Thyroid hormones suppress epsilon-PKC signalling, down-regulate connexin-43 and increase lethal arrhythmia susceptibility in non-diabetic and diabetic rat hearts.

We examined whether thyroid hormones affect myocardial e-PKC signalling, downstream target substrate, connexin-43 (Cx43) and arrhythmogenesis in non-diabetic and diabetic rats. Diabetes was induced by a single streptozotocin injection (50mg/kg, i.v.). Triiodothyronine (T 3 ) was applied by gavage (1 μg/kg of body weight for 10 days) to 4 weeks and 9 weeks diabetic and age-matched non-diabetic rats. Western blot analysis of Cx43 and e-PKC, immunofluorescence of Cx43, ultrastructure of cardiomyocytes and myocardial conduction velocity were performed. Isolated perfused heart preparation was used to test ventricular fibrillation susceptibility. T 3 significantly decreased e-PKC expression in non-diabetic and suppressed in diabetic rat heart ventricles. Decline of E-PKC signalling was associated with decrease of Cx43 phosphorylation in diabetic and to a greater extent in non-diabetic rat hearts. However, conduction velocity was significantly decreased in diabetic while enhanced due to T 3 and increased in non-diabetic T 3 -treated rat heart ventricles compared to non-treated. T 3 -induced down-regulation of Cx43 was associated with increased cardiac propensity to ventricular fibrillation. Findings indicate that activation of E-PKC signalling linked with phosphorylation of Cx43 is one of the mechanisms involved in the adaptation of the heart to hyperglycemia. Suppression of e-PKC and Cx43 phosphorylation by T 3 abolish benefit of adaptation rendering the heart prone to lethal arrhythmias.