Dapagliflozin improves diabetic cardiomyopathy by suppressing the STAT3-YY1 signaling axis in cardiac fibroblasts

Document Type : Original Article

Authors

1 Department of Cardiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, China

2 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

10.22038/ijbms.2025.87173.18843

Abstract

Objective(s): Cardiac fibroblast (CF) proliferation and activation drive cardiac fibrosis and heart failure. Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, ameliorates diabetic cardiomyopathy (DCM). We investigated whether DAPA exerts anti-fibrotic and cardioprotective effects on DCM by directly suppressing CF proliferation and activation independent of SGLT2 inhibition. 
Materials and Methods: CFs were isolated from mouse hearts. Mouse cardiac function and fibrosis were investigated using histological analysis, western blotting, and echocardiography. Additionally, genetic loss-of-function studies were conducted in vitro by small interfering RNA silencing and in vivo by lentivirus-mediated gene knockdown. 
Results: Compared with high-glucose-treated neonatal rat CFs, genetic loss-of-function of signal transducer and activator of transcription 3 (STAT3) or pretreatment with DAPA dramatically inhibited STAT3 phosphorylation and Yin Yang 1 (YY1) nuclear translocation, alleviated CF proliferation and activation, and reduced fibrosis. In diabetic db/db mice, administration of DAPA remarkably ameliorated diabetes-induced STAT3 activation, YY1 nuclear translocation, CF proliferation and activation, and reduced cardiac fibrosis and dysfunction. These in vitro and in vivo effects of DAPA were ameliorated by colivelin TFA, a potent activator of STAT3. Intriguingly, knockdown of SGLT2 did not have an inhibitory effect on CF proliferation and activation in db/db mice. 
Conclusion: DAPA reduces cardiac fibrosis and DCM. This may, at least in part, be attributable to the repression of the STAT3-YY1 signaling axis-mediated CF proliferation and activation, independent of SGLT2 inhibition. 

