Abstract
Empagliflozin (EMPA) is a SGLT-2 inhibitor that has positive effects on cardiovascular outcomes. In this study, we aim to evaluate the possible protective effects of EMPA against doxorubicin (DOX)-induced acute cardiotoxicity. Non-diabetic Sprague–Dawley rats were randomized into four groups. The control group received serum physiologic (1 ml), the EMPA group received EMPA, the DOX group was administered cumulatively 18 mg/kg body weight DOX. The DOX+EMPA group was administered DOX and EMPA. In the DOX group, LVDED (P < 0.05) and LVSED (P < 0.01), QTc interval (P < 0.001), the ratio of karyolysis and karyorrhexis (P < 0.001) and infiltrative cell proliferation (P < 0.001) were found to be higher than; EF, FS and normal cell morphology were lower than the control group (P < 0.001). In the DOX+EMPA group, LVEDD (P < 0.05) and LVESD (P < 0.01) values, QTc interval (P < 0.001), karyolysis and karyorrhexis ratios (P < 0.001) and infiltrative cell proliferation were lower (P < 0.01); normal cell morphology and EF were higher compared to the DOX group (P < 0.001). Our results showed that empagliflozin significantly ameliorated DOX-induced acute cardiotoxicity.
Similar content being viewed by others
Data Availability
All data relevant to the study are included in the article.
Code Availability
Not applicable.
References
Grempler, R., Thomas, L., Eckhardt, M., Himmelsbach, F., Sauer, A., Sharp, D. E., Bakker, R. A., Mark, M., Klein, T., & Eickelmann, P. (2012). Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: Characterisation and comparison with other SGLT-2 inhibitors. Diabetes, Obesity & Metabolism, 14(1), 83–90.
Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., Devins, T., Johansen, O. E., Woerle, H. J., Broedl, U. C., & Inzucchi, S. E. (2015). Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine, 373(22), 2117–2128.
Packer, M., Anker, S. D., Butler, J., Filippatos, G., Pocock, S. J., Carson, P., Januzzi, J., Verma, S., Tsutsui, H., Brueckmann, M., & Jamal, W. (2020). Cardiovascular and renal outcomes with empagliflozin in heart failure. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2022190
Cherney, D. Z., Perkins, B. A., Soleymanlou, N., Har, R., Fagan, N., Johansen, O. E., Woerle, H. J., Eynatten, M., & Broedl, U. C. (2014). The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovascular Diabetology, 13, 28.
Barnett, A. H., Mithal, A., Manassie, J., Jones, R., Rattunde, H., Woerle, H. J., & Broedl, U. C. (2014). Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: A randomised, double-blind, placebo-controlled trial. The Lancet Diabetes and Endocrinology, 2(5), 369–384.
Cardoso, C. R., Ferreira, M. T., Leite, N. C., & Salles, G. F. (2013). Prognostic impact of aortic stiffness in high-risk type 2 diabetic patients: The Rio deJaneiro type 2 diabetes cohort study. Diabetes Care, 36(11), 3772–3778.
Bakris, G. L., & Molitch, M. (2014). Microalbuminuria as a risk predictor in diabetes: The continuing saga. Diabetes Care, 37(3), 867–875.
Yurista, S. R., Sillje, H. H. W., Oberdorf-Maass, S. U., Schouten, E. M., Pavez Giani, M. G., Hillebrands, J. L., Goor, H., Veldhuisen, D. J., Boer, R. A., & Westenbrink, B. D. (2019). Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction. European Journal of Heart Failure, 21(7), 862–873.
Connelly, K. A., Zhang, Y., Visram, A., Advani, A., Batchu, S. N., Desjardins, J. F., Thai, K., & Gilbert, R. E. (2019). Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction. JACC Basic to Translational Science, 4(1), 27–37.
Lee, H. C., Shiou, Y. L., Jhuo, S. J., Chang, C. Y., Liu, P. L., Jhuang, W. J., Dai, Z. K., Chen, W. Y., Chen, Y. F., & Lee, A. S. (2019). The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovascular Diabetology, 18(1), 45.
