Skip to main content

Advertisement

SpringerLink
Log in

Effects of Dapagliflozin on Myocardial Gene Expression in BTBR Mice with Type 2 Diabetes

  • Original Article
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Background

Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is approved for the treatment of type 2 diabetes, heart failure, and chronic kidney disease. DAPA-HF and DELIVER trial results demonstrate that the cardiovascular protective effect of dapagliflozin extends to non-diabetic patients. Hence, the mechanism-of-action may extend beyond glucose-lowering and is not completely elucidated. We have previously shown that dapagliflozin reduces cardiac hypertrophy, inflammation, fibrosis, and apoptosis and increases ejection fraction in BTBR mice with type 2 diabetes.

Methods

We conducted a follow-up RNA-sequencing study on the heart tissue of these animals and performed differential expression and Ingenuity Pathway analysis. Selected markers were confirmed by RT-PCR and Western blot.

Results

SGLT2 had negligible expression in heart tissue. Dapagliflozin improved cardiac metabolism by decreasing glycolysis and pyruvate utilization enzymes, induced antioxidant enzymes, and decreased expression of hypoxia markers. Expression of inflammation, apoptosis, and hypertrophy pathways was decreased. These observations corresponded to the effects of dapagliflozin in the clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

RNA-sequencing read counts and differential expression results (Supplementary Table 1), IPA pathway analysis results without p-value cut-off (Supplementary Table 2), and z-score transformed expression values for Fig. 2 (Supplementary Table 3) are enclosed with this article. Raw FASTQ files could not be recovered.

References

  1. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57. https://doi.org/10.1056/NEJMoa1812389.

    Article  CAS  PubMed  Google Scholar 

  2. Cefalu WT, Kaul S, Gerstein HC, et al. Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? Reflections from a diabetes care editors' expert forum. Diabetes Care. 2018;41(1):14–31. https://doi.org/10.2337/dci17-0057.

    Article  CAS  PubMed  Google Scholar 

  3. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008. https://doi.org/10.1056/NEJMoa1911303.

    Article  CAS  PubMed  Google Scholar 

  4. Inzucchi SE, Claggett BL, Vaduganathan M, et al. Efficacy and safety of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction by baseline glycaemic status (DELIVER): a subgroup analysis from an international, multicentre, double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2022;10(12):869–81. https://doi.org/10.1016/S2213-8587(22)00308-4.

    Article  CAS  PubMed  Google Scholar 

  5. Joubert M, Jagu B, Montaigne D, et al. The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. Diabetes. 2017;66(4):1030–40. https://doi.org/10.2337/db16-0733.

    Article  CAS  PubMed  Google Scholar 

  6. Arow M, Waldman M, Yadin D, et al. Sodium-glucose cotransporter 2 inhibitor dapagliflozin attenuates diabetic cardiomyopathy. Cardiovasc Diabetol. 2020;19(1):7. https://doi.org/10.1186/s12933-019-0980-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Saleh S, Hanna G, El-Nabi SH, et al. Dapagliflozin, a sodium glucose cotransporter 2 inhibitors, protects cardiovascular function in type-2 diabetic murine model. J Genet. 2020;99:1–8. https://doi.org/10.1007/s12041-020-01196-9.

    Article  CAS  Google Scholar 

  8. Olgar Y, Turan B. A sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin comparison with insulin shows important effects on Zn(2+)-transporters in cardiomyocytes from insulin-resistant metabolic syndrome rats through inhibition of oxidative stress. Can J Physiol Pharmacol. 2019;97(6):528–35. https://doi.org/10.1139/cjpp-2018-0466.

    Article  CAS  PubMed  Google Scholar 

  9. Shi L, Zhu D, Wang S, Jiang A, Li F. Dapagliflozin attenuates cardiac remodeling in mice model of cardiac pressure overload. Am J Hypertens. 2019;32(5):452–9. https://doi.org/10.1093/ajh/hpz016.

    Article  CAS  PubMed  Google Scholar 

  10. Ye Y, Bajaj M, Yang HC, Perez-Polo JR, 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):119–32. https://doi.org/10.1007/s10557-017-6725-2.

    Article  CAS  PubMed  Google Scholar 

  11. Chen H, Tran D, Yang HC, et al. Dapagliflozin and ticagrelor have additive effects on the attenuation of the activation of the NLRP3 inflammasome and the progression of diabetic cardiomyopathy: an AMPK-mTOR interplay. Cardiovasc Drugs Ther. 2020;34(4):443–61. https://doi.org/10.1007/s10557-020-06978-y.

    Article  CAS  PubMed  Google Scholar 

  12. Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21. https://doi.org/10.1093/bioinformatics/bts635.

    Article  CAS  PubMed  Google Scholar 

  13. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. https://doi.org/10.1186/s13059-014-0550-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer; 2016.

    Book  Google Scholar 

  15. Mak TW, Hauck L, Grothe D, Billia F. p53 regulates the cardiac transcriptome. Proc Natl Acad Sci USA. 2017;114(9):2331–6. https://doi.org/10.1073/pnas.1621436114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Croteau D, Luptak I, Chambers JM, et al. Effects of sodium-glucose linked transporter 2 inhibition with ertugliflozin on mitochondrial function, energetics, and metabolic gene expression in the presence and absence of diabetes mellitus in mice. J Am Heart Assoc. 2021;10(13):e019995. https://doi.org/10.1161/JAHA.120.019995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang S, Liu H, Amarsingh GV, et al. Diabetic cardiomyopathy is associated with defective myocellular copper regulation and both defects are rectified by divalent copper chelation. Cardiovasc Diabetol. 2014;13:100. https://doi.org/10.1186/1475-2840-13-100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Uthman L, Kuschma M, Romer G, et al. Novel anti-inflammatory effects of canagliflozin involving hexokinase II in lipopolysaccharide-stimulated human coronary artery endothelial cells. Cardiovasc Drugs Ther. 2021;35(6):1083–94. https://doi.org/10.1007/s10557-020-07083-w.

    Article  CAS  PubMed  Google Scholar 

  19. Nair V, Schaub J, Alakwaa F, et al. WCN23-0761 SGLT2 inhibitor treatment may enhance kidney oxygenation and attenuate HIF1a expression in young persons with type 2 diabetes. Kindney Int Rep. 2023;8(3):S197–S8. https://doi.org/10.1016/j.ekir.2023.02.439.

    Article  Google Scholar 

  20. Nagatomo Y, Meguro T, Ito H, et al. Significance of AT1 receptor independent activation of mineralocorticoid receptor in murine diabetic cardiomyopathy. PLoS One. 2014;9(3):e93145. https://doi.org/10.1371/journal.pone.0093145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chao PC, Hsu CC, Yin MC. Anti-inflammatory and anti-coagulatory activities of caffeic acid and ellagic acid in cardiac tissue of diabetic mice. Nutr Metab (Lond). 2009;6:33. https://doi.org/10.1186/1743-7075-6-33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mushtaq I, Bashir Z, Sarwar M, et al. N-acetyl cysteine, selenium, and ascorbic acid rescue diabetic cardiac hypertrophy via mitochondrial-associated redox regulators. Molecules. 2021;26(23) https://doi.org/10.3390/molecules26237285.

  23. Kain V, Kumar S, Sitasawad SL. Azelnidipine prevents cardiac dysfunction in streptozotocin-diabetic rats by reducing intracellular calcium accumulation, oxidative stress and apoptosis. Cardiovasc Diabetol. 2011;10:97. https://doi.org/10.1186/1475-2840-10-97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ding W, Chang WG, Guo XC, et al. Exenatide protects against cardiac dysfunction by attenuating oxidative stress in the diabetic mouse heart. Front Endocrinol (Lausanne). 2019;10:202. https://doi.org/10.3389/fendo.2019.00202.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cotrin JC, de Souza GSM, Petito-da-Silva TI, et al. Empagliflozin alleviates left ventricle hypertrophy in high-fat-fed mice by modulating renin angiotensin pathway. J Renin Angiotensin Aldosterone Syst. 2022;2022:8861911. https://doi.org/10.1155/2022/8861911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Oshima H, Miki T, Kuno A, et al. Empagliflozin, an SGLT2 inhibitor, reduced the mortality rate after acute myocardial infarction with modification of cardiac metabolomes and antioxidants in diabetic rats. J Pharmacol Exp Ther. 2019;368(3):524–34. https://doi.org/10.1124/jpet.118.253666.

