Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 11, pp 1371–1382 | Cite as

Pretreatment with vildagliptin boosts ischemic-postconditioning effects on cardioprotection and expression profile of genes regulating autophagy and mitochondrial fission/fusion in diabetic heart with reperfusion injury

  • Lale Pirzeh
  • Vahab Babapour
  • Reza BadalzadehEmail author
  • Negar Panahi
Original Article


The burden of myocardial ischemia/reperfusion (IR) injury is 2–3-folds higher in diabetic patients, so protecting diabetic hearts is clinically important. Here, we investigated the effect of combinational therapy with vildagliptin and ischemic postconditioning (IPostC) on cardioprotection and the expression of genes regulating autophagy and mitochondrial function in diabetic hearts with IR injury. Type 2 diabetes was induced through high-fat diet and streptozotocin protocol in Wistar rats. Vildagliptin was orally administered to diabetic rats 5 weeks before IR injury. Myocardial-IR injury was modeled by ligation of left the coronary artery for 30 min followed by 60-min reperfusion, on a Langendorff-perfusion system. IPostC was applied at early reperfusion as 6 alternative cycles of 10-s reperfusion/ischemia. Creatine-kinase levels were measured spectrometrically, and infarct size was evaluated by TTC staining method. Left ventricles were harvested for assessing the expression levels of autophagy and mitochondrial-related genes using real-time PCR. Induction of diabetes significantly increased creatine-kinase release in comparison to healthy rats, and all treatments significantly reduced the release of enzyme toward control levels (P < 0.05). Only the combination therapy (IPostC + vildagliptin) could significantly reduce the infarct size of diabetic hearts as compared to untreated diabetic-IR group (P < 0.01). The levels of autophagy genes LC3 and p62 were significantly higher in diabetic groups than healthy ones. Induction of IR injury in diabetic hearts enhanced mitochondrial fission (drp-1) and reduced mitochondrial fusion (mfn1 and mfn2) genes. IPostC alone had no significant effect on the gene expression and vildagliptin alone could only affect LC3-II and mfn2 expressions. Nevertheless, administration of combination therapy significantly reduced the expression of both autophagy genes and increased both LC3-II/I and mfn2/1 ratios as compared with diabetic-IR hearts (P < 0.01–0.05). Application of this combination therapy could overcome the diabetes-induced failure of cardioprotection by individual treatments and improve mitochondrial dynamic and autophagy flux.


Combination therapy Diabetes Cardioprotection Infarction Postconditioning Mitochondria Autophagy 



The authors thank the Clinical Research Development Unit, Shohada Hospital and Molecular Medicine Research Center, Tabriz University of Medical Sciences for their kind supports.

Author contribution

VB and RB conceived and designed research. LP and RB conducted the experiments. LP, VB, and NP analyzed the data. LP, RB, and NP wrote the manuscript. All authors read and approved the manuscript.

Funding information

This study was supported by a grant from National Elites Foundation, Tehran—Iran, and Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz—Iran.

Compliance with ethical standards

All animal procedures and experimental interventions were carried out in accordance with the ethical guidelines and approved by the local Ethical Committee for Animal Research.

Conflict of interest

The authors declare that they have no conflicts of interest.


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Copyright information

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

Authors and Affiliations

  1. 1.Department Basic Sciences, Faculty of Veterinary Medicine, Sciences and Research BranchIslamic Azad UniversityTehranIran
  2. 2.Molecular Medicine Research CenterTabriz University of Medical SciencesTabrizIran
  3. 3.Drug Applied Research CenterTabriz University of Medical SciencesTabrizIran
  4. 4.Immunology Research CenterTabriz University of Medical SciencesTabrizIran

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