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Troglitazone administration limits infarct size by reduced phosphorylation of canine myocardial connexin43 proteins
Tsung-Ming Lee1, Tsai-Fwu Chou
1Department of Internal Medicine, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan. tsungm.lee@msa.hinet.net
Abstract:
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.
Insights
Troglitazone, an antioxidant, reduced infarct size in a canine model of acute myocardial infarction. This cardioprotective effect was linked to decreased phosphorylation of connexin43 protein.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Cellular Biology
Background:
- Troglitazone, a thiazolidinedione, exhibits antioxidant properties by scavenging reactive oxygen species.
- Reactive oxygen species can modulate the expression and phosphorylation of connexin43.
- Connexin43 plays a role in cellular communication and responses to ischemia-reperfusion injury.
Purpose of the Study:
- To investigate the cardioprotective effects of troglitazone in a canine model of acute myocardial infarction.
- To determine if troglitazone's cardioprotection is associated with altered connexin43 expression at the infarct border zone.
- To evaluate the impact of troglitazone on reactive oxygen species levels during myocardial ischemia-reperfusion.
Main Methods:
- Canine model of acute myocardial infarction induced by coronary artery occlusion.
- Intravenous administration of vehicle or troglitazone (1, 5, 50 mg/kg) prior to occlusion.
- Assessment of infarct size, superoxide anion levels (lucigenin-derived chemiluminescence), and connexin43 phosphorylation (Western blot, confocal microscopy).
Main Results:
- Troglitazone administration significantly reduced infarct size compared to vehicle control.
- A dose-dependent reduction in infarct size was observed, with the high-dose group showing significantly smaller infarcts than the low-dose group.
- Troglitazone inhibited the elevation of superoxide anions during reperfusion and enhanced the dephosphorylation of connexin43 at the infarct border zone.
- Infarct size positively correlated with the expression of phosphorylated connexin43.
Conclusions:
- Troglitazone demonstrates significant cardioprotective effects in acute myocardial infarction.
- The antioxidant properties of troglitazone contribute to its cardioprotection.
- Reduced phosphorylation of myocardial connexin43 is associated with the cardioprotective mechanism of troglitazone.
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