Impact of Dapagliflozin on Atherosclerosis through Inflammation and Oxidative Pathways

Zainab Abdlkadhim Aboshnin ^1*, Safa Azhar Razzaq ¹, Zahraa Ibraheim Jawad Shubber ²

Atherosclerotic patients need therapies targeting inflammation and oxidation. This study supports Dapagliflozin's use for clinical benefits in atherosclerosis.

Abstract

Background: Atherosclerosis is a prevalent pathological disorder considered a leading cause of death globally. The pathological process is characterized by fat deposition in the blood vessels, ultimately developing plaques. The atherosclerotic plaque was the final result of the inflammatory reaction and oxidative pathway. Dabagliflozine is a member of hypoglycemic drugs that are classified based on their action as Na-glucose co-transporter 2 inhibitors. Dabagliflozine, besides its blood glucose-lowering effects, may also exhibit cardiovascular protection by reducing oxidative damage. Our research aimed to evaluate how the drug (dabagliflozine) interacted with inflammation and oxidative processes to impact atherosclerosis. Materials and Methods: In this study, eighteen male mice were split into three groups: one fed a regular diet, one fed a cholesterol-rich diet, and one fed a cholesterol-rich diet with dapagliflozin. Blood samples were taken regularly over twelve weeks to analyze serum markers such as TNF-α, endothelin-1, and lipid levels. Results: Initially, there were no significant differences in serum markers among the groups. However, after twelve weeks, the mice treated with dapagliflozin showed notable reductions in TNF-α and endothelin-1 levels (though statistically insignificant). Moreover, there were significant improvements in HDL (the "good" cholesterol) levels, and significant decreases in VLDL and TG (triglycerides) levels (P<0.05). Total cholesterol (TC) and LDL (the "bad" cholesterol) levels also decreased, although not significantly. Conclusion: In conclusion, dapagliflozin demonstrated promising protective effects against atherosclerosis in mice by regulating inflammatory cytokine production and improving lipid profiles. These findings suggest that dapagliflozin may have potential therapeutic benefits in managing cardiovascular disease by targeting both inflammation and lipid metabolism. However, further research is needed to validate these results and explore the drug's effectiveness in humans.

Keywords:  Atherosclerosis, Inflammatory response, Cardiovascular damage, Dabagliflozine.

References

Abd-Ulhussein, H. K., & Rizij, F. A. J. (2019). Evaluation of the effect of dapagliflozin on atherosclerosis progression by interfering with inflammatory and oxidative stress pathways in rabbits. Medical Journal of Babylon, 16(1), 21.

Becker, L., Prado, K., Foppa, M., Martinelli, N., Aguiar, C., Furian, T., ... & Rohde, L. E. (2012). Endothelial dysfunction assessed by brachial artery ultrasound in severe sepsis and septic shock. Journal of critical care, 27(3), 316-e9.

Brauner, J. S., Rohde, L. E., & Clausell, N. (2000). Circulating endothelin-1 and tumor necrosis factor-α: early predictors of mortality in patients with septic shock. Intensive care medicine, 26, 305-313.

Cannon, C. P., Perkovic, V., Agarwal, R., Baldassarre, J., Bakris, G., Charytan, D. M., ... & Mahaffey, K. W. (2020). Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease according to baseline HbA1c, including those with HbA1c< 7% results from the CREDENCE trial. Circulation, 141(5), 407-410.

Chai, M., Ji, Q., Zhang, H., Zhou, Y., Yang, Q., Zhou, Y., ... & Zhao, Y. (2015). The protective effect of interleukin-37 on vascular calcification and atherosclerosis in apolipoprotein E-deficient mice with diabetes. Journal of Interferon & Cytokine Research, 35(7), 530-539.

Choy, E. H., & Panayi, G. S. (2001). Cytokine pathways and joint inflammation in rheumatoid arthritis. New England Journal of Medicine, 344(12), 907-916.

Feijóo-Bandín, S., Aragón-Herrera, A., Otero-Santiago, M., Anido-Varela, L., Moraña-Fernández, S., Tarazón, E., ... & Lago, F. (2022). Role of sodium-glucose co-transporter 2 inhibitors in the regulation of inflammatory processes in animal models. International Journal of Molecular Sciences, 23(10), 5634.

Freeman, B. D., Machado, F. S., Tanowitz, H. B., & Desruisseaux, M. S. (2014). Endothelin-1 and its role in the pathogenesis of infectious diseases. Life sciences, 118(2), 110-119.

Frostegård, J. (2013). Immunity, atherosclerosis and cardiovascular disease. BMC medicine, 11(1), 1-13.

Gao, W., Liu, H., Yuan, J., Wu, C., Huang, D., Ma, Y., ... & Ge, J. (2016). Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF-α mediated NF-κB pathway. Journal of cellular and molecular medicine, 20(12), 2318-2327.

George, J., Afek, A., Gilburd, B., Blank, M., Levy, Y., Aron-Maor, A., ... & Shoenfeld, Y. (1998). Induction of early atherosclerosis in LDL-receptor–deficient mice immunized with β2-glycoprotein I. Circulation, 98(11), 1108-1115.

Hansson, G. K. (2001). Immune mechanisms in atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology, 21(12), 1876-1890.

