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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

Dapagliflozin Protects H9c2 Cells Against Injury Induced by Lipopolysaccharide via Suppression of CX3CL1/CX3CR1 Axis and NF-κB Activity

Author(s): Yousef Faridvand, Maryam Nemati, Elham Zamani-Gharehchamani, Hamid Reza Nejabati, Arezoo Rezaie Nezhad Zamani, Samira Nozari, Nasser Safaie, Mohammad Nouri and Ahmadreza Jodati*

Volume 15, Issue 6, 2022

Published on: 13 January, 2022

Article ID: e081021197099 Pages: 8

DOI: 10.2174/1874467214666211008142347

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Abstract

Background: Dapagliflozin, a selective Sodium-glucose cotransporter-2 (SGLT2) inhibitor, has been shown to play a key role in the control and management of metabolic and cardiac diseases.

Objective: The current study aims to address the effects of dapagliflozin on the expression of fractalkine (FKN), known as CX3CL1, and its receptors CX3CR1, Nuclear factor-kappa B(NF-κB) p65 activity, Reactive oxygen species (ROS), and inflammation in LPS-treated H9c2 cell line.

Methods: H9c2 cells were cultured with lipopolysaccharide (LPS) to establish a model of LPS-induced damage, and then, subsequently were treated with dapagliflozin for 72 h. Our work included measurement of cell viability (MTT), Malondialdehyde (MDA), intracellular ROS, tumor necrosis factor-α (TNF-α), NF-κB activity, and expression of CX3CL1/CX3CR1.

Results: The results showed that LPS-induced reduction of cell viability was successfully rescued by dapagliflozin treatment. The cellular levels of MDA, ROS, and TNF-α, as an indication of cellular oxidative stress and inflammation, were significantly elevated in H9c2 cells compared to the control group. Furthermore, dapagliflozin ameliorated inflammation and oxidative stress through the modulation of the levels of MDA, TNF-α, and ROS. Correspondingly, dapagliflozin reduced the expression of CX3CL1/CX3CR1, NF-κB p65 DNA binding activity, and it also attenuated nuclear acetylated NF-κB p65 in LPS-induced injury in H9c2 cells compared to untreated cells.

Conclusion: These findings shed light on the novel pharmacological potential of dapagliflozin in the alleviation of LPS-induced CX3CL1/CX3CR1-mediated injury in inflammatory conditions such as sepsis-induced cardiomyopathy.

Keywords: Dapagliflozin, fractalkine, CX3CL1/CX3CR1, NF-κB, H9c2 cells, lipopolysaccharide.

