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Basic Research in Cardiology

, 114:35 | Cite as

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

  • Yochai BirnbaumEmail author
  • Dat Tran
  • Mandeep Bajaj
  • Yumei Ye
Original Contribution

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.

Keywords

DPP4 inhibitor GLP-1 Myocardial infarction Nlrp3/ASC inflammasome TLR4 microRNA 

Notes

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.

Compliance with ethical standards

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.

Supplementary material

395_2019_743_MOESM1_ESM.pdf (1.9 mb)
Supplementary material 1 (PDF 1917 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Section of Cardiology, Baylor College of Medicine, and the Texas Heart InstituteBaylor St Luke Medical CenterHoustonUSA
  2. 2.School of MedicineUniversity of Texas Medical BranchGalvestonUSA
  3. 3.Section of EndocrinologyBaylor College of MedicineHoustonUSA
  4. 4.The Department of Biochemistry and Molecular BiologyUniversity of Texas Medical BranchGalvestonUSA

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