Hedin, U., & Matic, L. P. (2019). Recent advances in therapeutic targeting of inflammation in atherosclerosis. Journal of vascular surgery, 69(3), 944-951.

Heerspink, H. J., Stefánsson, B. V., Correa-Rotter, R., Chertow, G. M., Greene, T., Hou, F. F., ... & Wheeler, D. C. (2020). Dapagliflozin in patients with chronic kidney disease. New England Journal of Medicine, 383(15), 1436-1446.

Hetherington, I., & Totary-Jain, H. (2022). Anti-atherosclerotic therapies: milestones, challenges, and emerging innovations. Molecular Therapy, 30(10), 3106-3117.

Hsia, D. S., Grove, O., & Cefalu, W. T. (2017). An update on SGLT2 inhibitors for the treatment of diabetes mellitus. Current opinion in endocrinology, diabetes, and obesity, 24(1), 73.

Leng, W., Ouyang, X., Lei, X., Wu, M., Chen, L., Wu, Q., ... & Liang, Z. (2016). The SGLT-2 inhibitor dapagliflozin has a therapeutic effect on atherosclerosis in diabetic ApoE−/− mice. Mediators of inflammation, 2016.

 Lindstrom, N. M., Moore, D. M., Zimmerman, K., & Smith, S. A. (2015). Hematologic assessment in pet rats, mice, hamsters, and gerbils: blood sample collection and blood cell identification. Clinics in Laboratory Medicine, 35(3), 629-640.

Liu, Z., Ma, X., Ilyas, I., Zheng, X., Luo, S., Little, P. J., ... & Xu, S. (2021). Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics. Theranostics, 11(9), 4502.

Marzolla, V., Armani, A., Mammi, C., Feraco, A., & Caprio, M. (2018). Induction of atherosclerotic plaques through activation of mineralocorticoid receptors in apolipoprotein E-deficient mice. JoVE (Journal of Visualized Experiments), (139), e58303.

McKenna, S., Gossling, M., Bugarini, A., Hill, E., Anderson, A. L., Rancourt, R. C., ... & Wright, C. J. (2015). Endotoxemia induces IκBβ/NF-κB–Dependent Endothelin-1 expression in hepatic macrophages. The Journal of Immunology, 195(8), 3866-3879.

Narula, J., Nakano, M., Virmani, R., Kolodgie, F. D., Petersen, R., Newcomb, R., ... & Finn, A. V. (2013). Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. Journal of the American College of Cardiology, 61(10), 1041-1051.

Pober, J. S., & Sessa, W. C. (2007). Evolving functions of endothelial cells in inflammation. Nature Reviews Immunology, 7(10), 803-815.

Probert, L. (2015). TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects. Neuroscience, 302, 2-22.

Resl, M., & Clodi, M. (2010). Diabetes and cardiovascular complications: Epidemiologie zur Morbidität und Mortalität. Wiener Medizinische Wochenschrift, 160, 3-7.

Stiekema, L. C., Willemsen, L., Kaiser, Y., Prange, K. H., Wareham, N. J., Boekholdt, S. M., ... & Kroon, J. (2021). Impact of cholesterol on proinflammatory monocyte production by the bone marrow. European Heart Journal, 42(42), 4309-4320.

Sugiyama, T., Yamamoto, E., Bryniarski, K., Xing, L., Fracassi, F., Lee, H., & Jang, I. K. (2018). Coronary plaque characteristics in patients with diabetes mellitus who presented with acute coronary syndromes. Journal of the American Heart Association, 7(14), e009245.

Sun, L., Zhang, W., Zhao, Y., Wang, F., Liu, S., Liu, L., ... & Xu, Y. (2020). Dendritic cells and T cells, partners in atherogenesis and the translating road ahead. Frontiers in immunology, 11, 1456.

‏‏Tanajak, P., Sa-Nguanmoo, P., Sivasinprasasn, S., Thummasorn, S., Siri-Angkul, N., Chattipakorn, S. C., & Chattipakorn, N. (2018). Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury. Journal of Endocrinology, 236(2), 69-84.

Weber, M. A., Mansfield, T. A., Cain, V. A., Iqbal, N., Parikh, S., & Ptaszynska, A. (2016). Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. The lancet Diabetes & endocrinology, 4(3), 211-220.

Yeoh, S. E., Docherty, K. F., Campbell, R. T., Jhund, P. S., Hammarstedt, A., Heerspink, H. J., ... & McMurray, J. J. (2023). Endothelin-1, Outcomes in Patients With Heart Failure and Reduced Ejection Fraction, and Effects of Dapagliflozin: Findings From DAPA-HF. Circulation, 147(22), 1670-1683.

Zhu, J., Liu, B., Wang, Z., Wang, D., Ni, H., Zhang, L., & Wang, Y. (2019). Exosomes from nicotine-stimulated macrophages accelerate atherosclerosis through miR-21-3p/PTEN-mediated VSMC migration and proliferation. Theranostics, 9(23), 6901.

Zhu, Y., Xian, X., Wang, Z., Bi, Y., Chen, Q., Han, X., ... & Chen, R. (2018). Research progress on the relationship between atherosclerosis and inflammation. Biomolecules, 8(3), 80.