Graphical Abstract

[1]
Liu, D.; Zeng, X.; Li, X.; Mehta, J.L.; Wang, X. Role of NLRP3 inflammasome in the pathogenesis of cardiovascular diseases. Basic Res. Cardiol., 2017, 113(1), 5.
[http://dx.doi.org/10.1007/s00395-017-0663-9] [PMID: 29224086]
[2]
Petrie, J.R.; Guzik, T.J.; Touyz, R.M. Diabetes, hypertension, and cardiovascular disease: Clinical insights and vascular mechanisms. Can. J. Cardiol., 2018, 34(5), 575-584.
[http://dx.doi.org/10.1016/j.cjca.2017.12.005] [PMID: 29459239]
[3]
Imanaka-Yoshida, K. Inflammation in myocardial disease: From myocarditis to dilated cardiomyopathy. Pathol. Int., 2020, 70(1), 1-11.
[http://dx.doi.org/10.1111/pin.12868] [PMID: 31691489]
[4]
Briasoulis, A.; Androulakis, E.; Christophides, T.; Tousoulis, D. The role of inflammation and cell death in the pathogenesis, progression and treatment of heart failure. Heart Fail. Rev., 2016, 21(2), 169-176.
[http://dx.doi.org/10.1007/s10741-016-9533-z] [PMID: 26872673]
[5]
Ehrman, R.R.; Sullivan, A.N.; Favot, M.J.; Sherwin, R.L.; Reynolds, C.A.; Abidov, A.; Levy, P.D. Pathophysiology, echocardiographic evaluation, biomarker findings, and prognostic implications of septic cardiomyopathy: a review of the literature. Crit. Care, 2018, 22(1), 112.
[http://dx.doi.org/10.1186/s13054-018-2043-8] [PMID: 29724231]
[6]
Fallach, R.; Shainberg, A.; Avlas, O.; Fainblut, M.; Chepurko, Y.; Porat, E.; Hochhauser, E. Cardiomyocyte Toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia. J. Mol. Cell. Cardiol., 2010, 48(6), 1236-1244.
[http://dx.doi.org/10.1016/j.yjmcc.2010.02.020] [PMID: 20211628]
[7]
Nemati, M.; Akseh, S.; Amiri, M.; Reza Nejabati, H.; Jodati, A.; Fathi Maroufi, N.; Faridvand, Y.; Nouri, M. Lactoferrin suppresses LPS-induced expression of HMGB1, microRNA 155, 146, and TLR4/MyD88/NF-кB pathway in RAW264.7 cells. Immunopharmacol. Immunotoxicol., 2021, 43(2), 153-159.
[http://dx.doi.org/10.1080/08923973.2021.1872616] [PMID: 33435756]
[8]
Nanchen, D; Klingenberg, R; Gencer, B; Raber, L; Carballo, D; von Eckardstein, A Inflammation during acute coronary syndromes - Risk of cardiovascular events and bleeding. Int. J. Cardiol., 2019, 287, 13-18.
[9]
Sorriento, D.; Iaccarino, G. Inflammation and cardiovascular diseases: The most recent findings; Multidisciplinary Digital Publishing Institute, 2019.
[10]
Fitchett, D.; Zinman, B.; Wanner, C.; Lachin, J.M.; Hantel, S.; Salsali, A.; Johansen, O.E.; Woerle, H.J.; Broedl, U.C.; Inzucchi, S.E. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur. Heart J., 2016, 37(19), 1526-1534.
[http://dx.doi.org/10.1093/eurheartj/ehv728] [PMID: 26819227]
[11]
Vettor, R.; Inzucchi, S.E.; Fioretto, P. The cardiovascular benefits of empagliflozin: SGLT2-dependent and -independent effects. Diabetologia, 2017, 60(3), 395-398.
[http://dx.doi.org/10.1007/s00125-016-4194-y] [PMID: 28074254]
[12]
Neal, B.; Perkovic, V.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Shaw, W.; Law, G.; Desai, M.; Matthews, D.R. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med., 2017, 377(7), 644-657.
[http://dx.doi.org/10.1056/NEJMoa1611925] [PMID: 28605608]
[13]
Lee, TM; Chang, NC; Lin, SZ Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med, 2017, 104, 298-310.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.01.035]
[14]
Ye, Y.; Bajaj, M.; Yang, H.C.; Perez-Polo, J.R.; Birnbaum, Y. SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc. Drugs Ther., 2017, 31(2), 119-132.
[http://dx.doi.org/10.1007/s10557-017-6725-2] [PMID: 28447181]
[15]
Lopaschuk, G.D.; Verma, S. Empagliflozin’s fuel hypothesis: Not so soon. Cell Metab., 2016, 24(2), 200-202.
[http://dx.doi.org/10.1016/j.cmet.2016.07.018] [PMID: 27508868]
[16]
Uthman, L.; Baartscheer, A.; Schumacher, C.A.; Fiolet, J.W.T.; Kuschma, M.C.; Hollmann, M.W. Direct cardiac actions of sodium glucose cotransporter 2 inhibitors target pathogenic mechanisms underlying heart failure in diabetic patients. Front. Physiol., 1575, 2018, 9.
