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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

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Abstract

Purpose

Ticagrelor, a P2Y12 receptor antagonist, and dapagliflozin, a sodium–glucose-cotransporter-2 inhibitor, suppress the activation of the NLRP3 inflammasome. The anti-inflammatory effects of dapagliflozin depend on AMPK activation. Also, ticagrelor can activate AMPK. We assessed whether dapagliflozin and ticagrelor have additive effects in attenuating the progression of diabetic cardiomyopathy in T2DM mice.

Methods

Eight-week-old BTBR and wild-type mice received no drug, dapagliflozin (1.5 mg/kg/day), ticagrelor (100 mg/kg/day), or their combination for 12 weeks. Heart function was evaluated by echocardiography and heart tissue samples were assessed for fibrosis, apoptosis, qRT-PCR, and immunoblotting.

Results

Both drugs attenuated the progression of diabetic cardiomyopathy as evident by improvements in left ventricular end-systolic and end-diastolic volumes and left ventricular ejection fraction, which were further improved by the combination. Both drugs attenuated the activation of the NOD-like receptor 3 (NLRP3) inflammasome and fibrosis. The effect of the combination was significantly greater than each drug alone on myocardial tissue necrotic factorα (TNFα) and interleukin-6 (IL-6) levels, suggesting additive effects. The combination had also a greater effect on ASC, collagen-1, and collagen-3 mRNA levels than each drug alone. While both drugs activated adenosine mono-phosphate kinase (AMPK), only dapagliflozin activated mTOR and increased RICTOR levels. Moreover, only dapagliflozin decreased myocardial BNP and Caspase-1 mRNA levels, and the effects of dapagliflozin on NLRP3 and collagen-3 mRNA levels were significantly greater than those of ticagrelor.

Conclusions

Both dapagliflozin and ticagrelor attenuated the progression of diabetic cardiomyopathy, the activation of the NLRP3 inflammasome, and fibrosis in BTBR mice with additive effects of the combination. While both dapagliflozin and ticagrelor activated AMPK, only dapagliflozin activated mTOR complex 2 (mTORC2) in hearts of BTBR mice.

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Funding

The study was funded by an investigator-initiated grant from AstraZeneca and the John S. Dunn Chair in Cardiology Research and Education.

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Author notes

  1. Huan Chen and Da Tran contributed equally to this work.

Authors and Affiliations

  1. The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, BSB 648, Galveston, TX, 77555, USA

    Huan Chen & Yumei Ye

  2. Department of Acupuncture, First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Huan Chen

  3. School of Medicine, University of Texas Medical Branch, Galveston, TX, USA

    Da Tran

  4. Biopharmaceutical R&D, AstraZeneca, Gothenburg, Sweden

    Hsiu-Chiung Yang & Sven Nylander

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

    Yochai Birnbaum

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  1. Huan Chen
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Correspondence to Yumei Ye.

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Conflict of Interest

Huan Chen declares no conflict of interest. Da Tran declares no conflict of interest. Hsiu-Chiung Yang is an employee of AstraZeneca. Sven Nylander is an employee of AstraZeneca. Yochai Birnbaum received a research grant from AstraZeneca. Yumei Ye received a research grant from AstraZeneca.

Ethical Statement

The experimental designs and animal care were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health (NIH publication no. 85-23, revised 1996) and approved by the Institutional Animal Care and Use Committee of the University of Texas Medical Branch.

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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 34, 443–461 (2020). https://doi.org/10.1007/s10557-020-06978-y

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