    Article  CAS  PubMed  Google Scholar 

  27. Nabrdalik-Lesniak D, Nabrdalik K, Sedlaczek K, et al. Influence of SGLT2 inhibitor treatment on urine antioxidant status in type 2 diabetic patients: a pilot study. Oxid Med Cell Longev. 2021;2021:5593589. https://doi.org/10.1155/2021/5593589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xue W, Liu Y, Zhao J, et al. Activation of HIF-1 by metallothionein contributes to cardiac protection in the diabetic heart. Am J Physiol Heart Circ Physiol. 2012;302(12):H2528–35. https://doi.org/10.1152/ajpheart.00850.2011.

    Article  CAS  PubMed  Google Scholar 

  29. Kim S, Jo CH, Kim GH. Effects of empagliflozin on nondiabetic salt-sensitive hypertension in uninephrectomized rats. Hypertens Res. 2019;42(12):1905–15. https://doi.org/10.1038/s41440-019-0326-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bessho R, Takiyama Y, Takiyama T, et al. Hypoxia-inducible factor-1alpha is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy. Sci Rep. 2019;9(1):14754. https://doi.org/10.1038/s41598-019-51343-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ghanim H, Abuaysheh S, Hejna J, et al. Dapagliflozin suppresses hepcidin and increases erythropoiesis. J Clin Endocrinol Metab. 2020;105(4) https://doi.org/10.1210/clinem/dgaa057.

  32. Peake BF, Nicholson CK, Lambert JP, et al. Hydrogen sulfide preconditions the db/db diabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner. Am J Physiol Heart Circ Physiol. 2013;304(9):H1215–24. https://doi.org/10.1152/ajpheart.00796.2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li C, Zhang J, Xue M, et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol. 2019;18(1):15. https://doi.org/10.1186/s12933-019-0816-2.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Xia Y, Gong L, Liu H, et al. Inhibition of prolyl hydroxylase 3 ameliorates cardiac dysfunction in diabetic cardiomyopathy. Mol Cell Endocrinol. 2015;403:21–9. https://doi.org/10.1016/j.mce.2015.01.014.

    Article  CAS  PubMed  Google Scholar 

  35. Han B, Baliga R, Huang H, Giannone PJ, Bauer JA. Decreased cardiac expression of vascular endothelial growth factor and redox imbalance in murine diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol. 2009;297(2):H829–35. https://doi.org/10.1152/ajpheart.00222.2009.

    Article  CAS  PubMed  Google Scholar 

  36. Gui C, Zeng ZY, Chen Q, et al. Neuregulin-1 promotes myocardial angiogenesis in the rat model of diabetic cardiomyopathy. Cell Physiol Biochem. 2018;46(6):2325–34. https://doi.org/10.1159/000489622.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang WY, Wang J, Li AZ. A study of the effects of SGLT-2 inhibitors on diabetic cardiomyopathy through miR-30d/KLF9/VEGFA pathway. Eur Rev Med Pharmacol Sci. 2020;24(11):6346–59. https://doi.org/10.26355/eurrev_202006_21533.

    Article  PubMed  Google Scholar 

  38. Wang M, Lv Q, Zhao L, et al. Metoprolol and bisoprolol ameliorate hypertrophy of neonatal rat cardiomyocytes induced by high glucose via the PKC/NF-kappaB/c-fos signaling pathway. Exp Ther Med. 2020;19(2):871–82. https://doi.org/10.3892/etm.2019.8312.

    Article  PubMed  Google Scholar 

  39. Nguyen T, Wen S, Gong M, et al. Dapagliflozin activates neurons in the central nervous system and regulates cardiovascular activity by inhibiting SGLT-2 in mice. Diabetes Metab Syndr Obes. 2020;13:2781–99. https://doi.org/10.2147/DMSO.S258593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Raut SK, Singh GB, Rastogi B, et al. miR-30c and miR-181a synergistically modulate p53-p21 pathway in diabetes induced cardiac hypertrophy. Mol Cell Biochem. 2016;417(1-2):191–203. https://doi.org/10.1007/s11010-016-2729-7.

    Article  CAS  PubMed  Google Scholar 

  41. Cheng Y, Li J, Wang C, et al. Inhibition of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 attenuates high glucose-induced cardiomyocyte apoptosis via regulation of miR-181a-5p. Exp Anim. 2020;69(1):34–44. https://doi.org/10.1538/expanim.19-0058.

    Article  CAS  PubMed  Google Scholar 

  42. Kim MN, Moon JH, Cho YM. Sodium-glucose cotransporter-2 inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body-induced NRF2 activation. Diabetes Obes Metab. 2021;23(11):2561–71. https://doi.org/10.1111/dom.14503.

