Abstract
Long QT syndrome (LQTS) is characterized by prolonged QT interval, leading to sudden cardiac death. Hyperglycemia is an important risk factor for LQTS, inhibiting the cardiac rapid component delayed rectifier K+ current (Iks), responsible for QT interval. We previously showed that the new ALR2 inhibitor BF-5m supplies cardioprotection from QT prolongation induced by high glucose concentration in the medium, reducing QT interval prolongation and preserving morphology. Here we investigated the effects of BF-5m on cell cytotoxicity and viability in H9c2 cells, and on cellular potassium ion channels expression.H9c2 cells were grown in medium with high glucose and high glucose plus the BF-5m by assessing the cytotoxic effects and the cell survival rate. In addition, KCNE1 and KCNQ1 expression in plasma and mitochondrial membranes were monitored. Also, the expression levels of miR-1 proved to suppress KCNQ1 and KCNE1, were analyzed.BF-5m treatment reduced the cytotoxic effects of high glucose on H9c2 cells by increasing cell survival rate and improving H9c2 morphology. Plasmatic KCNE1 and KCNQ1 expression levels were restored by BF-5m in H9c2 exposed to high glucose, down-regulating miR-1.These results suggest that BF-5m exerts cardioprotection from high glucose in rat heart ventricle H9c2 cells exposed to high glucose.
Highlights
Long QT syndrome (LQTS) is characterized by an abnormally long QT interval, caused by a decrease in repolarizing currents or an increase in depolarizing currents, with either congenital or acquired causes [1,2].It is well known that in diabetic patients the onset of QT prolongation is an important complication often associated with an increased risk of sudden cardiac death due to insurgence of lethal ventricular arrhythmias known as Torsade de Pointes or long QT syndrome [3, 4, 5]
Plasmatic KCNE1 and KCNQ1 expression levels were restored by BF-5m in H9c2 exposed to high glucose, down-regulating miR-1. These results suggest that BF-5m exerts cardioprotection from high glucose in rat heart ventricle H9c2 cells exposed to high glucose
H9c2 cells exposed to high glucose (33 mM) and pretreated with BF-5 m 0.01–0.025–0.05 μM showed a significant dose-dependently increase of cell survival compared to cells exposed to high glucose alone (BF-5m 0.01 μM P < 0.05 vs High glu; BF5m 0.025–0.05 μM P < 0.01 vs High glu), while the highest dose of BF-5m (0.1 μM) altered the amount of total cells in both glucose concentrations significantly reducing the cell viability (P < 0.01 vs Normal glu; P < 0.01 vs High glu) (Figure 1A, 1B), negatively interfering with mitochondrial succinate dehydrogenase activity
Summary
It is well known that in diabetic patients the onset of QT prolongation is an important complication often associated with an increased risk of sudden cardiac death due to insurgence of lethal ventricular arrhythmias known as Torsade de Pointes or long QT syndrome [3, 4, 5]. Hyperglycemia has been demonstrated to be one of the www.oncotarget.com most important risk factor [6, 7], and from experimental evidence it is well known that perfusing isolated hearts with high-glucose containing Krebs solution (33mM). Further findings obtained on isolated rat hearts perfused with high-glucose Krebs solution (33 mM). QT prolongation induced by the presence of a high glucose concentration into the medium [11], probably due to an interference with the potassium ion channels at the level of cardiac myocytes
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