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

Abstract

Objective: 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. Methods: 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. Results: 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 b 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 β-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. Conclusion: 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.

Larger transient outward K+ current and shorter action potential duration in Gα11 mutant mice

“…*p<0.05, **p<0.01, ***p<0.001 While the differences in Kv4.2 expression and in I to,f are in the same range, the difference in KChIP2 is approximately four times larger than the differences in I to,f and Kv4.2 expression. An increased ratio of KChIP2-to-Kv4.2 expression as observed in this study can be associated with a prolongation of the inactivation time constant and an acceleration of the recovery of I to,f [8], both of which are not observed in gna11 −/− mice. An explanation for this finding may be that at a certain ratio of KChIP2 to Kv4.2, the increase in inactivation time constant as well as the decrease in recovery time constant reach plateaus and become nearly independent of the ratio of KChIP2 to Kv4.2 [8].…”

“…An increased ratio of KChIP2-to-Kv4.2 expression as observed in this study can be associated with a prolongation of the inactivation time constant and an acceleration of the recovery of I to,f [8], both of which are not observed in gna11 −/− mice. An explanation for this finding may be that at a certain ratio of KChIP2 to Kv4.2, the increase in inactivation time constant as well as the decrease in recovery time constant reach plateaus and become nearly independent of the ratio of KChIP2 to Kv4.2 [8]. This probably is also the case in the gna11 −/− mice, where the doubled KChIP2b expression is without effect on the time constants.…”

Evaluation of remodeling in left and right ventricular myocytes from heterozygous (mRen2)27 transgenic rats

“…Neither the mRNA levels nor the protein levels of Kv4.2 and Kv1.4 were significantly modified both in left and right ventricles of TGR compared to CTR (results not shown). The unaffected Kv4.2 mRNA levels in TGR27 is in contrast to the decrease reported in SHR left ventricle (Goltz et al 2007). Depending of the cardiac hypertrophy model used, the Kv1.4 mRNA levels were found either not modified or decreased.…”

“…Moreover, I to kinetic parameters are not modified in endocardial and epicardial ventricular myocytes of TGR27 in contrast with the decrease observed (significant only in epicardial myocytes) in SHR (Goltz et al 2007). Taken together, the results argue for a possible different etiology of the cardiac remodeling in these two rat models (Goltz et al 2007). …”

“…The density was decreased but no significant change of kinetic parameters was noted. The decrease in I to density observed in TGR27 endocardial myocytes is in contrast with the absence of modification in SHR (Goltz et al 2007). Moreover, I to kinetic parameters are not modified in endocardial and epicardial ventricular myocytes of TGR27 in contrast with the decrease observed (significant only in epicardial myocytes) in SHR (Goltz et al 2007).…”