[PMID: 30519189]
[17]
Lesnik, P.; Haskell, C.A.; Charo, I.F. Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis. J. Clin. Invest., 2003, 111(3), 333-340.
[http://dx.doi.org/10.1172/JCI15555] [PMID: 12569158]
[18]
Teupser, D.; Pavlides, S.; Tan, M.; Gutierrez-Ramos, J.C.; Kolbeck, R.; Breslow, J.L. Major reduction of atherosclerosis in fractalkine (CX3CL1)-deficient mice is at the brachiocephalic artery, not the aortic root. Proc. Natl. Acad. Sci. USA, 2004, 101(51), 17795-17800.
[http://dx.doi.org/10.1073/pnas.0408096101] [PMID: 15596719]
[19]
Xuan, W.; Liao, Y.; Chen, B.; Huang, Q.; Xu, D.; Liu, Y.; Bin, J.; Kitakaze, M. Detrimental effect of fractalkine on myocardial ischaemia and heart failure. Cardiovasc. Res., 2011, 92(3), 385-393.
[http://dx.doi.org/10.1093/cvr/cvr221] [PMID: 21840883]
[20]
Faridvand, Y.; Haddadi, P.; Nejabati, H.R.; Ghaffari, S.; Zamani-Gharehchamani, E.; Nozari, S.; Nouri, M.; Jodati, A. Sulforaphane modulates CX3CL1/CX3CR1 axis and inflammation in palmitic acid-induced cell injury in C2C12 skeletal muscle cells. Mol. Biol. Rep., 2020, 47(10), 7971-7977.
[http://dx.doi.org/10.1007/s11033-020-05875-9] [PMID: 33034881]
[21]
Escher, F.; Vetter, R.; Kühl, U.; Westermann, D.; Schultheiss, H.P.; Tschöpe, C. Fractalkine in human inflammatory cardiomyopathy. Heart, 2011, 97(9), 733-739.
[http://dx.doi.org/10.1136/hrt.2010.205716] [PMID: 21357373]
[22]
Umehara, H.; Tanaka, M.; Sawaki, T.; Jin, Z.X.; Huang, C.R.; Dong, L.; Kawanami, T.; Karasawa, H.; Masaki, Y.; Fukushima, T.; Hirose, Y.; Okazaki, T. Fractalkine in rheumatoid arthritis and allied conditions. Mod. Rheumatol., 2006, 16(3), 124-130.
[http://dx.doi.org/10.3109/s10165-006-0471-9] [PMID: 16767549]
[23]
Husberg, C.; Nygård, S.; Finsen, A.V.; Damås, J.K.; Frigessi, A.; Oie, E.; Waehre, A.; Gullestad, L.; Aukrust, P.; Yndestad, A.; Christensen, G. Cytokine expression profiling of the myocardium reveals a role for CX3CL1 (fractalkine) in heart failure. J. Mol. Cell. Cardiol., 2008, 45(2), 261-269.
[http://dx.doi.org/10.1016/j.yjmcc.2008.05.009] [PMID: 18585734]
[24]
Frangogiannis, N.G.; Entman, M.L. Targeting the chemokines in myocardial inflammation. Circulation, 2004, 110(11), 1341-1342.
[http://dx.doi.org/10.1161/01.CIR.0000141560.18364.63] [PMID: 15364818]
[25]
Branco, A.F.; Pereira, S.P.; Gonzalez, S.; Gusev, O.; Rizvanov, A.A.; Oliveira, P.J. Gene expression profiling of H9c2 myoblast differentiation towards a cardiac-like phenotype. PLoS One, 2015, 10(6), e0129303.
[http://dx.doi.org/10.1371/journal.pone.0129303] [PMID: 26121149]
[26]
Cuevas, J. Molecular mechanisms of dysautonomia during heart failure. Focus on “Heart failure-induced changes of voltage-gated Ca2+ channels and cell excitability in rat cardiac postganglionic neurons”. Am. J. Physiol. Cell Physiol., 2014, 306(2), C121-C122.
[http://dx.doi.org/10.1152/ajpcell.00311.2013] [PMID: 24108866]
[27]
Ong, S; Rose, NR; Cihakova, D Natural killer cells in inflammatory heart disease. Clin Immunol, 2017, 175, 26-33.
[http://dx.doi.org/10.1016/j.clim.2016.11.010]
[28]
Rose, N.R. Critical cytokine pathways to cardiac inflammation. J. Interferon Cytokine Res., 2011, 31(10), 705-710.
[http://dx.doi.org/10.1089/jir.2011.0057] [PMID: 21861699]
[29]
Jatta, K.; Wågsäter, D.; Norgren, L.; Stenberg, B.; Sirsjö, A. Lipopolysaccharide-induced cytokine and chemokine expression in human carotid lesions. J. Vasc. Res., 2005, 42(3), 266-271.
[http://dx.doi.org/10.1159/000085721] [PMID: 15886490]
[30]
Filippatos, T.D.; Liontos, A.; Papakitsou, I.; Elisaf, M.S. SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses. Postgrad. Med., 2019, 131(2), 82-88.
[http://dx.doi.org/10.1080/00325481.2019.1581971] [PMID: 30757937]
[31]
Bonnet, F.; Scheen, A.J. Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: The potential contribution to diabetes complications and cardiovascular disease. Diabetes Metab., 2018, 44(6), 457-464.
