Nuclear Factor κB Downregulates the Transient Outward Potassium Current
            <i>I</i>
            <sub>to,f</sub>
            Through Control of KChIP2 Expression

Panama, Brian K.; Latour-Villamil, Desiree; Farman, Gerrie P.; Zhao, Dong; Bolz, Steffen‐Sebastian; Kirshenbaum, Lorrie A.; Backx, Peter H.

doi:10.1161/circresaha.110.229112

Cited by 58 publications

(55 citation statements)

References 33 publications

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“…Recent studies (10,22) have shown that MAPK and NF-B are involved in the downregulation of KChIP2 gene expression in the hypertrophied myocardium. However, data on membrane capacitance (Table 1) and data on cross-sectional areas of the myocyte (data not shown) indicate that there was no significant myocyte hypertrophy in either the Endo or Epi of OLETF rats at 25-30 wk of age.…”

Section: Discussionmentioning

confidence: 99%

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

Sato

Kobayashi

Kuno

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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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...

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Section: Discussionmentioning

confidence: 99%

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

Sato

Kobayashi

Kuno

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…133 Tbx3, expressed in the proximal region of the VCS, is also known to repress Cx40 and Cx43. 134 Furthermore, K V 4.2 encoding I to,f is regulated by several cardiac TF, such as Gata4-Fog2, 10 NF-kb, 135 and calcineurin-Nfat pathway. 12,136 In particular, it is notable that mice lacking Nfatc3 exhibit an identical phenotype to Irx5 KO mice with loss of I to,f transmural gradient in the heart without a change in Irx5 expression.…”

Section: Discussionmentioning

confidence: 99%

Iroquois Homeodomain Transcription Factors in Heart Development and Function

Kim

Rosén²,

Bruneau³

et al. 2012

Circulation Research

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Numerous cardiac transcription factors play overlapping roles in both the specification and proliferation of the cardiac tissues and chambers during heart development. It has become increasingly apparent that cardiac transcription factors also play critical roles in the regulation of expression of many functional genes in the prenatal and postnatal hearts. Accordingly, mutations of cardiac transcription factors cannot only result in congenital heart defects but also alter heart function thereby predisposing to heart disease and cardiac arrhythmias. In this review, we summarize the roles of Iroquois homeobox (Irx) family of transcription factors in heart development and function. In all, 6 Irx genes are expressed with distinct and overlapping patterns in the mammalian heart. Studies in several animal models demonstrate that Irx genes are important for the establishment of ventricular chamber properties, the ventricular conduction system, as well as heterogeneity of the ventricular repolarization Key Words: Iroquois homeobox Ⅲ cardiac transcription factor Ⅲ cardiac development T he heart is the first functional organ formed in the mammalian embryo in order to provide the necessary nutrients for growth and development. 1 Throughout life, the contraction sequence of the heart in each beat is orchestrated by well-defined electric activation patterns designed to enable efficient mechanical pumping of blood. Electric impulses begin in the auto-rhythmic cells of the sinoatrial node and propagate to the atria, thereby initiating contraction and blood propulsion into the relaxed and compliant ventricles. The electric impulses then proceed with highly controlled delay to the ventricles via the specialized ventricular conduction system (VCS), comprising sequentially the atrioventricular node, His bundles, left and right bundle branches, and Purkinje fiber network. Electrical stimulation of the VCS ultimately results in highly ordered ventricular contractions proceeding from the apex toward the base as well as from the endomyocardium to epimyocardium, 2,3 thus enabling efficient blood ejection into the systemic and pulmonary circulations. The ventricles then repolarize and relax in reverse order from epimyocardium to endomyocardium and from the base toward the apex.Efficient heart function requires the precise and harmonious union of structure and function, which is achieved by precisely controlled patterns of gene expression within different cardiac regions at developmental stages. For example, in the early embryo, cardiac transcription factors (TFs) such as Nkx2-5, 4 Gata, 5 Hand, 6 Nfat, 7 and the T-box family members 8 regulate many key aspects of heart development, including cardiac chamber septation, valve formation, and outflow tract morphogenesis. Consequently, mutations in these TFs are directly associated with several congenital heart diseases. 9 On the other hand, some of these same genes control expression of key functional genes regulating contractile and electric properties of the mature heart. 10 -13...

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“…Studies in experimental models indicate that the downregulation of I to expression in heart failure may be mediated by the Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) and calcineurin/nuclear factor of activated T-cells signaling cascades (157,228 CURRENT. Changes in L-type Ca 2ϩ current (I Ca-L ) density in diseased ventricles are variable, depending on the type of disease and its severity.…”

Section: Role Of Cardiac Dynamics In the Generation Of Ventricular Armentioning

confidence: 99%

Mechanisms of ventricular arrhythmias: a dynamical systems-based perspective

Cherry

Fenton

Gilmour

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Cherry EM, Fenton FH, Gilmour RF Jr. Mechanisms of ventricular arrhythmias: a dynamical systems-based perspective. Am J Physiol Heart Circ Physiol 302: H2451-H2463, 2012. First published March 30, 2012 doi:10.1152/ajpheart.00770.2011Defining the cellular electrophysiological mechanisms for ventricular tachyarrhythmias is difficult, given the wide array of potential mechanisms, ranging from abnormal automaticity to various types of reentry and kk activity. The degree of difficulty is increased further by the fact that any particular mechanism may be influenced by the evolving ionic and anatomic environments associated with many forms of heart disease. Consequently, static measures of a single electrophysiological characteristic are unlikely to be useful in establishing mechanisms. Rather, the dynamics of the electrophysiological triggers and substrates that predispose to arrhythmia development need to be considered. Moreover, the dynamics need to be considered in the context of a system, one that displays certain predictable behaviors, but also one that may contain seemingly stochastic elements. It also is essential to recognize that even the predictable behaviors of this complex nonlinear system are subject to small changes in the state of the system at any given time. Here we briefly review some of the short-, medium-, and long-term alterations of the electrophysiological substrate that accompany myocardial disease and their potential impact on the initiation and maintenance of ventricular arrhythmias. We also provide examples of cases in which small changes in the electrophysiological substrate can result in rather large differences in arrhythmia outcome. These results suggest that an interrogation of cardiac electrical dynamics is required to provide a meaningful assessment of the immediate risk for arrhythmia development and for evaluating the effects of putative antiarrhythmic interventions.alternans; dynamics; spiral waves; ventricle THIS REVIEW ARTICLE is part of a collection on Electrophysiology and Excitation-Contraction Coupling. Other articles appearing in this collection, as well as a full archive of all Review collections, can be found online at http://ajpheart. physiology.org/.

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Nuclear Factor κB Downregulates the Transient Outward Potassium Current I _to,f Through Control of KChIP2 Expression

Cited by 58 publications

References 33 publications

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

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

Iroquois Homeodomain Transcription Factors in Heart Development and Function

Mechanisms of ventricular arrhythmias: a dynamical systems-based perspective

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Nuclear Factor κB Downregulates the Transient Outward Potassium Current I to,f Through Control of KChIP2 Expression

Cited by 58 publications

References 33 publications

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

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

Iroquois Homeodomain Transcription Factors in Heart Development and Function

Mechanisms of ventricular arrhythmias: a dynamical systems-based perspective

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Product

Resources

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Nuclear Factor κB Downregulates the Transient Outward Potassium Current I _to,f Through Control of KChIP2 Expression

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

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