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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2015

Open Access 01-12-2015 | Original investigation

Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats

Authors: Hiromichi Murase, Atsushi Kuno, Takayuki Miki, Masaya Tanno, Toshiyuki Yano, Hidemichi Kouzu, Satoko Ishikawa, Toshiyuki Tobisawa, Makoto Ogasawara, Keitaro Nishizawa, Tetsuji Miura

Published in: Cardiovascular Diabetology | Issue 1/2015

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Abstract

Background

Type 2 diabetes mellitus (T2DM) worsens the outcome after myocardial infarction (MI). Here, we hypothesized that inhibition of dipeptidyl peptidase-4 (DPP-4) improves survival after MI in T2DM by modifying autophagy in the non-infarcted region of the heart.

Methods and results

Under baseline conditions, there was no significant difference between levels of myocardial autophagy marker proteins in OLETF, a rat model of T2DM, and in LETO, a non-diabetic control. However, in contrast to the response in LETO, LC3-II protein and LC3-positive autophagosomes in the non-infarcted region of the myocardium were not increased after MI in OLETF. The altered autophagic response in OLETF was associated with lack of AMPK/ULK-1 activation, attenuated response of Akt/mTOR/S6 signaling and increased Beclin-1–Bcl-2 interaction after MI. Treatment with vildagliptin (10 mg/kg/day s.c.), a DPP-4 inhibitor, suppressed Beclin-1–Bcl-2 interaction and increased both LC3-II protein level and autophagosomes in the non-infarcted region in OLETF, though it did not normalize AMPK/ULK-1 or mTOR/S6 signaling. Plasma insulin level, but not glucose level, was significantly reduced by vildagliptin at the dose used in this study. Survival rate at 48 h after MI was significantly lower in OLETF than in LETO (32 vs. 82%), despite similar infarct sizes. Vildagliptin improved the survival rate in OLETF to 80%, the benefit of which was abrogated by chloroquine, an autophagy inhibitor.

Conclusions

The results indicate that vildagliptin reduces T2DM-induced increase in post-MI acute mortality possibly by restoring the autophagic response through attenuation of Bcl-2-Beclin-1 interaction.
Appendix
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Metadata
Title
Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats
Authors
Hiromichi Murase
Atsushi Kuno
Takayuki Miki
Masaya Tanno
Toshiyuki Yano
Hidemichi Kouzu
Satoko Ishikawa
Toshiyuki Tobisawa
Makoto Ogasawara
Keitaro Nishizawa
Tetsuji Miura
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2015
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-015-0264-6

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