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

Cardiovascular Diabetology

Tetsuji Miura¹  Keitaro Nishizawa¹  Makoto Ogasawara¹  Toshiyuki Tobisawa¹  Satoko Ishikawa¹  Hidemichi Kouzu¹  Toshiyuki Yano¹  Masaya Tanno¹  Takayuki Miki¹  Atsushi Kuno²  Hiromichi Murase¹ 

[1] Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan;Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan

关键词: Mortality;    Myocardial infarction;    DPP-4 inhibitor;    Autophagy;    Type 2 diabetes;   

Others  :  1222735
DOI  :  10.1186/s12933-015-0264-6

 received in 2015-04-27, accepted in 2015-07-24,  发布年份 2015

【 摘 要 】

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 proteinsin 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.

【 授权许可】

   
2015 Murase et al.

【 图 表 】

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