Myocardial infarction in rat eliminates regional heterogeneity of AP profiles,I_toK⁺currents, and [Ca²⁺]_itransients

Abstract

(Ito) has been shown to vary between different regions of the normal myocardium and to be reduced in heart disease. In this study, we measured regional changes in action potential duration (APD), I to, and intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) transients of ventricular myocytes derived from the right ventricular free wall (RVW) and interventricular septum (SEP) 8 wk after myocardial infarction (MI). At ϩ40 mV, I to density in sham-operated hearts was significantly higher (P Ͻ 0.01) in the RVW (15.0 Ϯ 0.8 pA/pF, n ϭ 47) compared with the SEP (7.0 Ϯ 1.1 pA/pF, n ϭ 18). After MI, I to density was not reduced in SEP myocytes but was reduced (P Ͻ 0.01) in RVW myocytes (8.7 Ϯ 1.0 pA/pF, n ϭ 26) to levels indistinguishable from post-MI SEP myocytes. These changes in I to density correlated with Kv4.2 (but not Kv4.3) protein expression. By contrast, Kv1.4 expression was significantly higher in the RVW compared with the SEP and increased significantly after MI in RVW. APD measured at 50% or 90% repolarization was prolonged, whereas peak [Ca 2ϩ ]i transients amplitude was higher in the SEP compared with the RVW in sham myocytes. These regional differences in APD and [Ca 2ϩ ]i transients were eliminated by MI. Our results demonstrate that the significant regional differences in I to density, APD, and [Ca 2ϩ ]i between RVW and SEP are linked to a variation in Kv4.2 expression, which largely disappears after MI. right ventricle; septum; heart disease; contraction THERE ARE MARKED DIFFERENCES in the action potential duration (APD) in different regions of the mammalian ventricle (4,15,18,39,58). This electrical heterogeneity in normal myocardium correlates with regional differences in the Ca 2ϩ -independent transient outward K ϩ current density (I to ) (5,15,18,34,35,43) as well as in gene expression of K ϩ channels (8,16,58). APD prolongation and reductions in I to density occur in rat heart after left anterior descending coronary artery ligation (2, 43, 58), aortic banding (5, 22, 55), as well as after treatment with either catecholamine (11) or monocrotaline (32, 33). Depending on the model, the extent of I to density changes in disease may not be uniform throughout the ventricle (2, 5, 11, 22, 55), thereby leading to possible losses of electrical heterogeneity and increased susceptibility to arrhythmias (3).Aside from electrical heterogeneity, regional differences in other myocardial properties also exist. For example, systolic intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) is higher in the endocardium than in the epicardium (19,54), consistent with the notion that the endocardium may play a more important role in contraction compared with the epicardium. The underlying basis for the regional differences in contraction is currently unknown but may be related to a heterogeneous transmural expression of Ca 2ϩ handling proteins (26, 31). Alternatively, APD might also play a key role because the action potential profile is an important determinant of the inotropic state of the heart in both normal (7,42,54) and hy...

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

“…This mechanism (ie, Kv4.2 subunits limiting channel production) is also consistent with previous studies showing that changes in Kv4.2 are responsible for changes in I to,f and that I to,f channel production can be limited by Kv4.2 levels. [23][24][25] For example, we previously showed that Kv4.2 expression strongly correlates with I to,f different regions of the rat heart. 24 On the other hand, it was recently reported by Jin et al 25 25 which contrasts with decreases in Kv4.2 expression seen when KChIP2 increased with NF-B inhibition.…”

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

“…Previous studies have shown that transient outward K+ current (I to ) is frequently altered in cardiac disease models (40)(41)(42). Therefore, we sought to determine whether changes in I to contributed to APD shortening in Cdon −/− hearts.…”

The Role of Casein Kinase 2 in Ion Channel Remodeling After Myocardial Infarction

“…The cardiac IK1 stabilizes the resting membrane potential and is responsible for shaping the initial depolarization and final repolarization of the action potential [4,5]. Indeed, infarction generally entails significant cellular and molecular remodeling in the left ventricle, resulting in functional and biochemical alterations of the myocardium due to the modulation of IK1 [2].Therefore, focusing on a strategy to attenuate the pathogenic remodeling, such as decrease in IK1 after MI has been receiving increasing attention. Notably, a delayed rectifier potassium channel, Kir2.1, which is encoded by the KCNJ2 gene, has been studied because it has been demonstrated that Kir2.1 expression is decreased after MI [6].…”

“…The cardiac IK1 stabilizes the resting membrane potential and is responsible for shaping the initial depolarization and final repolarization of the action potential [4,5]. Indeed, infarction generally entails significant cellular and molecular remodeling in the left ventricle, resulting in functional and biochemical alterations of the myocardium due to the modulation of IK1 [2].…”

“…However, malfunctional remodeling due to pathological conditions is an ultimate disaster in disease pathogenesis, which leads to a poor outcome and high mortality [1]. Besides the cardiac enlargement of ventricular volume after myocardial infarction (MI), dysfunction due to electrophysiological remodeling such as a decrease in delayed rectifier potassium currents (IK) is a prominent feature showing reduced survival in patients with heart disease [2]. Cardiac inward rectifying potassium currents (Ik1) play an important role in shaping action potentials, which is a key character representing the electrical activity made by a multitude of various ion channels and transporters [3].…”