Keywords

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References

1. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci  2014; 71: 549-574.
2. Frangogiannis NG. Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Aspects Med 2019; 65: 70-99.
3. Souders CA, Bowers SLK, Baudino TA. Cardiac fibroblast: The renaissance cell. Circ Res 2009; 105: 1164-1176.
4. Piccoli MT, Gupta SK, Viereck J, Foinquinos A, Samolovac S, Kramer FL, et al. Inhibition of the cardiac fibroblast-enriched lncRNA Meg3 prevents cardiac fibrosis and diastolic dysfunction. Circ Res 2017; 121: 575-583.
5. Roubille F, Busseuil D, Merlet N, Kritikou EA, Rheaume E, Tardif JC. Investigational drugs targeting cardiac fibrosis. Expert Rev Cardiovas 2014; 12: 111-125.
6. Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: An update of mechanisms contributing to this clinical entity. Circ Res 2018; 122: 624-638.
7. Gordon S, Akopyan G, Garban H, Bonavida B. Transcription factor YY1: Structure, function, and therapeutic implications in cancer biology. Oncogene 2006; 25: 1125-1142.
8. Asensio-Lopez MC, Lax A, Fernandez del Palacio MJ, Sassi Y, Hajjar RJ, Januzzi JL, et al. Yin-Yang 1 transcription factor modulates ST2 expression during adverse cardiac remodeling post-myocardial infarction. J Mol Cell Cardiol 2019; 130: 216-233.
9. Yang T, Shu F, Yang H, Heng C, Zhou Y, Chen Y, et al. YY1: A novel therapeutic target for diabetic nephropathy orchestrated renal fibrosis. Metabolism 2019; 96: 33-45.
10. Bonavida B, Kaufhold S. Prognostic significance of YY1 protein expression and mRNA levels by bioinformatics analysis in human cancers: A therapeutic target. Pharmacol Therapeut 2015; 150: 149-168.
11. Lin X, Sime PJ, Xu H, Williams MA, LaRussa L, Georas SN, et al. Yin yang 1 is a novel regulator of pulmonary fibrosis. Am J Resp Crit Care 2011; 183: 1689-1697.
12. Liu X, Song X, Lu J, Chen X, Liang E, Liu X, et al. Neferine inhibits proliferation and collagen synthesis induced by high glucose in cardiac fibroblasts and reduces cardiac fibrosis in diabetic mice. Oncotarget 2016; 7: 61703-61715.
13. Harhous Z, Booz GW, Ovize M, Bidaux G, Kurdi M. An update on the multifaceted roles of STAT3 in the Heart. Front Cardiovasc Med 2019; 6: 150-168.
14. Dai B, Cui M, Zhu M, Su WL, Qiu MC, Zhang H. STAT1/3 and ERK1/2 synergistically regulate cardiac fibrosis induced by high glucose. Cell Physiol Biochem 2013; 32: 960-971.
15. Kwon JE, Lee SY, Seo HB, Moon YM, Ryu JG, Jung KA, et al. YinYang1 deficiency ameliorates joint inflammation in a murine model of rheumatoid arthritis by modulating Th17 cell activation. Immunol Lett 2018; 197: 63-69.
16. Kosasih FR, Bonavida B. Involvement of Yin Yang 1 (YY1) expression in T-cell subsets differentiation and their functions: Implications in T cell-mediated diseases. Crit Rev Immunol 2019; 39: 491-510.
17. Sun M, Sun Y, Ma J, Li K. YY1 promotes SOCS3 expression to inhibit STAT3-mediated neuroinflammation and neuropathic pain. Mol Med Rep 2021; 23: 103.
18. Arow M, Waldman M, Yadin D, Nudelman V, Shainberg A, Abraham NG, et al. Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy. Cardiovasc Diabetol 2020; 19: 7-19.
19. 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 Radical Bio Med 2017; 104: 298-310.
20. Xie H, Shen XY, Zhao N, Ye P, Ge Z, Hu ZY. Ivabradine ameliorates cardiac diastolic dysfunction in diabetic mice independent of heart rate reduction. Front Pharmacol 2021; 12: 696635-696649.
21. Jin XP, Ren YF, Wang LG, Xie H, Huang L, Zhang J, et al. Pim3 up-regulation by YY1 contributes to diabetes-induced cardiac hypertrophy and heart failure. Iran J Basic Med Sci 2025; 28: 245-253.
22. Moore A, Shindikar A, Fomison-Nurse I, Riu F, Munasinghe PE, Ram TP, et al. Rapid onset of cardiomyopathy in STZ-induced female diabetic mice involves the downregulation of pro-survival Pim-1. Cardiovasc Diabetol 2014; 13: 68-80.
23. Chandramouli C, Reichelt ME, Curl CL, Varma U, Bienvenu LA, Koutsifeli P, et al. Diastolic dysfunction is more apparent in STZ-induced diabetic female mice, despite less pronounced hyperglycemia. Sci Rep 2018; 8: 2346-2359.
24. Cappetta D, De Angelis A, Ciuffreda LP, Coppini R, Cozzolino A, Micciche A, et al. Amelioration of diastolic dysfunction by dapagliflozin in a non-diabetic model involves coronary endothelium. Pharmacol Res 2020; 157: 104781.
25. Zuo GF, Wang LG, Huang L, Ren YF, Ge Z, Hu ZY, et al. TAX1BP1 downregulation by STAT3 in cardiac fibroblasts contributes to diabetes-induced heart failure with preserved ejection fraction. Biochim Biophys Acta Mol Basis Dis 2024; 1870: 166979-166996.
26. Alex L, Russo I, Holoborodko V, Frangogiannis NG. Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction. Am J Physiol-Heart C 2018; 315: H934-H949.
27. Dillmann WH. Diabetic cardiomyopathy what is it and can it be fixed? Circ Res 2019; 124: 1160-1162.
28. Ma ZG, Yuan YP, Xu SC, Wei WY, Xu CR, Zhang X, et al. CTRP3 attenuates cardiac dysfunction, inflammation, oxidative stress and cell death in diabetic cardiomyopathy in rats. Diabetologia 2017; 60: 1126-1137.
29. Satou R, Cypress MW, Woods TC, Katsurada A, Dugas CM, Fonseca VA, et al. Blockade of sodium-glucose cotransporter 2 suppresses high glucose-induced angiotensinogen augmentation in renal proximal tubular cells. Am J Physiol-Renal 2020; 318: F67-F75.
30. Xu Y, Rong J, Zhang Z. The emerging role of angiotensinogen in cardiovascular diseases. J Cell Physiol 2021; 236: 68-78.
31. Starcevic JN, Janic M, Sabovic M. Molecular mechanisms responsible for diastolic dysfunction in diabetes mellitus patients. Int J Mol Sci 2019; 20: 1197-1219.
32. Bansal T, Chatterjee E, Singh J, Ray A, Kundu B, Thankamani V, et al. Arjunolic acid, a peroxisome proliferator-activated receptor α agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-β signaling. J Biol Chem 2017; 292: 16440-16462.
33. 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: 3770-3783.
34. Hübschle T, Thom E, Watson A, Roth J, Klaus S, Meyerhof W. Leptin-induced nuclear translocation of STAT3 immunoreactivity in hypothalamic nuclei involved in body weight regulation. J Neurosci 2001; 21: 2413-2424.
35. Thorn SR, Giesy SL, Myers MG, Jr., Boisclair YR. Mammary ductal growth is impaired in mice lacking leptin-dependent signal transducer and activator of transcription 3 signaling. Endocrinology 2010; 151: 3985-3995.
36. Gamber KM, Huo L, Ha S, Hairston JE, Greeley S, Bjorbaek C. Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity. PLoS One 2012; 7: e30485-30499.
37. Gao Q, Wolfgang MJ, Neschen S, Morino K, Horvath TL, Shulman GI, et al. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. P Natl Acad Sci Usa 2004; 101: 4661-4666.
38. Chiba T, Yamada M, Hashimoto Y, Sato M, Sasabe J, Kita Y, et al. Development of a femtomolar-acting humanin derivative named colivelin by attaching activity-dependent neurotrophic factor to its N terminus: Characterization of colivelin-mediated neuroprotection against Alzheimer’s disease-relevant insults in vitro and in vivo. J Neurosci 2005; 25: 10252-10261.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 11
November 2025
Pages 1563-1574

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