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

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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.

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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.

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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.

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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

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  1. Maria Ryaboshapkina
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  2. Regina Ye
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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.

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

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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 39, 43–61 (2025). https://doi.org/10.1007/s10557-023-07517-1

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