    Article  CAS  PubMed  Google Scholar 

  43. Park SH, Farooq MA, Gaertner S, et al. Empagliflozin improved systolic blood pressure, endothelial dysfunction and heart remodeling in the metabolic syndrome ZSF1 rat. Cardiovasc Diabetol. 2020;19(1):19. https://doi.org/10.1186/s12933-020-00997-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Van Linthout S, Seeland U, Riad A, et al. Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol. 2008;103(4):319–27. https://doi.org/10.1007/s00395-008-0715-2.

    Article  CAS  PubMed  Google Scholar 

  45. Wang SQ, Li D, Yuan Y. Long-term moderate intensity exercise alleviates myocardial fibrosis in type 2 diabetic rats via inhibitions of oxidative stress and TGF-beta1/Smad pathway. J Physiol Sci. 2019;69(6):861–73. https://doi.org/10.1007/s12576-019-00696-3.

    Article  CAS  PubMed  Google Scholar 

  46. Talior-Volodarsky I, Connelly KA, Arora PD, Gullberg D, McCulloch CA. alpha11 integrin stimulates myofibroblast differentiation in diabetic cardiomyopathy. Cardiovasc Res. 2012;96(2):265–75. https://doi.org/10.1093/cvr/cvs259.

    Article  CAS  PubMed  Google Scholar 

  47. Pan X, Phanish MK, Baines DL, Dockrell MEC. High glucose-induced Smad3 linker phosphorylation and CCN2 expression are inhibited by dapagliflozin in a diabetic tubule epithelial cell model. Biosci Rep. 2021;41(6) https://doi.org/10.1042/BSR20203947.

  48. Xiao T, Zeng O, Luo J, et al. Effects of hydrogen sulfide on myocardial fibrosis in diabetic rats: changes in matrix metalloproteinases parameters. Biomed Mater Eng. 2015;26(Suppl 1):S2033–9. https://doi.org/10.3233/BME-151508.

    Article  CAS  PubMed  Google Scholar 

  49. Dede E, Liapis D, Davos C, et al. The effects of exercise training on cardiac matrix metalloproteinases activity and cardiac function in mice with diabetic cardiomyopathy. Biochem Biophys Res Commun. 2022;586:8–13. https://doi.org/10.1016/j.bbrc.2021.11.013.

    Article  CAS  PubMed  Google Scholar 

  50. Dawood AF, Alzamil NM, Hewett PW, et al. Metformin protects against diabetic cardiomyopathy: an association between Desmin-Sarcomere injury and the iNOS/mTOR/TIMP-1 fibrosis axis. Biomedicines. 2022;10(5) https://doi.org/10.3390/biomedicines10050984.

  51. Meng L, Uzui H, Guo H, Tada H. Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts. Mol Med Rep. 2018;17(5):6887–92. https://doi.org/10.3892/mmr.2018.8688.

    Article  CAS  PubMed  Google Scholar 

  52. Li W, Lou X, Zha Y, et al. Single-cell RNA-seq of heart reveals intercellular communication drivers of myocardial fibrosis in diabetic cardiomyopathy. Elife. 2023:12. https://doi.org/10.7554/eLife.80479.

  53. Saucedo-Orozco H, Voorrips SN, Yurista SR, de Boer RA, Westenbrink BD. SGLT2 Inhibitors and ketone metabolism in heart failure. J Lipid Atheroscler. 2022;11(1):1–19. https://doi.org/10.12997/jla.2022.11.1.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen S, Coronel R, Hollmann MW, Weber NC, Zuurbier CJ. Direct cardiac effects of SGLT2 inhibitors. Cardiovasc Diabetol. 2022;21(1):45. https://doi.org/10.1186/s12933-022-01480-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Da Silva D, Ausina P, Alencar EM, et al. Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice. IUBMB Life. 2012;64(9):766–74. https://doi.org/10.1002/iub.1063.

