BNP gene transcription through a p38/NF-κB-dependent mechanism. J Clin Invest. 1999;104:1603–12.
Acknowledgements
The present study was supported by grants from the National Natural Science Foundation of China (81900219, 81530012, and 81800216), the Fundamental Research Funds for the Central Universities (2042019kf0062 and 2042018kf1032), the Development Center for Medical Science and Technology National Health and Family Planning Commission of China (2016ZX-008-01), and the National Key R&D Program of China (2018YFC1311300).
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SQM, ZG, DF, and QZT contributed to the conception and design of the study. SQM, ZG, SGH, NT, PA, DY, and MYW performed the experiments and collected the data. FYL, DF, SQM, ZG, and SGH contributed to the data analysis and interpretation. SQM, DF, ZG, and FYL drafted and wrote the manuscript. QZT, ZY and, HMW provided experimental sources and financial support. SQM, ZG, FYL, and SGH contributed equally to this manuscript. All authors read and approved the final version of the manuscript.
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Ma, Sq., Guo, Z., Liu, Fy. et al. 6-Gingerol protects against cardiac remodeling by inhibiting the p38 mitogen-activated protein kinase pathway. Acta Pharmacol Sin 42, 1575–1586 (2021). https://doi.org/10.1038/s41401-020-00587-z
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DOI: https://doi.org/10.1038/s41401-020-00587-z
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