Santos-Gallego, C. G., Requena-Ibanez, J. A., San Antonio, R., Ishikawa, K., Watanabe, S., Picatoste, B., Flores, E., Garcia-Ropero, A., Sanz, J., Hajjar, R., Fuster, V., & Badimon, J. J. (2019). Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. Journal of the American College of Cardiology, 73(15), 1931–1944.
Blum, J. L., Flynn, P. J., Yothers, G., Asmar, L., Geyer, C. E., Jr., Jacobs, S. A., Robert, N. J., Hopkins, J. O., O’Shaughnessy, J. A., Dang, C. T., Gómez, H. L., Fehrenbacher, L., Vukelja, S. J., Lyss, A. P., Paul, D., Brufsky, A. M., Jeong, J. H., Colangelo, L. H., Swain, S. M., … Wolmark, N. (2017). Anthracyclines in early breast cancer: The ABC trials-USOR 06–090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG oncology). Journal of Clinical Oncology, 35(23), 2647–2655.
Luminari, S., Montanini, A., & Federico, M. (2011). Anthracyclines: A cornerstone in the management of non-Hodgkin’s lymphoma. Hematology Reports, 3(3s), e4.
Keohan, M. L., & Taub, R. N. (1997). Chemotherapy for advanced sarcoma: Therapeutic decisions and modalities. Seminars in Oncology, 24(5), 572–579.
Terwilliger, T., & Abdul-Hay, M. (2017). Acute lymphoblastic leukemia: A comprehensive review and 2017 update. Blood Cancer Journal, 7(6), e577.
Bristow, M. R., Billingham, M. E., Mason, J. W., & Daniels, J. R. (1978). Clinical spectrum of anthracycline antibiotic cardiotoxicity. Cancer Treatment Reports, 62(6), 873–879.
Singal, P. K., & Iliskovic, N. (1998). Doxorubicin-induced cardiomyopathy. New England Journal of Medicine, 339(13), 900–905.
Oh, C. M., Cho, S., Jang, J. Y., Kim, H., Chun, S., Choi, M., Park, S., & Ko, Y. G. (2019). Cardioprotective potential of an SGLT2 inhibitor against doxorubicin-induced heart failure. Korean Circulation Journal, 49(12), 1183–1195.
Sabatino, J., De Rosa, S., Tamme, L., Iaconetti, C., Sorrentino, S., Polimeni, A., Mignogna, C., Amorosi, A., Spaccarotella, C., Yasuda, M., & Indolfi, C. (2020). Empagliflozin prevents doxorubicin-induced myocardial dysfunction. Cardiovascular Diabetology, 19(1), 66.
Sayed-Ahmed, M. M., Al-Shabanah, O. A., Hafez, M. M., Aleisa, A. M., & Al-Rejaie, S. S. (2010). Inhibition of gene expression of heart fatty acid binding protein and organic cation/carnitine transporter in doxorubicin cardiomyopathic rat model. European Journal of Pharmacology, 640(1–3), 143–149.
Baris, V. O., Gedikli, E., Yersal, N., Muftuoglu, S., & Erdem, A. (2019). Protective effect of taurine against doxorubicin-induced cardiotoxicity in rats: Echocardiographical and histological findings. Amino Acids, 51(10–12), 1649–1655.
Kosecik, M., Erel, O., Sevinc, E., & Selek, S. (2005). Increased oxidative stress in children exposed to passive smoking. International Journal of Cardiology, 100(1), 61–64.
Georgiadis, N., Tsarouhas, K., Rezaee, R., Nepka, H., Kass, G. E. N., Dorne, J. C. M., Stagkos, D., Toutouzas, K., Spandidos, D. A., Kouretas, D., & Tsitsimpikou, C. (2020). What is considered cardiotoxicity of anthracyclines in animal studies. Oncology Reports, 44(3), 798–818.