    Article  CAS  PubMed  Google Scholar 

  56. Sousa Fialho MDL, Purnama U, Dennis K, et al. Activation of HIF1alpha rescues the hypoxic response and reverses metabolic dysfunction in the diabetic heart. Diabetes. 2021;70(11):2518–31. https://doi.org/10.2337/db21-0398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Byrne NJ, Rajasekaran NS, Abel ED, Bugger H. Therapeutic potential of targeting oxidative stress in diabetic cardiomyopathy. Free Radic Biol Med. 2021;169:317–42. https://doi.org/10.1016/j.freeradbiomed.2021.03.046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sha W, Hu F, Xi Y, Chu Y, Bu S. Mechanism of ferroptosis and its role in type 2 diabetes mellitus. J Diabetes Res. 2021;2021:9999612. https://doi.org/10.1155/2021/9999612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Katunga LA, Gudimella P, Efird JT, et al. Obesity in a model of gpx4 haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathy. Mol Metab. 2015;4(6):493–506. https://doi.org/10.1016/j.molmet.2015.04.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Baseler WA, Dabkowski ER, Jagannathan R, et al. Reversal of mitochondrial proteomic loss in type 1 diabetic heart with overexpression of phospholipid hydroperoxide glutathione peroxidase. Am J Physiol Regul Integr Comp Physiol. 2013;304(7):R553–65. https://doi.org/10.1152/ajpregu.00249.2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Feng W, Wang Y, Cai L, Kang YJ. Metallothionein rescues hypoxia-inducible factor-1 transcriptional activity in cardiomyocytes under diabetic conditions. Biochem Biophys Res Commun. 2007;360(1):286–9. https://doi.org/10.1016/j.bbrc.2007.06.057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Huang S, Wang J, Men H, et al. Cardiac metallothionein overexpression rescues diabetic cardiomyopathy in Akt2-knockout mice. J Cell Mol Med. 2021;25(14):6828–40. https://doi.org/10.1111/jcmm.16687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gu J, Yan X, Dai X, et al. Metallothionein preserves Akt2 activity and cardiac function via inhibiting TRB3 in diabetic hearts. Diabetes. 2018;67(3):507–17. https://doi.org/10.2337/db17-0219.

    Article  CAS  PubMed  Google Scholar 

  64. Gu J, Cheng Y, Wu H, et al. Metallothionein is downstream of Nrf2 and partially mediates sulforaphane prevention of diabetic cardiomyopathy. Diabetes. 2017;66(2):529–42. https://doi.org/10.2337/db15-1274.

    Article  CAS  PubMed  Google Scholar 

  65. Kobylecki CJ, Afzal S, Nordestgaard BG. Genetically low antioxidant protection and risk of cardiovascular disease and heart failure in diabetic subjects. EBioMedicine. 2015;2(12):2010–5. https://doi.org/10.1016/j.ebiom.2015.11.026.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Gao YH, Li CX, Shen SM, et al. Hypoxia-inducible factor 1alpha mediates the down-regulation of superoxide dismutase 2 in von Hippel-Lindau deficient renal clear cell carcinoma. Biochem Biophys Res Commun. 2013;435(1):46–51. https://doi.org/10.1016/j.bbrc.2013.04.034.

    Article  CAS  PubMed  Google Scholar 

  67. Bohuslavova R, Kolar F, Sedmera D, et al. Partial deficiency of HIF-1alpha stimulates pathological cardiac changes in streptozotocin-induced diabetic mice. BMC Endocr Disord. 2014;14:11. https://doi.org/10.1186/1472-6823-14-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gao Q, Guan L, Hu S, et al. Study on the mechanism of HIF1a-SOX9 in glucose-induced cardiomyocyte hypertrophy. Biomed Pharmacother. 2015;74:57–62. https://doi.org/10.1016/j.biopha.2015.07.009.

    Article  CAS  PubMed  Google Scholar 

  69. Huang YT, Liu CH, Yang YC, et al. ROS- and HIF1alpha-dependent IGFBP3 upregulation blocks IGF1 survival signaling and thereby mediates high-glucose-induced cardiomyocyte apoptosis. J Cell Physiol. 2019;234(8):13557–70. https://doi.org/10.1002/jcp.28034.

    Article  CAS  PubMed  Google Scholar 

  70. Packer M. Mechanisms leading to differential hypoxia-inducible factor signaling in the diabetic kidney: modulation by SGLT2 inhibitors and hypoxia mimetics. Am J Kidney Dis. 2021;77(2):280–6. https://doi.org/10.1053/j.ajkd.2020.04.016.

    Article  CAS  PubMed  Google Scholar 

  71. Kondo K, Ishigaki Y, Gao J, et al. Bach1 deficiency protects pancreatic beta-cells from oxidative stress injury. Am J Physiol Endocrinol Metab. 2013;305(5):E641–8. https://doi.org/10.1152/ajpendo.00120.2013.

