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Division of Cardiology, Johns Hopkins University, Baltimore, Maryland
Submitted 5 June 2003 ; accepted in final form 3 December 2004
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ABSTRACT |
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Ito; IK1, IK; action potential; heart failure
Functional downregulation of K currents is a recurring theme in hypertrophied and failing ventricular myocardium. However, the specific changes in K current expression differ depending on the species and the model of heart failure (4). A reduction in the density of the transient outward current (Ito) is the most consistent ionic current change in cardiac hypertrophy and failure, but downregulation of the inward rectifying potassium current (IK1) (5, 24) and the two components of the delayed rectifier potassium current (IK), IKr and IKs (46), have also been described.
The molecular basis of the differences in K current density in the failing heart is not clear but is likely to be multifactorial. In an effort to better understand the fundamental mechanisms of K current downregulation in the failing heart, we studied the ionic currents in ventricular myocytes isolated from control rabbits and those with pacing-induced heart failure. We correlated K current densities with mRNA and immunoreactive protein levels encoding the major K channel subunits expressed in the rabbit ventricle. Similar to previous reports (46), we found a reduction in Ito (encoded by Kv4.3, Kv4.2, and KChIP2), IK (encoded by Erg, KvLQT1, and minK), and IK1 (encoded by Kir2.1) densities in cells isolated from failing compared with control hearts. The reduction in Ito density observed was associated with a decrease in Kv4.2, KChIP2, and Kv4.3 long splice variant but not total immunoreactive protein. The decreased functional expression of IK1 was associated with a significant change in the level of the Kir2.1 mRNA without a significant change in the total immunoreactive protein. On the other hand, the decreased functional expression of IK was not associated with a significant change in KvLQT1, minK, and Erg mRNA or KvLQT1 and minK immunoreactive protein.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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75 mmHg. The hearts were removed from the perfusion apparatus, and the atria, the right ventricle, and the papillary muscles were trimmed away. In a subset of control hearts (N = 10), the subendocardial and subepicardial layers (<1 mm thick) of the left ventricle were isolated, and the rest of the left ventricular wall is referred to as the midmyocardial layer, although this was the most heterogeneous preparation containing cells from all layers of the heart. All three layers were minced and incubated in a shaking 37°C bath for another 10 min in collagenase-containing solution. Cells were then filtered through a nylon mesh and stored at room temperature in the Krebs buffer containing 1 mmol/l Ca2+ for up to 7 h. Only Ca2+-tolerant, rod-shaped cells with clear cross striations and without spontaneous contractions or granulations were selected for experiments. Electrophysiological recordings. All electrophysiological recordings were performed in myocytes from the midmyocardial layer of the left ventricular free wall unless otherwise is indicated.
The external solution for AP measurements contained (in mmol/l) 138 NaCl, 4 KCl, 2 CaCl2, 1 MgCl2, 10 glucose, 0.33 NaH2PO4, and 10 HEPES (pH 7.4 with NaOH). For the recording of Ito only, 0.3 mmol/l CdCl2 was added to the bath solution. The pipette solution for recording APs and Ito contained (in mmol/l) 140 KCl, 5 NaCl, 1 MgCl2, 10 HEPES, 2 EGTA, and 4 Mg-ATP; pH 7.4.
The external solution for IK recordings contained (in mmol/l) 140 N-methyl-D-glucamine, 5.4 KCl, 0.1 CaCl2, 1 MgCl2, 0.5 CdCl2, 10 glucose, and 10 HEPES (pH 7.4 with NaOH). The pipette solution for IK1 and IK recordings contained (in mmol/l) 120 potassium glutamate, 10 KCl, 2 MgCl2, 10 HEPES, 5 EGTA, 2 Mg-ATP, and QX314 5; pH 7.4. IK1 was blocked by superfusion with 2 mmol/l BaCl2.
Whole cell currents were recorded using an Axopatch 200A amplifier (Axon Instruments). Cell capacitance was calculated by integrating the area under an uncompensated capacity transient elicited by a 10-mV depolarizing pulse from a holding potential of –80 mV. Whole cell currents were low-pass filtered at 1 kHz and digitized at 5 kHz via a Digidata 1200 A/D (Axon Instruments) interface for off-line analysis. The data were analyzed using custom-written software.
APs were recorded at a rate of 0.5 Hz at 37°C; steady-state typically developed after five cardiac cycles. In all protocols AP data represent at least 10 cardiac cycles under steady-state conditions. A square-wave current pulse of 2 ms duration at 50% above the threshold was used to elicit action potentials.
