Abstract
BackgroundIn spite of disrupted repolarization of diabetic heart, some studies report less tendency of diabetic heart to develop ventricular arrhythmias suggesting effective compensatory mechanism. We hypothesized that myocardial alterations in HCN2 and HCN4 channels occur under hyperglycaemia.MethodsDiabetes was induced in rats using a single injection of streptozotocin (STZ; 55 mg/kg body weight, i.p.). Basal ECG was measured. Expression of mRNA for HCN channels, potassium channels and microRNA 1 and 133a were measured in ventricular tissues. Protein expression of HCN2 channel isoform was assessed in five different regions of the heart by western blotting. Differentiated H9c2 cell line was used to examine HCN channels expression under hyperglycaemia in vitro.ResultsSix weeks after STZ administration, heart rate was reduced, QRS complex duration, QT interval and T-wave were prolonged in diabetic rats compared to controls. mRNA and protein expressions of HCN2 decreased exclusively in the ventricles of diabetic rats. HCN2 expression levels in atria of STZ rats and H9c2 cells treated with excess of glucose were not changed. MicroRNA levels were stable in STZ rat hearts. We found significantly decreased mRNA levels of several potassium channels participating in repolarization, namely Kcnd2 (Ito1), Kcnh2 (IKr), Kcnq1 (IKs) and Kcnj11 (IKATP).ConclusionsThis result together with downregulated HCN2 channels suggest that HCN channels might be an integral part of ventricular electric remodelling and might play a role in cardiac repolarization projected in altered arrhythmogenic profile of diabetic heart.
Highlights
In spite of disrupted repolarization of diabetic heart, some studies report less tendency of diabetic heart to develop ventricular arrhythmias suggesting effective compensatory mechanism
In healthy atrial and ventricular cardiomyocytes which do not display spontaneous activity [10], HCN channels are barely expressed when compared to their stable expression in pacemaker cells [14]..An enhanced expression of myocardial HCN channels contributes to increased pacemaker current (If) which relates to ventricular and atrial arrhythmias in failing hearts [15]
Downregulated Hcn2 and potassium currents regulating genes Interestingly, we found a downregulation of mRNA of Hcn2 channels responsible for If current exclusively in left ventricles of diabetic rats
Summary
In spite of disrupted repolarization of diabetic heart, some studies report less tendency of diabetic heart to develop ventricular arrhythmias suggesting effective compensatory mechanism. Diabetic heart exhibits pro-arrhythmogenic electrocardiographic abnormalities such as abnormal repolarization [2] mostly related. Cardiac HCN channels are of particular importance for heart rhythm. HCN channels, when overexpressed, were reported to prolong the repolarization of ventricular action potential and thereby increase the arrhythmogenic potential [14]. HCN channels are supposed to functionally antagonize K+ currents during late repolarization thanks to slow deactivation kinetics. Their upregulation in hypertrophic heart relates to prolonged QT interval and the increased arrhythmogenic potential [13]. The overexpression of myocardial HCN occurs in various conditions, including cardiac hypertrophy [17], acute myocardial infarction [18] and heart failure [15] while the reduction of myocardial HCN is rather related to atria and to impaired sinus rhythm [19, 20]
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