Diminished Kv4.2/3 but not KChIP2 levels reduce the cardiac transient outward K+ current in spontaneously hypertensive rats

Abstract

A reduction of the Ca(2+)-independent transient outward potassium current (I(to)) in epicardial but not in endocardial myocytes of the left ventricle has been observed in cardiac hypertrophy and is thought to contribute to the electrical vulnerability associated with this pathology. In the present study we investigated the molecular mechanisms underlying regional alterations in I(to) in hypertrophied hearts of spontaneously hypertensive rats (SHR) using the whole-cell patch-clamp technique, quantitative RT-PCR and heterologous expression of underlying ion channel subunits. I(to) was significantly smaller in epicardial myocytes of SHR than in Wistar-Kyoto (WKY) controls (11.1+/-0.9 pA/pF, n=20 vs. 16.8+/-1.7 pA/pF, n=20, p<0.01), but not different in endocardial myocytes from both groups. Quantitative RT-PCR analysis of the genes encoding I(to) revealed significantly lower levels of Kv4.2 and Kv4.3 mRNA in the epicardial region of SHR rats compared to WKY rats. In contrast, mRNA expression levels of all three splice variants of the beta-subunit KChIP2 were significantly higher in both endo- and epicardial myocytes from SHR than from WKY rats. In parallel, inactivation of I(to), which is negatively modulated by KChIP2, was slowed down in SHR while recovery from inactivation remained unchanged. Heterologous co-expression of increasing amounts of KChIP2b together with a fixed amount of Kv4.2 in Xenopus laevis oocytes revealed a hyperbolic relation of recovery from inactivation and inactivation time constant, demonstrating that KChIP2 preferentially affects inactivation, if its expression level is high. These results suggest that downregulation of I(to) in the left ventricle of SHR is mediated by a reduced expression of Kv4.2 and Kv4.3 (but not of KChIP2), whereas the slower inactivation of I(to) can be explained by increased expression levels of KChIP2 in SHR.