IK1 and Ito were studied at room temperature. IK1 was elicited from a holding potential of –20 mV by voltage steps of 500 ms from –150 mV to +50 mV in 10-mV increments every 6 s. This protocol was repeated in the presence of 2 mmol/l BaCl2, and IK1 is given as the Ba-sensitive current. Ito was elicited from a holding potential of –80 mV by voltage steps of 500 ms from –40 mV to +80 mV in 10-mV increments every 6 s. Standard pulse protocols were used to assay the biophysical properties of Ito. The protocols designed to elucidate the impact of variations in Ito on the AP were performed exclusively in cells from control hearts. In these hearts, cells were isolated from the subendocardial, midmyocardial, and the subepicardial layers of the left ventricle.
IK was studied at 37°C and was elicited from a holding potential of –50 mV by voltage steps of 3 s from –40 mV to +80 mV in 10-mV increments of 10 s.
mRNA analysis. The steady-state levels of mRNA reflect the balance between transcription and degradation and were measured by either ribonuclease protection assay (RPA) or kinetic real-time PCR (RT-PCR) using left ventricular apical myocardium.
Preparation of cRNA probes. The DNA fragments used to generate rabbit-specific riboprobes were amplified from reverse-transcribed total rabbit ventricular RNA using the PCR. The PCR products were cloned into pCR2.1 (Invitrogen) and, if necessary, subcloned into the EcoRI site of pSP70 (Promega). The region spanning the forward and reverse primers was cloned into pBS SK–, and the probe was transcribed using the T3 promoter. All constructs were confirmed by DNA sequencing (310 Genetic Analyzer, Perkin-Elmer). The Na+ channel template was designed to protect a fragment in the I-II linker of the Na+ channel unique to the cardiac isoform, so that this is a myocyte-specific probe. The rabbit cardiac Na+ channel (Nav1.5) probe spans nucleotides 1655 to 1801 (146 bp) and is shown in Table 2.
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Steady-state mRNA levels were quantified by exposing the gels on a storage phosphor screen, then scanning on a phosphoimager (Molecular Dynamics); quantification of the transcript levels was performed using ImageQuant software (Molecular Dynamics). The level of mRNA expression is given by the relative density of the protected fragment normalized to the density of the control-protected fragment, the rabbit cardiac Na channel (Nav1.5), thereby normalizing for both RNA loading and the fraction of the sample that is derived from cardiac myocytes. This value was normalized to a reference sample to permit comparison among protection assays.
Real-time PCR. Fluorescence-based kinetic real-time PCR was performed using a Perkin-Elmer Applied Biosystems model 7900 sequence-detection system. Total RNA was isolated from the rabbit ventricle using the Qiagen RNeasy kit with on-column DNase digestion. The 5' nuclease activity of Taq DNA polymerase cleaves the probe, and a fluorescent signal is generated that is proportional to the amount of starting target template. Each reporter signal is then divided by the fluorescence of an internal reference dye (ROX) to normalize for non-PCR-related fluorescence and to the 18S RNA level. All primers and probes were synthesized by Applied Biosystems (Foster City, CA) and are shown in Table 1. The rabbit KChIP2 sequence was obtained by PCR amplification using the following primer pair: (5'-TTGTCGGTGATTCTTCGGGGAA-3') and (5'-CTAGATGACATTGTCAAAGAGC-3').
The level of gene expression was normalized to a reference sample to permit comparison among samples.
Protein analysis. Western analysis blots were performed on tissue lysates from rapidly frozen ventricular tissue, as previously described (33). Proteins were separated on nongradient gels between 7.5 and 15% acrylamide, depending on the specific channel subunit to be measured. The same protein sample from a control heart was run on every gel and used as a reference for normalization across gels, and expression of the housekeeping gene GAPDH was used to verify uniform protein loading and transfer.
Commercially available and custom-made primary antibodies to K channel subunits were used. Antibodies to Kv4.3 (AB5194; human) and Kv4.2 (AB5360; rat) were purchased from Chemicon (Temecula, CA), and the anti-Kv1.4 antibody (APC007; rat) was from Alomone. Anti-ERG antibodies from both Chemicon (AB5908) and Alomone (APC062) exhibited high background and lack of specificity for ERG in the rabbit ventricle and heterologously expressed human ether-a-go-go gene (HERG). A custom-made antibody was generated that recognizes the long splice variant of Kv4.3 (human) by using the 19-amino acid insert in this variant (27). The polyclonal antibody to KChIP2S/T (human) was raised to an epitope SYDQLTDSVDDE that spans the splice excision site in KChIP2 and is present in KChIP2S and 2T (13). The polyclonal antibody to KChIP2 has been previously described (2, 13). The anti-KvLQT1 antibody (human) was generated by immunization of rabbits with conjugated peptides with the sequence DPPEERRLDHFSVDGYDSSVRK. Custom-made antibodies to Kir2.1 directed against the epitope LHGDLDASKESKAC (AA109-122), which is 100% homologous among the rabbit, dog, and human, were generated in the chicken (Covance Research Products; Dublin, PA). Affinity-purified IgY from egg yolks was used as the primary antibody and anti-chicken IgY as the secondary antibody (Affinity Bioreagents; Golden, CO) in Kir2.1 Western blot analyses.
