title: Neonatal exendin-4 leads to protection from reperfusion injury and reduced rates of oxidative phosphorylation in the adult rat heart.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Suzanne B
authors.initials: SB
authors.lastname: Brown
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Libonati
authors.forename: Mary A
authors.initials: MA
authors.lastname: Selak
authors.forename: Richard P
authors.initials: RP
authors.lastname: Shannon
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Simmons
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000077270:Exenatide; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D018384:Oxidative Stress / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010455:Peptides; D017392:Thiobarbituric Acid Reactive Substances; D014688:Venoms; D000077270:Exenatide; D013482:Superoxide Dismutase; D002118:Calcium