Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca2+-activated K+ (SK) channels are involved in the pathogenesis of ventricular arrhythmias in heart failure. This study aimed to test the hypothesis that SK channel activity is increased via the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway in hypertensive cardiac hypertrophy. Normotensive Wistar-Kyoto rats (WKYs) and spontaneous hypertensive rats (SHRs) were used. Whole cell membrane currents were recorded in isolated ventricular myocytes by the patch-clamp method, and the apamin-sensitive K+ current (IKAS), inhibited by apamin (100 nM), an SK channel blocker, was evaluated. The IKAS at 40 mV was present in SHRs, whereas it was hardly detectable in WKYs (0.579±0.046 pA/pF vs. 0.022±0.062 pA/pF, both n=6, p<0.05). IKAS was almost completely abolished by 1 μM of KN-93, a CaMKII inhibitor, in SHRs. Optical recordings of the left ventricular anterior wall action potentials revealed that apamin prolonged the late phase of repolarization only in SHRs. A Western blot analysis of the SK channel protein isoforms demonstrated that SK2 was significantly increased in SHRs compared to WKYs (SK2/GAPDH 0.66±0.07 vs. 0.40±0.02, both n=6, p<0.05), whereas SK1 and SK3 did not differ between the groups. In addition, autophosphorylated CaMKII was significantly increased in SHRs (pCaMKII/GAPDH 0.80±0.06 vs. 0.58±0.06, both n=6, p<0.05) despite a comparable total amount of CaMKII between the groups. In conclusion, SK channels are upregulated via the enhanced activation of CaMKII in cardiac hypertrophy in SHRs.
- SK channel
- cardiac hypertrophy
- Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology