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Neonatal Exendin-4 Leads to Protection from Reperfusion Injury and Reduced Rates of Oxidative Phosphorylation in the Adult Rat Heart

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Abstract

Purpose

Glucagon like peptide-1 (7-36) amide (GLP-1) is an incretin hormone with multiple salutary cardiovascular effects. A short course of the GLP-1 analogue Exendin-4 (Ex-4) in the neonatal period prevents the development of mitochondrial dysfunction and oxidative stress in a rat prone to obesity and diabetes. We sought to evaluate whether neonatal Ex-4 can exert the same effect in the normal rat heart, as well as whether Ex-4 could affect susceptibility to cardiac reperfusion injury.

Methods

After birth, Sprague Dawley rat pups were given either Ex-4 (1 nmole/kg body weight) or vehicle (1% BSA in 0.9% saline) subcutaneously for 6 days. Animals were studied at juvenile (4–6 weeks) and adult (8–9 months) ages. Using the Langendorff isolated perfused heart, cardiovascular function was assessed at baseline and following ischemia-reperfusion. Mitochondria were isolated from fresh heart tissue, and oxidative phosphorylation and calcium sequestration were analyzed. TBARS, MnSOD activity, and non-enzymatic anti-oxidant capacity were measured to assess the degree of oxidative stress present in the two groups.

Results

Both at the juvenile and adult age, Ex-4 treated rats demonstrated improved recovery from an ischemic insult. Rates of oxidative phosphorylation were globally reduced in adult, but not juvenile Ex-4 treated animals. Furthermore, mitochondria isolated from adult Ex-4 treated rats sequestered less calcium before undergoing the mitochondrial permeability transition. Oxidative stress did not differ between groups at any time point.

Conclusion

A short course of Exendin-4 in the neonatal period leads to protection from ischemic injury and a preconditioned mitochondrial phenotype in the adult rat.

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Acknowledgements

This work was supported by the National Institutes of Health grant #DK55704 and AG20898 (RAS), and T32 HL 007843-12 (SBB). We thank Hongshun Niu for his expert technical assistance.

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Authors and Affiliations

  1. Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Suzanne B. Brown, Richard P. Shannon & Rebecca A. Simmons

  2. Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Mary A. Selak

  3. University of Pennsylvania School of Nursing, Philadelphia, PA, USA

    Joseph R. Libonati

  4. University of Pennsylvania School of Medicine, BRB II/III, Rm. 1308, 421 Curie Blvd, Philadelphia, PA‎, 19104, USA

    Rebecca A. Simmons

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  1. Suzanne B. Brown
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  2. Joseph R. Libonati
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Correspondence to Rebecca A. Simmons.

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Brown, S.B., Libonati, J.R., Selak, M.A. et al. Neonatal Exendin-4 Leads to Protection from Reperfusion Injury and Reduced Rates of Oxidative Phosphorylation in the Adult Rat Heart. Cardiovasc Drugs Ther 24, 197–205 (2010). https://doi.org/10.1007/s10557-010-6242-z

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