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DPP-4 inhibition by linagliptin prevents cardiac dysfunction and inflammation by targeting the Nlrp3/ASC inflammasome

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Abstract

We compared the effects of linagliptin (Lina, a DPP4 inhibitor) and GLP-1 receptor activation by exenatide followed by exendin-4 in an infusion pump (EX) on infarct size (IS), post-infarction activation of the inflammasome and remodeling in wild-type (WT) and db/db diabetic mice. Mice underwent 30 min ischemia followed by 24 h reperfusion. IS was assessed by TTC. Additional mice underwent permanent coronary artery occlusion. Echocardiography was performed 2w after infarction. Activation of the inflammasome in the border zone of the infarction was assessed by rt-PCR and ELISA 2w after reperfusion. Further in vitro experiments were done using primary human cardiofibroblasts and cardiomyocytes exposed to simulated ischemia–reoxygenation. Lina and EX limited IS in both the WT and the db/db mice. Lina and EX equally improved ejection fraction in both the WT and the db/db mice. mRNA levels of ASC, NALP3, IL-1β, IL-6, Collagen-1, and Collagen-3 were higher in the db/db mice than in the WT mice. Infarction increased these levels in the WT and db/db mice. Lina more than EX attenuated the increase in ASC, NALP3, IL-1β, IL-6, Collagen-1 and Collagen-3, TNFα and IL-1β, and decreased apoptosis, especially in the db/db mice. In vitro experiments showed that Lina, but not EX, attenuated the increase in TLR4 expression, an effect that was dependent on p38 activation with downstream upregulation of Let-7i and miR-146b levels. Lina and EX had similar effects on IS and post-infarction function, but Lina attenuated the activation of the inflammasome and the upregulation of collagen-1 and collagen-3 more than direct GLP-1 receptor activation. This effect depends on p38 activation with downstream upregulation of miR-146b levels that suppresses TLR4 expression.

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Funding

This research was made possible by an independent grant from Boehringer Ingelheim Pharmaceuticals, Inc. who provided both Study Material and financial support for the study. John S. Dunn Chair in Cardiology Research and Education.

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Authors and Affiliations

  1. Section of Cardiology, Baylor College of Medicine, and the Texas Heart Institute, Baylor St Luke Medical Center, Houston, TX, USA

    Yochai Birnbaum

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

    Dat Tran

  3. Section of Endocrinology, Baylor College of Medicine, Houston, TX, USA

    Mandeep Bajaj

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

    Yumei Ye

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  1. Yochai Birnbaum
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  2. Dat Tran
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  3. Mandeep Bajaj
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Correspondence to Yochai Birnbaum.

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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, Sanofi Aventis, and Novo Nordisk. Dr. Birnbaum receives research grants from Astra Zeneca. Dr. Tran has no conflict of interest.

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Birnbaum, Y., Tran, D., Bajaj, M. et al. DPP-4 inhibition by linagliptin prevents cardiac dysfunction and inflammation by targeting the Nlrp3/ASC inflammasome. Basic Res Cardiol 114, 35 (2019). https://doi.org/10.1007/s00395-019-0743-0

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