Troglitazone administration limits infarct size by reduced phosphorylation of canine myocardial connexin43 proteins

Abstract

Lee , Tsung-Ming, and Tsai-Fwu Chou. Troglitazone administration limits infarct size by reduced phosphorylation of canine myocardial connexin43 proteins. Am J Physiol Heart Circ Physiol 285: H1650-H1659, 2003 10.1152 10. / ajpheart.00407.2002 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 ϭ 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 Ϯ 7% vs. 23 Ϯ 10% of the risk region in the low-dose group, P ϭ 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 ϭ 0.73, P Ͻ 0.0001). This result demonstrated that the cardioprotective effect of troglitazone as an antioxidant may be associated with reduced phosphorylation of myocardial connexin43 protein.

Pioglitazone attenuates myocardial ischemia-reperfusion injury via up-regulation of ERK and COX-2

“…In addition to the apoptotic component of cell death contributing to the extension of infarct size during reperfusion, Zhao et al (18) demonstrated that pharmacologic inhibition of the reperfusion-induced apoptotic component of cell death also resulted in improved contractile function of ischemic canine hearts. In healthy, diabetic, or obese animals, PPARγ agonists reduced the size of myocardial infarcts (19). These effects are associated with increased uptake of glucose and improved sensitivity to insulin.…”

Role of Pleiotropic Properties of Peroxisome Proliferator‐Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection

“…Other mechanisms through which PPARs have been shown to inhibit NF-jΒ signaling include decreased protein kinase activation such as ERK1/2, JNK, Akt, and GSK3b [68, 118,119] and regulation of the expression of the inhibitor IjBa [120,121]. In addition, activated PPARb/d has been shown to release the co-repressor Bcl-6 to exert its antiinflammatory actions [122,123]. However, it is not clear yet whether this mechanism is relevant for the anti-inflammatory effects of PPARs in cardiac myocytes.…”

PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty

“…In normal or insulin-resistant rodents, treatment with PPAR-␥ activators improved contractile recovery and/or reduced infarct size after ischemia and reperfusion (140)(141)(142)(143)(144)(145)(146)(147)(148)(149). Intravenous troglitazone reduced myocardial infarct size in dogs ( 150 ). Chronic, oral troglitazone suppressed infl ammatory responses and improved postischemic contractile function in pigs ( 151 ), but the protective effects of troglitazone may have been due to its ␣ -tocopherol moiety rather than PPAR-␥ activation, as treatment with equimolar by guest, on www.jlr.org Downloaded from cardiovascular outcomes ( 92,187 ).…”

“…In vivo studies indicate a potential for TZD drugs to infl uence cardiac arrhythmias. In dogs, troglitazone promotes dephosphorylation of connexin 43, a gap junction protein, in response to ischemia and reperfusion ( 150 ), an effect with possible pro-arrhythmic consequences. In pigs, acute treatment with troglitazone, rosiglitazone, or pioglitazone, resulting in clinically relevant plasma concentrations, blocks cardiac ATP-sensitive potassium (K ATP ) channels, promotes ischemic ventricular fi brillation, and impairs the success of defi brillation ( 24,26 ).…”