    Article  CAS  PubMed  Google Scholar 

  72. Yan B, Jiao S, Zhang HS, et al. Prolyl hydroxylase domain protein 3 targets Pax2 for destruction. Biochem Biophys Res Commun. 2011;409(2):315–20. https://doi.org/10.1016/j.bbrc.2011.05.012.

    Article  CAS  PubMed  Google Scholar 

  73. Li CL, Liu B, Wang ZY, et al. Salvianolic acid B improves myocardial function in diabetic cardiomyopathy by suppressing IGFBP3. J Mol Cell Cardiol. 2020;139:98–112. https://doi.org/10.1016/j.yjmcc.2020.01.009.

    Article  CAS  PubMed  Google Scholar 

  74. Lai J, Chen F, Chen J, et al. Overexpression of decorin promoted angiogenesis in diabetic cardiomyopathy via IGF1R-AKT-VEGF signaling. Sci Rep. 2017;7:44473. https://doi.org/10.1038/srep44473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ramakrishnan S, Anand V, Roy S. Vascular endothelial growth factor signaling in hypoxia and inflammation. J Neuroimmune Pharmacol. 2014;9(2):142–60. https://doi.org/10.1007/s11481-014-9531-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lu H, Fedak PW, Dai X, et al. Integrin-linked kinase expression is elevated in human cardiac hypertrophy and induces hypertrophy in transgenic mice. Circulation. 2006;114(21):2271–9. https://doi.org/10.1161/CIRCULATIONAHA.106.642330.

    Article  CAS  PubMed  Google Scholar 

  77. Wicik Z, Nowak A, Jarosz-Popek J, et al. Characterization of the SGLT2 interaction network and its regulation by SGLT2 inhibitors: a bioinformatic analysis. Front Pharmacol. 2022;13:901340. https://doi.org/10.3389/fphar.2022.901340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gupte M, Umbarkar P, Lal H. Mechanistic insights of empagliflozin-mediated cardiac benefits: nearing the starting line : editorial to: "Empagliflozin improves left ventricular diastolic dysfunction in a genetic model of type 2 diabetes" by N. Hammoudi et al. Cardiovasc Drugs Ther. 2017;31(3):229–32. https://doi.org/10.1007/s10557-017-6741-2.

    Article  PubMed  Google Scholar 

  79. Min W, Bin ZW, Quan ZB, Hui ZJ, Sheng FG. The signal transduction pathway of PKC/NF-kappa B/c-fos may be involved in the influence of high glucose on the cardiomyocytes of neonatal rats. Cardiovasc Diabetol. 2009;8:8. https://doi.org/10.1186/1475-2840-8-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wang M, Zhang WB, Zhu JH, Fu GS, Zhou BQ. Breviscapine ameliorates hypertrophy of cardiomyocytes induced by high glucose in diabetic rats via the PKC signaling pathway. Acta Pharmacol Sin. 2009;30(8):1081–91. https://doi.org/10.1038/aps.2009.95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Radovits T, Korkmaz S, Matyas C, et al. An altered pattern of myocardial histopathological and molecular changes underlies the different characteristics of type-1 and type-2 diabetic cardiac dysfunction. J Diabetes Res. 2015;2015:728741. https://doi.org/10.1155/2015/728741.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Oh CC, Lee J, D'Souza K, et al. Activator protein-1 and caspase 8 mediate p38alpha MAPK-dependent cardiomyocyte apoptosis induced by palmitic acid. Apoptosis. 2019;24(5-6):395–403. https://doi.org/10.1007/s10495-018-01510-y.

    Article  CAS  PubMed  Google Scholar 

  83. Zhu N, Huang B, Zhu L, Wang Y. Potential mechanisms of triptolide against diabetic cardiomyopathy based on network pharmacology analysis and molecular docking. J Diabetes Res. 2021;2021:9944589. https://doi.org/10.1155/2021/9944589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wernig G, Chen SY, Cui L, et al. Unifying mechanism for different fibrotic diseases. Proc Natl Acad Sci USA. 2017;114(18):4757–62. https://doi.org/10.1073/pnas.1621375114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wrann CD, Rosen ED. New insights into adipocyte-specific leptin gene expression. Adipocyte. 2012;1(3):168–72. https://doi.org/10.4161/adip.20574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wrann CD, Eguchi J, Bozec A, et al. FOSL2 promotes leptin gene expression in human and mouse adipocytes. J Clin Invest. 2012;122(3):1010–21. https://doi.org/10.1172/JCI58431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Li J, Li S, Hu Y, et al. The expression level of mRNA, protein, and DNA methylation status of FOSL2 of Uyghur in XinJiang in type 2 diabetes. J Diabetes Res. 2016;2016:5957404. https://doi.org/10.1155/2016/5957404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Liang Y, Yuan W, Zhu W, et al. Macrophage migration inhibitory factor promotes expression of GLUT4 glucose transporter through MEF2 and Zac1 in cardiomyocytes. Metabolism. 2015;64(12):1682–93. https://doi.org/10.1016/j.metabol.2015.09.007.

