Combination of Vildagliptin and Ischemic Postconditioning in Diabetic Hearts as a Working Strategy to Reduce Myocardial Reperfusion Injury by Restoring Mitochondrial Function and Autophagic Activity

Purpose: Diabetic hearts are resistant to cardioprotection by ischemic-postconditioning (IPostC). Protection of diabetic hearts and finding related interfering mechanisms would have clinical benefits. This study investigated the combination effects of vildagliptin (Vilda) and IPostC on cardioprotection and the levels of autophagy and mitochondrial function following myocardial ischemia/reperfusion (I/R) injury in type-II diabetic rats. Methods: Diabetes was established by high fat diet/low dose of streptozotocin and lasted for 12 weeks. The diabetic rats received Vilda (6 mg/kg/day, orally) for one month before I/R. Myocardial regional ischemia was induced through the ligation of left coronary artery, and IPostC was applied immediately at the onset of reperfusion. The infarct size was assessed by a computerised planimetry and left ventricles samples were harvested for cardiac mitochondrial function studies (ROS production, membrane potential and staining) and western blotting was used for determination of autophagy markers. Results: None of Vilda or IPostC but combination of them could significantly reduce the infarct size of diabetic hearts, comparing to control (P<0.001). IPostC could not significantly affect p62 expression level in diabetic hearts, but pre-treatment with Vilda alone (p<0.05) and in combination with IPostC (p<0.01) more significantly decreased p62 expression in comparison with corresponding control group. The expression of LC3B-II and LC3BII/LC3BI as well as mitochondrial ROS production were decreased significantly in treatment groups (p<0.001). Mitochondrial membrane depolarization was significantly higher and mitochondrial density was lower in untreated diabetic I/R hearts than treated groups (p<0.001). IPostC in combination with vildagliptin prevented the mitochondrial membrane depolarization and increased the mitochondrial content more potent than IPostC alone in diabetic hearts. Conclusion: Combination of vildagliptin and IPostC in diabetic hearts was a well-working strategy to reduce myocardial I/R damages by restoring mitochondrial membrane potential and ROS production and modulating the autophagic activity in I/R hearts.

• Publication year

  2018

• Venue

  Advanced Pharmaceutical Bulletin

• Publication date

  2018-06-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.15171/apb.2018.037PMID 30023334PMCID 6046419
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Treatment groups lowered the LC3B-II/LC3B-I ratio and mitochondrial reactive oxygen species, and the vildagliptin plus ischemic postconditioning combination preserved mitochondrial membrane potential and mitochondrial content better than ischemic postconditioning alone.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• Vildagliptin pre-treatment, alone or together with ischemic postconditioning, decreased p62 expression, while ischemic postconditioning alone did not significantly change p62.

  Confidence 0.96

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• Combining vildagliptin with ischemic postconditioning reduced infarct size in type-II diabetic rats with myocardial ischemia/reperfusion injury, whereas either intervention alone did not significantly do so.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review

• autophagic activity

  cellular process, pathway

  The cellular autophagy process evaluated through western blot markers in myocardial tissue.

  Aliases: autophagy markers, autophagy

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• infarct size

  outcome, measurement

  The measured extent of necrotic myocardial tissue after ischemia/reperfusion.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• ischemic postconditioning

  intervention, cardioprotective procedure

  A reperfusion-phase intervention applied immediately at the onset of reperfusion after coronary ischemia.

  Aliases: IPostC

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• lc3b-ii/lc3b-i ratio

  biomarker, ratio

  A western blot autophagy marker derived from the relative abundance of lipidated LC3B-II and LC3B-I.

  Aliases: LC3B-II, LC3BII/LC3BI

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• mitochondrial content

  measurement, mitochondrial function

  The abundance or density of mitochondria in the left ventricular tissue samples.

  Aliases: mitochondrial density

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• mitochondrial membrane potential

  measurement, mitochondrial function

  The electrochemical gradient across the inner mitochondrial membrane used here to assess mitochondrial integrity.

  Aliases: mitochondrial membrane depolarization

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• mitochondrial reactive oxygen species

  measurement, biomarker

  Reactive oxygen species generated by mitochondria and measured as part of mitochondrial function assessment.

  Aliases: mitochondrial ROS

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• myocardial ischemia/reperfusion injury

  condition, injury

  Cardiac tissue damage caused by temporary coronary artery occlusion followed by reperfusion.

  Aliases: myocardial I/R injury, I/R injury

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• p62

  protein, biomarker

  An autophagy-related adaptor protein whose expression was measured by western blotting in heart tissue.

  Aliases: p62 expression

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• type-ii diabetic rats

  animal model, model organism

  Rats made diabetic by high-fat diet and low-dose streptozotocin and then used for myocardial ischemia/reperfusion experiments.

  Aliases: diabetic rats

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• vildagliptin

  drug, treatment

  An oral dipeptidyl peptidase-4 inhibitor used as the pre-treatment drug in the diabetic rat model.

  Aliases: Vilda

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review

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