[http://dx.doi.org/10.1016/j.diabet.2018.09.005] [PMID: 30266577]
[32]
Cappetta, D; De Angelis, A; Ciuffreda, LP; Coppini, R; Cozzolino, A; Miccichè, A Amelioration of diastolic dysfunction by dapagliflozin in a non-diabetic model involves coronary endothelium. Pharmacol. Res., 2020, 157, 104781.
[http://dx.doi.org/10.1016/j.phrs.2020.104781]
[33]
Packer, M. Interplay of AMPK/SIRT1 Activation and Sodium Influx Inhibition Mediates the Renal Benefits of SGLT2 Inhibitors in Type 2 Diabetes: a Novel Conceptual Framework. Diabetes Obes. Metab., 2020.
[http://dx.doi.org/10.1111/dom.13961]
[34]
Leng, W.; Wu, M.; Pan, H.; Lei, X.; Chen, L.; Wu, Q.; Ouyang, X.; Liang, Z. The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus. Ann. Transl. Med., 2019, 7(18), 429.
[http://dx.doi.org/10.21037/atm.2019.09.03] [PMID: 31700865]
[35]
Lorenzo, O; Picatoste, B; Ares-Carrasco, S; Ramirez, E; Egido, J; Tunon, J Potential role of nuclear factor kappaB in diabetic cardiomyopathy. Mediators Inflamm, 2011, 2011, 652097.
[36]
Bhavsar, P.K.; Sukkar, M.B.; Khorasani, N.; Lee, K.Y.; Chung, K.F. Glucocorticoid suppression of CX3CL1 (fractalkine) by reduced gene promoter recruitment of NF-kappaB. FASEB J., 2008, 22(6), 1807-1816.
[http://dx.doi.org/10.1096/fj.07-094235] [PMID: 18230685]
[37]
Li, M.; Gou, Y.; Yu, H.; Ji, T.; Li, Y.; Qin, L.; Sun, W. Mechanism of metformin on LPS-induced bacterial myocarditis. Dose Response, 2019, 17(2), 1559325819847409.
[http://dx.doi.org/10.1177/1559325819847409] [PMID: 31205455]
[38]
Arab, HH; Al-Shorbagy, MY; Saad, MA Activation of autophagy and suppression of apoptosis by dapagliflozin attenuates experimental inflammatory bowel disease in rats: Targeting AMPK/mTOR, HMGB1/RAGE and Nrf2/HO-1 pathways. Chem Biol Interact, 2021, 335, 109368.
[39]
Arow, M.; Waldman, M.; Yadin, D.; Nudelman, V.; Shainberg, A.; Abraham, N.G.; Freimark, D.; Kornowski, R.; Aravot, D.; Hochhauser, E.; Arad, M. Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy. Cardiovasc. Diabetol., 2020, 19(1), 7.
[http://dx.doi.org/10.1186/s12933-019-0980-4] [PMID: 31924211]
[40]
Tirmenstein, M.; Dorr, T.E.; Janovitz, E.B.; Hagan, D.; Abell, L.M.; Onorato, J.M.; Whaley, J.M.; Graziano, M.J.; Reilly, T.P. Nonclinical toxicology assessments support the chronic safety of dapagliflozin, a first-in-class sodium-glucose cotransporter 2 inhibitor. Int. J. Toxicol., 2013, 32(5), 336-350.
[http://dx.doi.org/10.1177/1091581813505331] [PMID: 24097127]
[41]
Chang, Y.K.; Choi, H.; Jeong, J.Y.; Na, K.R.; Lee, K.W.; Lim, B.J.; Choi, D.E. Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury. PLoS One, 2016, 11(7), e0158810.
[http://dx.doi.org/10.1371/journal.pone.0158810] [PMID: 27391020]
[42]
Zhu, H.; Shan, L.; Schiller, P.W.; Mai, A.; Peng, T. Histone deacetylase-3 activation promotes tumor necrosis factor-alpha (TNF-alpha) expression in cardiomyocytes during lipopolysaccharide stimulation. J. Biol. Chem., 2010, 285(13), 9429-9436.
[http://dx.doi.org/10.1074/jbc.M109.071274] [PMID: 20097764]
[43]
Njerve, I.U.; Solheim, S.; Lunde, K.; Hoffmann, P.; Arnesen, H.; Seljeflot, I. Fractalkine levels are elevated early after PCI-treated ST-elevation myocardial infarction; no influence of autologous bone marrow derived stem cell injection. Cytokine, 2014, 69(1), 131-135.
[http://dx.doi.org/10.1016/j.cyto.2014.05.022] [PMID: 24930044]
[44]
Robinson, L.A.; Nataraj, C.; Thomas, D.W.; Howell, D.N.; Griffiths, R.; Bautch, V.; Patel, D.D.; Feng, L.; Coffman, T.M. A role for fractalkine and its receptor (CX3CR1) in cardiac allograft rejection. J. Immunol., 2000, 165(11), 6067-6072.
[http://dx.doi.org/10.4049/jimmunol.165.11.6067] [PMID: 11086038]
[45]
Apostolakis, S.; Spandidos, D. Chemokines and atherosclerosis: focus on the CX3CL1/CX3CR1 pathway. Acta Pharmacol. Sin., 2013, 34(10), 1251-1256.
[http://dx.doi.org/10.1038/aps.2013.92] [PMID: 23974513]

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