Carvalho, C., Santos, R. X., Cardoso, S., Correia, S., Oliveira, P. J., Santos, M. S., & Moreira, P. (2009). Doxorubicin: The good, the bad and the ugly effect. Current Medicinal Chemistry, 16(25), 3267–3285.
Doyle, J. J., Neugut, A. I., Jacobson, J. S., Grann, V. R., & Hershman, D. L. (2005). Chemotherapy and cardiotoxicity in older breast cancer patients: A population-based study. Journal of Clinical Oncology, 23(34), 8597–8605.
Sorensen, K., Levitt, G. A., Bull, C., Dorup, I., & Sullivan, I. D. (2003). Late anthracycline cardiotoxicity after childhood cancer: A prospective longitudinal study. Cancer, 97(8), 1991–1998.
Lipshultz, S. E., Lipsitz, S. R., Sallan, S. E., Dalton, V. M., Mone, S. M., Gelber, R. D., & Colan, S. D. (2005). Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. Journal of Clinical Oncology, 23(12), 2629–2636.
Iarussi, D., Indolfi, P., Casale, F., Martino, V., Di Tullio, M. T., & Calabro, R. (2005). Anthracycline-induced cardiotoxicity in children with cancer: Strategies for prevention and management. Paediatric Drugs, 7(2), 67–76.
Lee, T. I., Chen, Y. C., Lin, Y. K., Chung, C. C., Lu, Y. Y., Kao, Y. H., & Chen, Y. J. (2019). Empagliflozin attenuates myocardial sodium and calcium dysregulation and reverses cardiac remodeling in streptozotocin-induced diabetic rats. International Journal of Molecular Sciences, 20(7), 1680.
Baartscheer, A., Schumacher, C. A., Wust, R. C., Fiolet, J. W., Stienen, G. J., Coronel, R., & Zuurbier, C. J. (2017). Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits. Diabetologia, 60(3), 568–573.
Hilmer, S. N., Cogger, V. C., Muller, M., & Le Couteur, D. G. (2004). The hepatic pharmacokinetics of doxorubicin and liposomal doxorubicin. Drug Metabolism and Disposition, 32(8), 794–799.
Tewey, K. M., Rowe, T. C., Yang, L., Halligan, B. D., & Liu, L. F. (1984). Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science, 226(4673), 466–468.
Lyu, Y. L., Lin, C. P., Azarova, A. M., Cai, L., Wang, J. C., & Liu, L. F. (2006). Role of topoisomerase IIbeta in the expression of developmentally regulated genes. Molecular and Cellular Biology, 26(21), 7929–7941.
Tsutsui, K., Tsutsui, K., Hosoya, O., Sano, K., & Tokunaga, A. (2001). Immunohistochemical analyses of DNA topoisomerase II isoforms in developing rat cerebellum. The Journal of Comparative Neurology, 431(2), 228–239.
Cui, N., Wu, F., Lu, W. J., Bai, R., Ke, B., Liu, T., Li, L., La, F., & Cui, M. (2019). Doxorubicin-induced cardiotoxicity is maturation dependent due to the shift from topoisomerase IIalpha to IIbeta in human stem cell derived cardiomyocytes. Journal of Cellular and Molecular Medicine, 23(7), 4627–4639.
Kalyanaraman, B. (2020). Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: Have we been barking up the wrong tree? Redox Biology, 29, 101394.
Vejpongsa, P., & Yeh, E. T. (2014). Topoisomerase 2beta: A promising molecular target for primary prevention of anthracycline-induced cardiotoxicity. Clinical Pharmacology and Therapeutics, 95(1), 45–52.
Riehle, C., & Abel, E. D. (2012). PGC-1 proteins and heart failure. Trends in Cardiovascular Medicine, 22(4), 98–105.
Yin, J., Guo, J., Zhang, Q., Cui, L., Zhang, L., Zhang, T., Zhao, J., Li, J., Middleton, A., Carmichael, P. L., & Peng, S. (2018). Doxorubicin-induced mitophagy and mitochondrial damage is associated with dysregulation of the PINK1/parkin pathway. Toxicology in Vitro, 51, 1–10.