Chemiluminescent detection was performed by using hyperfilm-ECL (Amersham Life Science) after incubation with an anti-IgG horseradish peroxidase secondary antibody. The exposed film was digitally scanned, and band densities were quantified using ImageQuant software (Molecular Dynamics). The amount of immunoreactive protein was quantified as the density of all specific bands normalized to GAPDH for protein loading. This ratio was normalized by the density of the same reference sample run on every gel to facilitate comparisons across gels. The variability of the signal from the duplicate determinations was mandated to be <15%.
Statistical analysis. Pooled data are presented as means ± SD or SE. Statistical comparisons were made using an unpaired t-test. Linear regressions were compared by an analysis of covariance. A P value <0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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APD and K current densities in control and failing myocardium. Representative AP recordings in ventricular myocytes isolated from the midmyocardial layer of control and failing hearts are shown in Figure 1A. Whereas the resting membrane potential was unchanged (data not shown), the AP duration (APD) is longer in the myocyte isolated from the failing heart compared with that isolated from the control heart. The APD at 90% repolarization (APD90) was significantly longer in cells isolated from failing ventricles compared with control ventricles (Fig. 1B; 17 cells isolated from 12 control and 12 cells from 5 failing ventricles; control 394 ± 114 vs. failing 539 ± 162 ms, P < 0.05).
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60% in cells isolated from failing hearts compared with normal hearts (Fig. 3, A–C). The reduction of Ito density was not a consequence of altered Ito voltage dependence or kinetics. The voltage dependencies of activation and steady-state inactivation (Fig. 3D) were unchanged as were the kinetics of current decay (Fig. 3E) in cells isolated from failing hearts compared with cells from control hearts. Apparent differences in current density may, in principal, result from changes in the recovery from inactivation. The recovery of Ito in cells from both control and failing ventricles were best fit by a biexponential function (Fig. 3F). Neither the time constants nor the fraction of the more slowly recovering current component were different in cells isolated from control and failing hearts. Thus the decrease in Ito density is best explained by a decreased number of functional channels in the membrane (24).
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Figure 6A shows that a representative RPA for the Kir2 family of channel genes Kir2.1, but not Kir2.2 or Kir2.3, was detected in the rabbit ventricle while all three isoforms were present in brain. When normalized to the mRNA level for cardiac Na channel (Nav1.5), there is a significant decrease in steady-state levels of Kir2.1 mRNA in the failing ventricle compared with the control rabbit ventricle (Fig. 6B).
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Protein expression in control and failing hearts. We measured the steady-state levels of immunoreactive proteins in tissues isolated from the same hearts in which current recordings and mRNA measurements were made to gain insight into the underlying mechanism of K current downregulation in the failing heart. Figure 7 shows representative Western blot analyses together with summary data for each channel subunit. The specificity of the bands for each of the channel subunits was determined by competition with the peptide epitope and/or the absence of reactivity with preimmune serum.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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60%, IK1 by 50% (at voltages negative to EK), and IK by 35%. Our Ito data are in agreement with several previous reports in human (5, 51), canine (24, 28), and rabbit (41, 46) left ventricular myocytes. Several notable exceptions are studies of compensated hypertrophy, which were associated with either no change (8, 47) or an increase in Ito density (29). The variance in detail regarding basal current densities and changes in heart failure may be due to differences in specific models or regions of the left ventricle from which the myocytes were isolated.
