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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

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Abstract

Purpose

We assessed whether (1) dapagliflozin (Dapa, an SGLT2-inhibitor) attenuates the deterioration of heart function Nlrp3 and inflammasome activation in diabetic mice. (2) The effects can be augmented with saxagliptin (Saxa), a DDP4-inhibitor. (3) Dapa effect is possibly SGLT2-independent on cardiofibroblasts in vitro.

Methods

Type 2 diabetic (BTBR ob/ob) and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Glucose tolerance test and echocardiogram were performed. Cardiofibroblasts from WT and BTBR hearts were incubated with Dapa and exposed to LPS.

Results

Left ventricular ejection fraction (LVEF) was 81 ± 1% in the WT and 53 ± 1% in the T2D-cont mice. Dapa and Dapa+Saxa improved LVEF to 68 ± 1 and 74.6 ± 1% in the BTBR mice (p < 0.001). The mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, and TNFα were significantly higher in the BTBR compared to the WT hearts; and Dapa and Dapa+Saxa significantly attenuated these levels. Likewise, protein levels of NLRP3, TNFα, and caspase-1 were higher in the BTBR compared to the WT hearts and Dapa, and to a greater extent Dapa+Saxa, attenuated the increase in the BTBR mice. Collagen-1 and collagen-3 mRNA levels significantly increased in the BTBR mice and these increases were attenuated by Dapa and Dapa+Saxa. P-AMPK/total-AMPK ratio was significantly lower in the BTBR mice than in the WT mice. Dapa and Dapa+Saxa equally increased the ratio in the BTBR mice. This in vitro study showed that NALP3, ASC, IL-1β, and caspase-1 mRNA levels were higher in the BTBR cardiofibroblasts and attenuated with Dapa. The effect was AMPK-dependent and SGLT1-independent.

Conclusions

Dapa attenuated the activation of the inflammasome, fibrosis, and deterioration of LVEF in BTBR mice. The anti-inflammatory, anti-fibrotic effects are likely SGLT2- and glucose-lowering-independent, as they were replicated in the in vitro model. The effects on remodeling were augmented when Saxa was added to Dapa. Yet, adding Saxa to Dapa did not result in a greater effect on myocardial fibrosis and collagen levels.

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Author information

Author notes

  1. Yumei Ye and Mandeep Bajaj contributed equally to this work.

Authors and Affiliations

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

    Yumei Ye & Jose R. Perez-Polo

  2. The Section of Endocrinology, The Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Mandeep Bajaj

  3. Translational Science, CVMD, iMED, Astrazeneca, Mölndal, Sweden

    Hsiu-Chiung Yang

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

    Yochai Birnbaum

Authors
  1. Yumei Ye
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  2. Mandeep Bajaj
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  5. Yochai Birnbaum
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Corresponding author

Correspondence to Yochai Birnbaum.

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Funding

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

Conflict of Interest

Dr. Ye received research grants from Astra Zeneca and Boehringer Ingelheim. Dr. Bajaj received research grants from AstraZeneca, Boehringer Ingelheim, Eli-Lilly, and Novo Nordisk. He has received lecture fees from Takeda Pharmaceuticals and Sanofi Aventis and is a consultant to Merck and Genentech. Dr. Yang is an employee of Astra Zeneca. Dr. Perez-Polo reports no conflict of interest. Dr. Yochai Birnbaum received research grants from Astra Zeneca and he is a speaker for AstraZeneca.

Research Involving Animals

Mice received humane care in compliance 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). The protocol was approved by the University of Texas Medical Branch IACUC, Galveston, Texas, USA.

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Ye, Y., Bajaj, M., Yang, HC. et al. 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 31, 119–132 (2017). https://doi.org/10.1007/s10557-017-6725-2

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