Villeneuve, C., Guilbeau-Frugier, C., Sicard, P., Lairez, O., Ordener, C., Duparc, T., Paulis, D., Couderc, B., Spreux-Varoquaux, O., Tortosa, F., Garnier, A., Knauf, C., Valet, P., Borchi, E., Nediani, C., Gharib, A., Ovize, M., Delisle, M. B., Parini, A., & Mialet-Perez, J. (2013). p53-PGC-1alpha pathway mediates oxidative mitochondrial damage and cardiomyocyte necrosis induced by monoamine oxidase-A upregulation: Role in chronic left ventricular dysfunction in mice. Antioxidants & Redox Signaling, 18(1), 5–18.
Di, W., Lv, J., Jiang, S., Lu, C., Yang, Z., Ma, Z., Hu, W., Yang, Y., & Xu, B. (2018). PGC-1: The energetic regulator in cardiac metabolism. Current Issues in Molecular Biology, 28, 29–46.
Kirkham, A. A., & Davis, M. K. (2015). Exercise prevention of cardiovascular disease in breast cancer survivors. Journal of Oncology, 2015, 917606.
Russell, L. K., Mansfield, C. M., Lehman, J. J., Kovacs, A., Courtois, M., Saffitz, J. E., Medeiros, D. M., Valencik, M. L., McDonald, J. A., & Kelly, D. P. (2004). Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circulation Research, 94(4), 525–533.
Arai, M., Tomaru, K., Takizawa, T., Sekiguchi, K., Yokoyama, T., Suzuki, T., & Nagai, R. (1998). Sarcoplasmic reticulum genes are selectively down-regulated in cardiomyopathy produced by doxorubicin in rabbits. Journal of Molecular and Cellular Cardiology, 30(2), 243–254.
Barçin, C., Safali, M., Köse, S., Kurşaklioğlu, H., Eri̇nç, K., Işik, E., & Demi̇rtaş, E. (2001). Follow-up of corrected QT interval in the detection of doxorubicin cardiomyopathy: An experimental study. Turk Kardiyol Dern Ars, 29(6), 354–9.
Kalivendi, S. V., Konorev, E. A., Cunningham, S., Vanamala, S. K., Kaji, E. H., Joseph, J., & Kalyanaraman, B. (2005). Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: Role of mitochondrial reactive oxygen species and calcium. The Biochemical Journal, 389(Pt 2), 527–539.
Wenningmann, N., Knapp, M., Ande, A., Vaidya, T. R., & Ait-Oudhia, S. (2019). Insights into doxorubicin-induced cardiotoxicity: Molecular mechanisms, preventive strategies, and early monitoring. Molecular Pharmacology, 96(2), 219–232.
Llach, A., Mazevet, M., Mateo, P., Villejouvert, O., Ridoux, A., Rucker-Martin, C., Ribeiro, M., Fischmeister, R., Crozatier, B., Benitah, J. P., Morel, E., & Gómez, A. M. (2019). Progression of excitation-contraction coupling defects in doxorubicin cardiotoxicity. Journal of Molecular and Cellular Cardiology, 126, 129–139.
Baris, V. O., Dincsoy, B., Gedikli, E., & Erdemb, A. (2020). Empagliflozin significantly attenuates sotalol-induced QTc prolongation in rats. Kardiologia Polska, 79(1), 53–57.
Chang, W. T., Lin, Y. W., Ho, C. H., Chen, Z. C., Liu, P. Y., & Shih, J. Y. (2020). Dapagliflozin suppresses ER stress and protects doxorubicin-induced cardiotoxicity in breast cancer patients. Archives of Toxicology, 95(2), 659–671.
Dhingra, R., Margulets, V., Chowdhury, S. R., Thliveris, J., Jassal, D., Fernyhough, P., Gerald, W. D., & Kirshenbaum, A. L. (2014). Bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling. Proceedings of the National Academy of Sciences, 111(51), E5537–E5544.
