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Development of a Zebrafish Larvae Model for Diabetic Heart Failure With Reduced Ejection Fraction

  • Inho Kim (Department of Internal Medicine, Seoul National University Hospital) ;
  • Seung Hyeok Seok (Department of Microbiology and Immunology, Seoul National University College of Medicine) ;
  • Hae-Young Lee (Department of Internal Medicine, Seoul National University Hospital)
  • Received : 2022.08.01
  • Accepted : 2022.11.09
  • Published : 2023.01.01

Abstract

Background and Objectives: Diabetes mellitus (DM)-associated heart failure (HF) causes high morbidity and mortality. In this study, we established a zebrafish larvae model for in vivo research on diabetic HF. Methods: DM-like phenotypes were induced by treating zebrafish larvae with a combination of D-glucose (GLU) and streptozotocin (STZ). HF was induced by treatment with terfenadine (TER), a potassium channel blocker. Additionally, myocardial contractility, motility, and viability were evaluated. Results: The zebrafish larvae treated with a combination of GLU and STZ showed significantly higher whole-body glucose concentrations, lower insulin levels, and higher phosphoenolpyruvate carboxykinase levels, which are markers of abnormal glucose homeostasis, than the group treated with only GLU, with no effect on viability. When treated with TER, DM zebrafish showed significantly less myocardial fractional shortening and more irregular contractions than the non-DM zebrafish. Furthermore, in DM-HF with reduced ejection fraction (rEF) zebrafish, a significant increase in the levels of natriuretic peptide B, a HF biomarker, markedly reduced motility, and reduced survival rates were observed. Conclusions: We established a DM-HFrEF zebrafish model by sequentially treating zebrafish larvae with GLU, STZ, and TER. Our findings indicate the potential utility of the developed zebrafish larvae model not only in screening studies of new drug candidates for DM-HFrEF but also in mechanistic studies to understand the pathophysiology of DM-HFrEF.

Keywords

Acknowledgement

This work was supported by a National Research Foundation (NRF) grant funded by the Korean government (2020R1A2C2010202).

