Troglitazone administration limits infarct size by reduced phosphorylation of canine myocardial connexin43 proteins.
Troglitazone, an antidiabetic thiazolidinedione, has been shown to have a scavenging effect on reactive oxygen species, which can modulate expression of connexin43. The study purpose was to evaluate whether troglitazone provides cardioprotection and to assess whether the cardioprotection is associated with an attenuated expression of connexin43 at the border of infarction in a canine model of acute myocardial infarction. Vehicle or troglitazone (1, 5, and 50 mg/kg; n = 14 for each group) was given intravenously 15 min before the coronary artery occlusion. Among the survivors, infarct size was significantly larger in the control than in the supplemented groups. There was a significantly lower infarct size in the high-dose group compared with that in the low-dose group (15 +/- 7% vs. 23 +/- 10% of the risk region in the low-dose group, P = 0.04). Reperfusion caused a significant elevation in superoxide anions as measured by lucigenin-derived chemiluminescence, which was significantly inhibited in animals treated with troglitazone. Connexin43 underwent dephosphorylation in response to ischemia-reperfusion measured by Western blot in control hearts at the border zone; these changes were significantly enhanced by troglitazone administration. Confocal microscopy confirmed the changes of junctional complexes. The magnitude of infarct size positively correlated with the magnitude of phosphorylated connexin43 expression assessed by Western blot analysis (r = 0.73, P < 0.0001). This result demonstrated that the cardioprotective effect of troglitazone as an antioxidant may be associated with reduced phosphorylation of myocardial connexin43 protein.
Lee
Tsung-Ming
TM
Department of Internal Medicine, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan. tsungm.lee@msa.hinet.net
Chou
Tsai-Fwu
TF
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology*; D018031:Connexin 43 / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology*; D006439:Hemodynamics; D007328:Insulin / Q000097:blood; D008297:Male; D018613:Microscopy, Confocal; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D013481:Superoxides / Q000097:blood; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D001786:Blood Glucose; D002316:Cardiotonic Agents; D002839:Chromans; D018031:Connexin 43; D016166:Free Radical Scavengers; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D013481:Superoxides; D000077288:Troglitazone