Although PPAR-gamma agonist rosiglitazone has been used to improve insulin sensitizing in type II diabetes patients, growing evidence in both basic and clinical studies indicated that it could decrease cardiac function, have proarrhythmic effect and increased cardiac mortality. However, how rosiglitazone facilitates fatal arrhythmias including ventricular fibrillation (VF) during ischemia and reperfusion (I/R) is unknown. In the present study, we tested the hypothesis that rosiglitazone facilitates VF occurrence during I/R by decreasing the level of phosphorylated connexin43.Methods
Sixteen male Wistar rats were used. In each rat, either rosiglitazone (1mg/kg) or normal saline solution was administered intravenously. Then, the left anterior descending coronary artery was ligated for 30 minutes and released to promote reperfusion for 120 minutes. Cardiac function before ischemia and during I/R was determined using the pressure-volume recording system. The level of phosphorylated connexin43 at serine368 residues, Bax and Bcl-2, and the infarct size were also determined.Results
Rosiglitazone increased both the arrhythmia score and VF incidence in I/R rats (Figure), without preventing cardiac dysfunction. The phosphorylated connexin43 level in rosiglitazone-treated hearts was markedly decreased in both ischemic and non-ischemic myocardium, compared to the vehicle-treated rats (Figure). The infarct size was also markedly decreased in rosiglitazone-treated rats. However, the Bax/Bcl-2 ratio was not different between the two groups.Conclusions
Rosiglitazone facilitated the occurrence of VF during I/R by decreasing the phosphorylation of connexin43 in the heart. This proarrhythmic effect of rosiglitazone could be responsible for increased mortality reported previously.