title: Effect of pioglitazone on the abrogated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart.
abstract: OBJECTIVE
  The signaling pathways upstream of glycogen synthase kinase-3β (GSK-3β) get reduced during ischemic preconditioning (IPC) in hyperlipidemic rat heart. Pioglitazone, an insulin sensitizer, exerts cardioprotection through GSK-3β. The objective of the study is to investigate the role of pioglitazone on the attenuated cardioprotective effect of IPC in hyperlipidemic rat heart.
  
  
  METHODS
  The rats were administered high-fat diet for 8 weeks to induce experimental hyperlipidemia (HL). After mounting on a Langendorff apparatus, isolated perfused hearts were given four cycles of IPC; each consists of 5 min of both ischemia and reperfusion followed by 30 min of ischemia and 120 min of reperfusion. Insulin (50 mU/ml) was perfused alone and in combination with pioglitazone (2 μM), while in other groups, this combination was repeated with wortmannin (100 nM), a selective PI3K inhibitor and rapamycin (1 nM), a selective mammalian target of rapamycin (mTOR) inhibitor, separately, and in combination. Myocardial injury was assessed by measuring infarct size and the levels of creatinine kinase-myocardial band (CK-MB) and lactate dehydrogenase (LDH) in the coronary effluent.
  
  
  RESULTS
  IPC significantly decreased the infarct size and levels of LDH and CK-MB in normal but not in HL rat heart. Perfusion of insulin along with pioglitazone significantly reduced the infarct size and release of CK-MB and LDH in IPC-treated HL rat hearts. Perfusion of wortmannin or rapamycin alone significantly and in combination almost completely abolished the pioglitazone-induced restored cardioprotection (P < 0.05).
  
  
  CONCLUSIONS
  Cardioprotective effect of IPC gets lost in hyperlipidemic rat heart. The results suggest that perfusion of pioglitazone restored the cardioprotective effect of IPC in hyperlipidemic rat heart, an effect that may be via PI3K and mTOR.
authors.affiliation: Department of Pharmacology, I.S.F. College of Pharmacy, Moga, Punjab, India.
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Mittal
authors.affiliation: Department of Pharmacy, BITS, Pilani, Rajasthan, India.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Taliyan
authors.affiliation: Department of Pharmacology, I.S.F. College of Pharmacy, Moga, Punjab, India.
authors.forename: P L
authors.initials: PL
authors.lastname: Sharma
authors.affiliation: Department of Pharmacology AIIMS, New Delhi, India.
authors.forename: Harlokesh Narayan
authors.initials: HN
authors.lastname: Yadav
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D005260:Female; D006321:Heart / Q000187:drug effects*; D006949:Hyperlipidemias / Q000097:blood*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D019194:Ischemic Preconditioning; D008297:Male; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D014280:Triglycerides; D002784:Cholesterol; D000077205:Pioglitazone
keywords: Creatinine kinase; glycogen synthase kinase-3β; ischemia-reperfusion; lactate dehydrogenase; myocardial injury; pioglitazone; rapamycin; wortmannin