    Article  CAS  PubMed  Google Scholar 

  89. Wang J, Tong C, Yan X, et al. Limiting cardiac ischemic injury by pharmacological augmentation of macrophage migration inhibitory factor-AMP-activated protein kinase signal transduction. Circulation. 2013;128(3):225–36. https://doi.org/10.1161/CIRCULATIONAHA.112.000862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhang D, Golubkov VS, Han W, et al. Identification of Annexin A4 as a hepatopancreas factor involved in liver cell survival. Dev Biol. 2014;395(1):96–110. https://doi.org/10.1016/j.ydbio.2014.08.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Monkemann H, De Vriese AS, Blom HJ, et al. Early molecular events in the development of the diabetic cardiomyopathy. Amino Acids. 2002;23(1-3):331–6. https://doi.org/10.1007/s00726-001-0146-y.

    Article  CAS  PubMed  Google Scholar 

  92. Kitada K, Nakano D, Ohsaki H, et al. Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy. J Diabetes Complications. 2014;28(5):604–11. https://doi.org/10.1016/j.jdiacomp.2014.05.010.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Almeida De Oliveira A, Faustino J, Pedrosa Nunes KJH. Abstract P190: transcriptomic data analysis reveals sex-related differences in the interplay between toll-like receptor 4 and heat-shock protein 70 in the aorta of type 2 diabetic donors. Hypertension. 2019;74(Suppl_1):AP190-AP. https://doi.org/10.1161/hyp.74.suppl_1.P190.

    Article  Google Scholar 

  94. Fiorese CJ, Schulz AM, Lin YF, et al. The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Curr Biol. 2016;26(15):2037–43. https://doi.org/10.1016/j.cub.2016.06.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Juliana CA, Yang J, Rozo AV, et al. ATF5 regulates beta-cell survival during stress. Proc Natl Acad Sci USA. 2017;114(6):1341–6. https://doi.org/10.1073/pnas.1620705114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pei-Yuan Z, Yu-Wei L, Xiang-Nan Z, et al. Overexpression of Axl reverses endothelial cells dysfunction in high glucose and hypoxia. J Cell Biochem. 2019;120(7):11831–41. https://doi.org/10.1002/jcb.28462.

    Article  CAS  PubMed  Google Scholar 

  97. Wu W, Xu H, Meng Z, et al. Axl is essential for in-vitro angiogenesis induced by vitreous from patients with proliferative diabetic retinopathy. Front Med (Lausanne). 2021;8:787150. https://doi.org/10.3389/fmed.2021.787150.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Su SC, Chiang CF, Hsieh CH, et al. Growth arrest-specific 6 modulates adiponectin expression and insulin resistance in adipose tissue. J Diabetes Investig. 2021;12(4):485–92. https://doi.org/10.1111/jdi.13412.

    Article  CAS  PubMed  Google Scholar 

  99. Arai H, Nagai K, Doi T. Role of growth arrest-specific gene 6 in diabetic nephropathy. Vitam Horm. 2008;78:375–92. https://doi.org/10.1016/S0083-6729(07)00015-5.

    Article  CAS  PubMed  Google Scholar 

  100. Ljubimov AV, Burgeson RE, Butkowski RJ, et al. Basement membrane abnormalities in human eyes with diabetic retinopathy. J Histochem Cytochem. 1996;44(12):1469–79. https://doi.org/10.1177/44.12.8985139.

    Article  CAS  PubMed  Google Scholar 

  101. Burlina S, Banfi C, Brioschi M, et al. Is the placental proteome impaired in well-controlled gestational diabetes? J Mass Spectrom. 2019;54(4):359–65. https://doi.org/10.1002/jms.4336.