Lebrecht, D., Kokkori, A., Ketelsen, U. P., Setzer, B., & Walker, U. A. (2005). Tissue-specific mtDNA lesions and radical-associated mitochondrial dysfunction in human hearts exposed to doxorubicin. The Journal of Pathology, 207(4), 436–444.
Muindi, J. R., Sinha, B. K., Gianni, L., & Myers, C. E. (1984). Hydroxyl radical production and DNA damage induced by anthracycline-iron complex. FEBS Letters, 172(2), 226–230.
Fang, X., Wang, H., Han, D., Xie, E., Yang, X., Wei, J., Gu, S., Gao, F., Zhu, N., Yin, X., Cheng, Q., Zhang, P., Dai, W., Chen, J., Yan, F., Yang, H. T., Linkermann, A., Gu, W., Min, J., & Wang, F. (2019). Ferroptosis as a target for protection against cardiomyopathy. Proceedings of the National Academy of Sciences, 116(7), 2672–2680.
Smith, R. A., Porteous, C. M., Gane, A. M., & Murphy, M. P. (2003). Delivery of bioactive molecules to mitochondria in vivo. Proceedings of the National Academy of Sciences, 100(9), 5407–5412.
Zhang, S., Liu, X., Bawa-Khalfe, T., Lu, L. S., Lyu, Y. L., Liu, L. F., & Yeh, E. T. H. (2012). Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nature Medicine, 18(11), 1639–1642.
Bures, J., Jirkovska, A., Sestak, V., Jansova, H., Karabanovich, G., Roh, J., Sterb, M., Simunek, T., & Kovarikova, P. (2017). Investigation of novel dexrazoxane analogue JR-311 shows significant cardioprotective effects through topoisomerase IIbeta but not its iron chelating metabolite. Toxicology, 392, 1–10.
Ichikawa, Y., Ghanefar, M., Bayeva, M., Wu, R., Khechaduri, A., Naga Prasad, S. V., Mutharasan, R. K., Naik, T. J., & Ardehali, H. (2014). Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. The Journal of Clinical Investigation, 124(2), 617–630.
Lopaschuk, G. D., & Verma, S. (2020). Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: A state-of-the-art review. JACC Basic to Translational Science, 5(6), 632–644.
Dodos, F., Halbsguth, T., Erdmann, E., & Hoppe, U. C. (2008). Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults. Clinical Research in Cardiology, 97(5), 318–326.
Ma, Y., Kang, W., Bao, Y., Jiao, F., & Ma, Y. (2013). Clinical significance of ischemia-modified albumin in the diagnosis of doxorubicin-induced myocardial injury in breast cancer patients. PLoS One, 8(11), e79426.
Acknowledgements
We thank Mustafa Kılıçkap and Meltem Tuncer for their constructive commentaries.
Funding
This work was supported by the Turkish Cardiovascular Academy society.
Author information
Authors and Affiliations
Contributions
VÖB analyzed and interpreted the data and wrote manuscript, ABD and EG performed animal trial, SZ and SM performed the histological examination of the heart, AE was a major contributor in writing the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflicts of interest.
Ethical Approval
This study was conducted after its approval at the Hacettepe University Faculty of Medicine Ethics Committee’s meeting (Date: 11.11.2019, No: 2019/12) (Decision No: 2015/12-07). Experimental studies were conducted in accordance with the Declaration of Helsinki and the Guide for the Care and Use of Laboratory Animals published by the American National Health Organization. This research involves only animal participants; therefore informed consent wasn’t needed.
Additional information
Handling Editor: Y. Robert Li.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Barış, V.Ö., Dinçsoy, A.B., Gedikli, E. et al. Empagliflozin Significantly Prevents the Doxorubicin-induced Acute Cardiotoxicity via Non-antioxidant Pathways. Cardiovasc Toxicol 21, 747–758 (2021). https://doi.org/10.1007/s12012-021-09665-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12012-021-09665-y