Type 2 diabetes induces subendocardium-predominant reduction in transient outward K⁺ current with downregulation of Kv4.2 and KChIP2

Abstract

In the present study, we examined if and how cardiac ion channels are modified by type 2 diabetes mellitus (T2DM). Subendocardial (Endo) myocytes and subepicardial (Epi) myocytes were isolated from left ventricles of Otsuka-Long-Evans-Tokushima Fatty rats (OLETF) rats, a rat model of T2DM, and Otsuka-Long-Evans-Tokushima (LETO) rats (nondiabetic control rats). Endo and Epi myocytes were used for whole cell patch-clamp recordings and for protein and mRNA analyses. Action potential durations in Endo and Epi myocytes were longer in OLETF rats than in LETO rats, and the difference was larger in Endo myocytes. Steady-state transient outward K ϩ current (Ito) density was reduced in Endo but not Epi myocytes of OLETF rats compared with LETO rats, although the contribution of the fast component of Ito recovery from inactivation was smaller in both Endo and Epi myocytes of OLETF rats than in LETO rats. Kv4.2 protein was reduced only in Endo myocytes in OLETF rats, although voltage-gated K ϩ channel-interacting protein 2 (KChIP2) protein levels in both Endo and Epi myocytes were lower in OLETF rats than in LETO rats. Corresponding regional differences in mRNA levels of KChIP2 and Kv4.2 were observed between OLETF and LETO rats. mRNA levels of Iroquois homeobox 5 in Endo myocytes were 53% higher in OLETF rats than in LETO rats. Densities of inward rectifier K ϩ current and L-type Ca 2ϩ current and mRNA levels of Kv4.3 and Kv1.4 were similar in OLETF and LETO rats. In conclusion, T2DM induces Endo-predominant prolongation of the action potential duration via a reduction of the fast component of (18). Diabetes is one of the diseases underlying heart failure with preserved left ventricular (LV) ejection fraction (2), and the prognosis of heart failure has been shown to be substantially worsened by diabetes. A number of studies in the past two decades have disclosed abnormalities in the microcirculation, mitochondria, and metabolism in diabetic hearts, as recently reviewed elsewhere (18). However, knowledge of electrical remodeling in the heart by type 2 DM (T2DM) is very limited. Most of the earlier studies used models of type 1 DM (T1DM; i.e., streptozotocin-induced and alloxan-induced diabetes) and showed that the action potential (AP) duration (APD) was prolonged and that the transient outward K ϩ current (I to ), L-type Ca 2ϩ current (I Ca,L ), and inward rectifier K ϩ current (I K1 ) were reduced in T1DM (31,38,45). However, it remains unclear whether T2DM induces the same electrical remodeling as that induced by T1DM. Hyperglycemia is a common feature in all animal models of diabetes, but plasma levels of insulin and lipids are different in T1DM and T2DM and also in models of T2DM (28,44). In addition, characteristics of LV pressurevolume relationship are different in T1DM and T2DM (25), indicating a possible difference in modifications of excitationcontraction coupling between the two types of DM.In the present study, we aimed to characterize the influence of T2DM on APD and ion currents in cardiomyocytes. We used Ots...

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

“…In agreement with previous findings with other experimental models of diabetes,43, 44, 45, 46, 47, 48 outward Kv currents and I CaL were significantly reduced in STZ myocytes (Figure 8A through 8D and Figure S7). These alterations may respectively promote and oppose prolongation of AP duration.…”

“…Alterations of the spatial heterogeneity of ion channel expression and AP duration have been previously reported in rodent models of diabetes,45, 56, 57 which are consistent, at least in part, with our observation of a preferential prolongation of duration of MAPs in the epicardial/apical region of STZ hearts. The altered regional properties of cardiac tissue may have affected locally the refractoriness of the myocardium, negatively interfering with electrical conduction and pattern of impulse propagation.…”

“…Reductions of the K + channel subunit, Kv4.2, interacting protein KChIP2, and Ca 2+ channel α‐1C subunit have been proposed as molecular substrates for the decreased Kv currents and I CaL in myocytes from rodent models of diabetes 43, 45, 46, 47, 57, 59. Our electrophysiological data support the possibility that similar alterations occur in the STZ‐hyperglycemic mouse model employed here.…”

Targeting caveolin-3 for the treatment of diabetic cardiomyopathy

“…A recent study of a mouse model of T2DM has also shown heterogeneity in ion channel remodelling across the heart wall and also linked the reduction of the potassium current amplitude with the down-regulation of K v 4.2 and its accessory -subunit KChIP2 (Sato, et al, 2014). KChIP2…”

Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

“…Previous studies have shown that the differential expression of both KChIP2 and Kv4.2 proteins across the ventricular wall may determine the transmural I to gradient in mouse, rat, canine, and human hearts323334. In a rat model of type 2 diabetes, Sato et al 34. found an ENDO-predominant prolongation of the APD via a reduction of steady-state I to induced by type 2 diabetes, in which downregulation of Kv4.2 and KChIP2 proteins may be involved.…”