The molecular mechanism of Ito downregulation in structural heart disease is likely to be multifactorial. It has been argued that divergent gene products may underlie Ito in different regions of the heart (e.g., Kv4 vs. Kv1.4). In rabbit atria (50) Kv1.4 plays a prominent role in the formation of Ito; however, our data are consistent with the preponderance of evidence that supports the hypothesis that the Kv4 family of genes are the major contributors to the formation of Ito in the mammalian ventricle (15–17, 22). Intriguingly, Kv1.4 mRNA has been found in the ventricle in a number of species and even increases in abundance in heart failure (7). Indeed, Kv1.4 (KCNA4) mRNA and protein are expressed in the rabbit ventricle, but the level of protein is unchanged in the failing heart, similar to studies in human heart failure (23). Moreover, the biophysical features of Ito in cells isolated from normal or failing hearts do not suggest a role for Kv1.4 in rabbit ventricular Ito (36).
The specific Kv4 family member that underlies Ito may differ depending on the species. In humans and dogs it appears that Kv4.3 (KCND3) exclusively is the pore-forming subunit (16). In the rat, both Kv4.2 (KCND2) and Kv4.3 are expressed, and it is the transmural expression of Kv4.2 that appears to vary (15). It has been argued that KChIP2 is the key determinant of Ito density across the wall of the mammalian heart and indeed a steep mRNA gradient exists (13, 39). The role of KChIP2 in controlling the regional density of Ito in the ventricle is uncertain. Our data suggest that alterations in the expression of Kv4.2, and to a lesser extent KChIP2, underlie the downregulation of Ito in the failing rabbit ventricle (Figs. 6 and 7). Both the long and short splice variant of Kv4.3 (27) are expressed in the rabbit ventricle; the significance of the dramatic reduction in the immunoreactive long splice variant is uncertain.
IK1 density has been reported to increase (26), decrease (8), or remain unchanged (1, 9, 42, 48) in the hypertrophied heart. Similar inconsistencies have been observed in pacing tachycardia models: reduced IK1 density has been seen in the dog (24), whereas unchanged current density was found in the rabbit (37, 41, 46). In human heart failure, reduced IK1 density was associated with no change in the steady-state level of Kir2.1 mRNA in failing hearts compared with control hearts (23). We found no significant expression of Kir2.2 and Kir2.3 mRNA (Fig. 6A) in the rabbit ventricle similar to results in the canine heart (32). In contrast to the human studies, we found that the decreased IK1 density is associated with a modest but significant reduction in the level of the Kir2.1 mRNA without a significant change at the protein level.
Studies of the delayed rectifier K currents in hypertrophic and failing hearts are more limited, and measurements of mRNA and protein levels of the IK subunits are scarce. Myocytes from hypertrophied cat (18, 19) and dog (47) ventricles exhibit a reduction in the density of one or both of the components of IK, whereas other studies of cells isolated from pressure-overload guinea pig (1, 42) or spontaneously hypertensive rat (8) ventricles demonstrate no change in IK. In the rabbit tachycardia pacing-induced heart failure model (46), both IKr and IKs were significantly smaller than those in control hearts, whereas in the analogous canine model IKs was significantly reduced (28) without a significant change in the voltage dependence or kinetics of the currents. The decreased functional expression of IK in this study was not associated with a significant change in KvLQT1, minK and Erg mRNA, or KvLQT1 and minK immunoreactive protein, similar to our previous studies of HERG in human HF (23), but distinct from another report of a decrease in KvLQT1 mRNA in failing human hearts compared with control human hearts (11). In contrast, in the chronic atrioventricular block-induced hypertrophy model in the dog, minK but not KvLQT1 mRNA was decreased, whereas both immunoreactive minK and KvLQT1 were significantly downregulated in the hypertrophied ventricle (38).
In summary, Ito, IK1, and IK are functionally downregulated in the failing rabbit ventricle, and the molecular basis of the current reduction varies for each of the currents. These data, in the context of the findings in other models of cardiac hypertrophy and failure, highlight the complexity of ion channel regulation in structural heart disease. The reduction in mRNA levels of Kv4.2 and KChIP2 may result from a change in the balance between transcription and mRNA degradation that suggests the possibility of transcriptional regulation of the subunits encoding Ito in the failing heart, but the precise molecular mechanism is unknown. In the case of the other K channel subunits, steady-state levels of mRNA are not altered, yet the level of immunoreactive protein may change (Kv4.3L) and current density may change without a significant change in mRNA or immunoreactive protein levels of the relevant subunits (IK1, IK). The complexity of electrical remodeling in the failing heart is further exaggerated by other mechanisms of posttranslational modulation of channel function. Such mechanisms include altered subcellular localization of channel proteins, modified subunit interactions such as has been observed between KCNE2 and KCNE3 and KvLQT1 (43, 45), and altered neurohumoral signaling, for example, the effect of 
-adrenergic stimulation on IKs (31, 49). The diversity of mechanisms that are associated with alterations the electrophysiology in the failing heart suggest that ion channels are downstream effectors of a number of interacting signaling pathways.