References

  1. McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol 2014;2:843-51. https://doi.org/10.1016/S2213-8587(14)70031-2
  2. Kong MG, Jang SY, Jang J, et al. Impact of diabetes mellitus on mortality in patients with acute heart failure: a prospective cohort study. Cardiovasc Diabetol 2020;19:49.
  3. Jang SY, Jang J, Yang DH, et al. Impact of insulin therapy on the mortality of acute heart failure patients with diabetes mellitus. Cardiovasc Diabetol 2021;20:180.
  4. Sharma A, Pagidipati NJ, Califf RM, et al. Impact of regulatory guidance on evaluating cardiovascular risk of new glucose-lowering therapies to treat type 2 diabetes mellitus: lessons learned and future directions. Circulation 2020;141:843-62. https://doi.org/10.1161/CIRCULATIONAHA.119.041022
  5. Parng C, Seng WL, Semino C, McGrath P. Zebrafish: a preclinical model for drug screening. Assay Drug Dev Technol 2002;1:41-8. https://doi.org/10.1089/154065802761001293
  6. Grunwald DJ, Streisinger G. Induction of recessive lethal and specific locus mutations in the zebrafish with ethyl nitrosourea. Genet Res 1992;59:103-16. https://doi.org/10.1017/S0016672300030317
  7. Jurczyk A, Roy N, Bajwa R, et al. Dynamic glucoregulation and mammalian-like responses to metabolic and developmental disruption in zebrafish. Gen Comp Endocrinol 2011;170:334-45. https://doi.org/10.1016/j.ygcen.2010.10.010
  8. Howe K, Clark MD, Torroja CF, et al. The zebrafish reference genome sequence and its relationship to the human genome. Nature 2013;496:498-503. https://doi.org/10.1038/nature12111
  9. Missinato MA, Zuppo DA, Watkins SC, Bruchez MP, Tsang M. Zebrafish heart regenerates after chemoptogenetic cardiomyocyte depletion. Dev Dyn 2021;250:986-1000. https://doi.org/10.1002/dvdy.305
  10. Huang CJ, Tu CT, Hsiao CD, Hsieh FJ, Tsai HJ. Germ-line transmission of a myocardium-specific GFP transgene reveals critical regulatory elements in the cardiac myosin light chain 2 promoter of zebrafish. Dev Dyn 2003;228:30-40. https://doi.org/10.1002/dvdy.10356
  11. Quan H, Oh GC, Seok SH, Lee HY. Fimasartan, an angiotensin II receptor antagonist, ameliorates an in vivo zebrafish model of heart failure. Korean J Intern Med 2020;35:1400-10. https://doi.org/10.3904/kjim.2019.038
  12. Gu G, Na Y, Chung H, Seok SH, Lee HY. Zebrafish Larvae Model of Dilated Cardiomyopathy Induced by Terfenadine. Korean Circ J 2017;47:960-9. https://doi.org/10.4070/kcj.2017.0080
  13. Members of the Panel on Euthanasia. AVMA guidelines for the euthanasia of animals: 2020 edition. Schaumburg (IL): American Veterinary Medical Association; 2020.
  14. diIorio PJ, Moss JB, Sbrogna JL, Karlstrom RO, Moss LG. Sonic hedgehog is required early in pancreatic islet development. Dev Biol 2002;244:75-84. https://doi.org/10.1006/dbio.2002.0573
  15. Andersson O, Adams BA, Yoo D, et al. Adenosine signaling promotes regeneration of pancreatic β cells in vivo. Cell Metab 2012;15:885-94. https://doi.org/10.1016/j.cmet.2012.04.018
  16. Lee Y, Yang J. Development of a zebrafish screening model for diabetic retinopathy induced by hyperglycemia: Reproducibility verification in animal model. Biomed Pharmacother 2021;135:111201.
  17. Singh A, Castillo HA, Brown J, Kaslin J, Dwyer KM, Gibert Y. High glucose levels affect retinal patterning during zebrafish embryogenesis. Sci Rep 2019;9:4121.
  18. Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 2001;50:537-46.
  19. Huang CC, Chen PC, Huang CW, Yu J. Aristolochic acid induces heart failure in zebrafish embryos that is mediated by inflammation. Toxicol Sci 2007;100:486-94. https://doi.org/10.1093/toxsci/kfm235
  20. Matrone G, Taylor JM, Wilson KS, et al. Laser-targeted ablation of the zebrafish embryonic ventricle: a novel model of cardiac injury and repair. Int J Cardiol 2013;168:3913-9. https://doi.org/10.1016/j.ijcard.2013.06.063
  21. Jimenez-Amilburu V, Jong-Raadsen S, Bakkers J, Spaink HP, Marin-Juez R. GLUT12 deficiency during early development results in heart failure and a diabetic phenotype in zebrafish. J Endocrinol 2015;224:1-15. https://doi.org/10.1530/JOE-14-0539
  22. Kronlage M, Dewenter M, Grosso J, et al. O-GlcNAcylation of histone deacetylase 4 protects the diabetic heart from failure. Circulation 2019;140:580-94. https://doi.org/10.1161/CIRCULATIONAHA.117.031942
  23. Jeon YW, Kim HC. Factors associated with awareness, treatment, and control rate of hypertension among Korean young adults aged 30-49 years. Korean Circ J 2020;50:1077-91. https://doi.org/10.4070/kcj.2020.0208
  24. Zang L, Shimada Y, Nishimura N. Development of a novel zebrafish model for type 2 diabetes mellitus. Sci Rep 2017;7:1461. 
  25. Zhang M, Lv XY, Li J, Xu ZG, Chen L. The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Exp Diabetes Res 2008;2008:704045.
  26. Tanaka S, Hayashi T, Toyoda T, et al. High-fat diet impairs the effects of a single bout of endurance exercise on glucose transport and insulin sensitivity in rat skeletal muscle. Metabolism 2007;56:1719-28. https://doi.org/10.1016/j.metabol.2007.07.017
  27. Kolk MV, Meyberg D, Deuse T, et al. LAD-ligation: a murine model of myocardial infarction. J Vis Exp 2009;(32):1438.