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Effect of empagliflozin on cardiac biomarkers in a zebrafish model of heart failure: clues to the EMPA-REG OUTCOME trial?

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Abstract

The sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin was recently reported to reduce heart failure-associated hospitalizations and cardiovascular mortality amongst individuals with type 2 diabetes at high cardiovascular risk. We sought to elucidate the underlying mechanism(s) for these protective effects using a validated zebrafish heart failure model to evaluate the impact of empagliflozin on the expression of biomarkers of heart failure and mortality. We used aristolochic acid (AA) to induce heart failure in developing cmlc2::GFP transgenic zebrafish embryos and monitored BNP signaling in nppb::Luc transgenic zebrafish with a luciferase reporter assay. Empagliflozin markedly reduced the morphological and functional cardiac changes induced by AA; dampened AA-enhanced expression of brain natriuretic peptide and atrial natriuretic peptide; and reduced embryonic mortality. Furthermore, morpholino-mediated knockdown of the slc5A2 gene mimicked the changes evoked by empagliflozin in developing zebrafish embryos previously exposed to AA. We report herein the first mechanistic data demonstrating a salutary benefit of SGLT2 inhibition on critical pathways of heart failure signaling. These findings provide important translational clues to the cardiovascular benefits documented in the EMPA-REG OUTCOME study.

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Abbreviations

AA:

Aristolochic acid

ANP:

Atrial natriuretic peptide

BNP:

Brain natriuretic peptide

cox-2:

Cyclooxygenase-2

dpf:

Days post fertilization

EMPA:

Empagliflozin

GATA4:

GATA Binding Protein 4

GFP:

Green fluorescence protein

Hpf:

Hours post fertilization

IL-1β:

Interleukin-1β

MEF2:

Myocyte enhancer factor-2

MO:

Morpholino

RT-qPCR:

Quantitative reverse transcription polymerase chain reaction

SGLT2:

Sodium–glucose cotransporter 2

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Acknowledgements

This work was supported by grants from the Heart & Stroke Foundation of Canada to S. Verma, Natural Sciences and Engineering Research Council of Canada (NSERC) to XYW, Brain Canada Foundation/Health Canada to X-Y. Wen and Canada Foundation for Innovation (CFI) to X-Y. Wen and S. Verma. S. Verma is the Canada Research Chair in Atherosclerosis at the University of Toronto. X. Shi is a visiting scientist at St. Michael’s Hospital and the University of Toronto and is sponsored by the China Scholarship Council (CSC).

Authors’ contributions

SV and X-YW designed the studies. XS and X-YW designed the experiments. XS, JY, KB-A, KKS, XL and AQ conducted the experiments. XS, SV, KKS, AG and X-YW interpreted the data. XS and X-YW drafted the manuscript. SV and AQ critically edited the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Department of Medicine and Physiology, University of Toronto, 209 Victoria Street, LKSKI Rm 519, Toronto, ON, M5B 1T8, Canada

    Xingjuan Shi, Junghwa Yun, Koroboshka Brand-Arzamendi & Xiao-Yan Wen

  2. Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada

    Subodh Verma, Krishna K. Singh, Ankit Garg & Adrian Quan

  3. Division of Vascular Surgery, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada

    Krishna K. Singh

  4. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Xingjuan Shi, Subodh Verma, Koroboshka Brand-Arzamendi, Krishna K. Singh & Xiao-Yan Wen

  5. Department of Surgery, University of Toronto, Toronto, ON, Canada

    Subodh Verma & Krishna K. Singh

  6. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Subodh Verma

  7. Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing, China

    Xingjuan Shi & Xiangdong Liu

Authors
  1. Xingjuan Shi
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  2. Subodh Verma
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  3. Junghwa Yun
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  4. Koroboshka Brand-Arzamendi
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  5. Krishna K. Singh
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  6. Xiangdong Liu
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  7. Ankit Garg
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  8. Adrian Quan
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  9. Xiao-Yan Wen
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Corresponding authors

Correspondence to Subodh Verma or Xiao-Yan Wen.

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Shi, X., Verma, S., Yun, J. et al. Effect of empagliflozin on cardiac biomarkers in a zebrafish model of heart failure: clues to the EMPA-REG OUTCOME trial?. Mol Cell Biochem 433, 97–102 (2017). https://doi.org/10.1007/s11010-017-3018-9

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  • DOI: https://doi.org/10.1007/s11010-017-3018-9

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