Mechanisms of AP prolongation. The reduction in K current densities differentially contributes to the APD prolongation in pacing-induced heart failure in the rabbit. The outward component of IK1 at voltages positive to the reversal for potassium (Fig. 3C) contributes to phase 3 repolarization. Therefore, a reduction of IK1 density should prolong the terminal phases of the AP. The density of the IK is significantly reduced in cells isolated from failing ventricular myocardium, suggesting an important role for delayed rectifier currents in controlling ventricular repolarization (1, 42). Although direct data are limited, mutations in IK-encoding genes in the long QT syndrome (25) and the effects of drugs with class III antiarrhythmic action are compelling evidence for the importance of IKr and IKs in ventricular repolarization in the human heart.
In contrast, Ito is brief and there are no specific inhibitors of this current; thus its role in setting the APD in larger animals and humans remains controversial. Most of the studies examining Ito in heart failure have used Ca2+-buffered internal solutions, thus distorting any possible role of calcium-dependent processes. Under these conditions, several lines of evidence suggest that Ito can significantly influence the overall APD (5, 21, 24, 40). Nevertheless, it is not clear whether this conclusion would also apply under more physiological conditions. Indeed, simulations employing the canine left ventricular myocyte model suggest that at physiological densities Ito has little effect on the APD. It is only when the current density is increased to levels that mimic those observed in rodents that the current significantly shortens the APD (3, 20). Thus Ito may play a different role in repolarization of the rabbit ventricular myocyte compared with other species such as the dog and human.
In this and other models of heart failure, reduced Ito density is associated with prolongation of the APD (5, 24 and Fig. 5B). The correlation between Ito density and APD does not imply causality; indeed the correlation coefficient of the regression line in Fig. 5B is only 0.64, indicating that other factors are involved in the regulation of the APD in this model. For example, by setting the plateau potential, Ito affects many downstream membrane currents like L-type Ca current (20), delayed rectifier currents, and the Na+/Ca2+ exchanger current.
Limitations of the study. A significant limitation of this study is that the comparison of currents, transcripts, and proteins are by their nature correlative and do not prove participation of subunits in the generation of a given current. Indeed, although we cannot state with certainty that any change in a channel subunit is the proximate cause of the alteration in a given ionic current, it is possible that a change in some other regulatory molecule, that we did not measure, produced the change in current. However, an important first step in understanding the molecular basis of remodeling in heart failure is the characterization of the changes in channel subunit mRNA and protein that are known to underlie specific ionic currents.
The intracellular Ca2+ concentration was buffered in the present study by EGTA to reproduce the experimental conditions of previous studies (5, 24) thus altering several membrane currents. Buffering intracellular Ca2+ will impact the crosstalk that occurs between cell surface membrane currents and intracellular Ca2+ homeostatic mechanisms (33, 53). Calcium-induced inactivation of the L-type calcium channel is attenuated, slowing the current decay. The calcium-dependent transient outward chloride current (Ito2), if present, is probably completely blocked and the Na+/Ca2+ exchange current is reduced (6).
The cells used in this study were all obtained from the left ventricular free wall, whereas the tissues used for mRNA and protein measurements were from the apex of the heart. We cannot exclude regional differences in mRNA, protein, and current expression in heart failure. In addition, we chose to confine our current measurements to cells isolated from a single transmural section of the left ventricle to avoid the confounding influence of baseline differences in current density that have been described in normal hearts (3, 10, 47). This highlights a general limitation of studies in which electrophysiological measurements are made on isolated myocytes from one region of the heart and molecular biological and protein chemical studies are done on another region.
The absence of a change in the level of immunoreactive protein on a Western blot analysis does not exclude the possibility of a different subcellular distribution of the channel proteins with an alteration in the expression of surface membrane expression. Because of limitations in the amount tissue available for analysis in any given animal, we chose not to perform the Western blot analyses on membrane fractions.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
* J. Rose and A. A. Armoundas contributed equally to this work. 
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, N = 4 rabbits, n = 8 cells) compared with cells isolated from control myocardium (
, N = 4, n = 9). D: outward component of IK1 tends to decrease, but the difference between cells isolated from control and failing hearts did not reach statistical significance. Data are means ± SE. *P < 0.05 vs. control.
) between cells from control (
, N = 5 rabbits, n = 36 cells) compared with cells isolated from control myocardium (
, N = 6, n = 38). Data are means ± SE. *P < 0.05 vs. control.