    Article  CAS  PubMed  Google Scholar 

  102. Zhang Y, Cui L, Guan G, et al. Matrine suppresses cardiac fibrosis by inhibiting the TGF-beta/Smad pathway in experimental diabetic cardiomyopathy. Mol Med Rep. 2018;17(1):1775–81. https://doi.org/10.3892/mmr.2017.8054.

    Article  CAS  PubMed  Google Scholar 

  103. Malek V, Gaikwad AB. Telmisartan and thiorphan combination treatment attenuates fibrosis and apoptosis in preventing diabetic cardiomyopathy. Cardiovasc Res. 2019;115(2):373–84. https://doi.org/10.1093/cvr/cvy226.

    Article  CAS  PubMed  Google Scholar 

  104. Che H, Wang Y, Li Y, et al. Inhibition of microRNA-150-5p alleviates cardiac inflammation and fibrosis via targeting Smad7 in high glucose-treated cardiac fibroblasts. J Cell Physiol. 2020;235(11):7769–79. https://doi.org/10.1002/jcp.29386.

    Article  CAS  PubMed  Google Scholar 

  105. Frangogiannis NG. Cardiac fibrosis. Cardiovasc Res. 2021;117(6):1450–88. https://doi.org/10.1093/cvr/cvaa324

    Article  CAS  PubMed  Google Scholar 

  106. Wang Y, Yu K, Zhao C, et al. Follistatin attenuates myocardial fibrosis in diabetic cardiomyopathy via the TGF-beta-Smad3 pathway. Front Pharmacol. 2021;12:683335. https://doi.org/10.3389/fphar.2021.683335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dong L, Li JC, Hu ZJ, et al. Deletion of Smad3 protects against diabetic myocardiopathy in db/db mice. J Cell Mol Med. 2021;25(10):4860–9. https://doi.org/10.1111/jcmm.16464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Panchapakesan U, Pegg K, Gross S, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells--renoprotection in diabetic nephropathy? PLoS One. 2013;8(2):e54442. https://doi.org/10.1371/journal.pone.0054442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Xu H, Qing T, Shen Y, et al. RNA-seq analyses the effect of high-salt diet in hypertension. Gene. 2018;677:245–50. https://doi.org/10.1016/j.gene.2018.07.069.

    Article  CAS  PubMed  Google Scholar 

  110. Gallini R, Lindblom P, Bondjers C, Betsholtz C, Andrae J. PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice. Exp Cell Res. 2016;349(2):282–90. https://doi.org/10.1016/j.yexcr.2016.10.022.

    Article  CAS  PubMed  Google Scholar 

  111. Ye Y, Jia X, Bajaj M, Birnbaum Y. Dapagliflozin attenuates Na(+)/H(+) exchanger-1 in cardiofibroblasts via AMPK activation. Cardiovasc Drugs Ther. 2018;32(6):553–8. https://doi.org/10.1007/s10557-018-6837-3.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Hsiu-Chiung Yang and Stefano Bartesaghi for the administrative management of the collaboration. We would like to thank the NGS Core facility of the University of Texas for the generation and pre-processing of the RNA-sequencing experiment.

Funding

This research has been funded by AstraZeneca. The first author is an AstraZeneca employee and had direct involvement in the data analysis, interpretation, and planning of the follow-up experiments.

Author information

Authors and Affiliations

  1. Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

    Maria Ryaboshapkina

  2. University of Texas at Austin, Austin, TX, USA

    Regina Ye

  3. The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA

    Yumei Ye

  4. The Section of Cardiology, The Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA

    Yochai Birnbaum

Authors
  1. Maria Ryaboshapkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Regina Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yumei Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yochai Birnbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.R.—computational analysis of RNA-seq data, hypotheses for follow-up experiments, and first manuscript draft. Y.Y. and Y.B.—study design, in vivo experiments, RT-PCR, and protein quantification. R.Y—literature search, data analysis, and editing the manuscript. All authors contributed to data interpretation, revised the manuscript, and approved the final version.

Corresponding author

Correspondence to Yochai Birnbaum.

Ethics declarations

Conflict of Interest

M.R. is an employee of AstraZeneca and may hold company shares/stocks. Y.Y. and Y. B. received the research grant from AstraZeneca.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(XLSX 6130 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ryaboshapkina, M., Ye, R., Ye, Y. et al. Effects of Dapagliflozin on Myocardial Gene Expression in BTBR Mice with Type 2 Diabetes. Cardiovasc Drugs Ther (2023). https://doi.org/10.1007/s10557-023-07517-1

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10557-023-07517-1

Keywords

Search

Navigation