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

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. 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. 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. 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.