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Alpha-lipoic acid preconditioning plus ischemic postconditioning provides additional protection against myocardial reperfusion injury of diabetic rats: modulation of autophagy and mitochondrial function

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Abstract

Background

Investigating the interaction of diabetes with ischemic postconditioning (IPostC)-associated cardioprotection in myocardial ischemia/reperfusion (I/R) damage is of great clinical importance. The present work was designed to determine the possible synergistic effects of alpha-lipoic acid (LA) preconditioning and IPostC on myocardial I/R damage in type-II diabetic rats through modulating autophagy, and the involvement of mitochondrial function.

Methods

High-fat diet/low dose of streptozotocin-induced type-II diabetic model with duration of 12 weeks was used in this study. LA (100 mg/kg/day) was administered orally in diabetic rats for 5 weeks before I/R. Myocardial I/R was established on Langendorff apparatus through the ligation of left anterior descending coronary artery for 35 min, then reperfusion for 60 min. IPostC was carried out immediately at the beginning of the reperfusion. At the end of the experiment, myocardial infarct size (IS), autophagy markers at both gene and protein levels, and mitochondrial ROS production and membrane potential were assessed.

Results

Combined conditioning with LA and ischemia significantly decreased the IS of diabetic hearts (P < 0.05), however, single therapies had no significant effects. LA in combination with IPostC more significantly decreased LC3 and p62 mRNA levels (P < 0.01), and LC3II/LC3I and p62 protein levels (P < 0.01). Also, this combined therapy decreased mitochondrial ROS generation and membrane depolarization (P < 0.01).

Conclusions

Pretreatment with LA in diabetic rats notably restored cardioprotection by IPostC via modulating autophagy and restoring mitochondrial function. This combined conditioning might be an effective strategy to diminish I/R damage in diabetic hearts.

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Data availability

The datasets used during the present work are available from the corresponding author on reasonable request.

Abbreviations

I/R:

Ischemia/reperfusion

IHD:

Ischemic heart disease

IPostC:

Ischemic postconditioning

LA:

Alpha-lipoic acid

HOMA1-IR:

Homeostasis model assessment of insulin resistance

LC3:

Microtubule-associated proteins 1A/1B light chain 3

HFD/STZ:

High-fat diet/streptozotocin

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Acknowledgements

The authors appreciate the National Institute for Medical Research Development (NIMAD) for their supports, also the help of Dr. Nasrin Abolhasanpour in providing information about some parts of the initial draft of the manuscript.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work has been supported by a grant from National Institute for Medical Research Development, Iran (NIMAD; grant No. 957279), and direct contribution of Molecular Medicine Research Center, Tabriz University of Medical Sciences, Iran (No: 66545).

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Authors and Affiliations

  1. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Behnaz Mokhtari & Mahdi Abdoli-Shadbad

  2. Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Behnaz Mokhtari, Mahdi Abdoli-Shadbad, Alireza Alihemmati & Reza Badalzadeh

  3. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Aniseh Javadi

  4. Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Aniseh Javadi & Reza Badalzadeh

  5. Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Badalzadeh

Authors
  1. Behnaz Mokhtari
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  2. Mahdi Abdoli-Shadbad
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  3. Alireza Alihemmati
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  4. Aniseh Javadi
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  5. Reza Badalzadeh
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Contributions

BM and MA performed the experimental tests, and gathered and analyzed the data. BM wrote the manuscript. AA and AJ contributed in interpretation of the results. RB did the study design, supervised the whole project, and contributed in interpretation of the results. RB and BM critically revised the manuscript and finalized the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Reza Badalzadeh.

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Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

All experimental protocols and procedures were approved by the Institutional Animal Ethical Committee at the Faculty of Medicine of Tabriz University of Medical Sciences (Ethical code: IR.NIMAD.REC.1396.029).

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Mokhtari, B., Abdoli-Shadbad, M., Alihemmati, A. et al. Alpha-lipoic acid preconditioning plus ischemic postconditioning provides additional protection against myocardial reperfusion injury of diabetic rats: modulation of autophagy and mitochondrial function. Mol Biol Rep 49, 1773–1782 (2022). https://doi.org/10.1007/s11033-021-06987-6

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