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

Abstract

BackgroundType 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 resultsUnder 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0264-6) contains supplementary material, which is available to authorized users.

Alterations of voltage‐dependent K+ channels in the mesenteric artery during the early and chronic phases of diabetes

“…Several type 1 diabetic disease models including diabetes‐prone (DP) BB rats and streptozotocin (STZ)‐induced diabetic models have been used to study type 1 diabetes . Type 2 diabetes is characterized by insulin resistance, for which db/db mice, OLETF rats, and ZFDM rats serve as experimental animal models . Among these, the OLETF rat is a useful animal model for type II diabetes .…”

Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts

“…; Murase et al. ). Vehicle‐treated LETO and OLETF and empagliflozin‐treated OLETF were divided into two subgroups depending on whether a sham operation (Sham) or coronary ligation to induce MI was performed.…”

“…We found that activation of autophagy, a stress‐responsive intracellular digestion system, in the noninfarcted region is blunted by diabetes, possibly contributing to insufficient mechanical compensation (Murase et al. ). In addition, we found that empagliflozin significantly improved ATP generation together with increased ketone utilization and upregulated superoxide dismutase 2 (SOD2) and catalase expression in the noninfarcted region of the heart after MI in OLETF (Oshima et al.…”

“…; Murase et al. ), Otsuka Long‐Evans Tokushima Fatty rats (OLETF), a model of obese type 2 DM, mimicked patients with type 2 DM in terms of a significant increase in the mortality after acute myocardial infarction (MI) (Marso et al. ; De Luca et al.…”

“…; Murase et al. ), despite preserved contractility and only mildly impaired relaxation of the left ventricle in OLETF (Takada et al. ; Kouzu et al.…”