© 2001 American Heart Association, Inc.
Cellular Biology |
Independent Regulation of Cardiac Kv4.3 Potassium Channel Expression by Angiotensin II and Phenylephrine
From the Department of Pharmacology (T.-T.Z., K.T., E.S.L.) and Cardiovascular Institute (A.F.R.S., C.Z.), School of Medicine, University of Pittsburgh, Pittsburgh, Pa.
Correspondence to Edwin S. Levitan, E1351 Biomedical Science Tower, Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261. E-mail levitan{at}server.pharm.pitt.edu
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Abstract |
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Abstract—Hypertrophied cardiac myocytes exhibit prolonged action potentials and decreased transient outward potassium current (Ito). Because Kv4.3 is a major contributor to Ito, we studied regulation of its expression in neonatal rat cardiac myocytes in response to the known stimulators of cardiac myocyte hypertrophy, angiotensin II (Ang II) and phenylephrine (PE). RNase protection assays and immunoblots revealed that Ang II and PE each downregulate Kv4.3 mRNA and protein. However, although PE induces a faster and more extensive hypertrophic response than Ang II, the PE effect on Kv4.3 mRNA develops slowly and is sustained, whereas Ang II rapidly and transiently decreases Kv4.3 mRNA expression. Turnover measurements revealed that Kv4.3 mRNA is very stable, with a half-life >20 hours. This suggests that Ang II must destabilize the channel mRNA. In contrast, PE does not affect the rate of Kv4.3 mRNA degradation. To test for transcriptional regulation, the 5' flanking region of the rat Kv4.3 gene was cloned, and Kv4.3 promoter-reporter constructs were expressed in cardiac myocytes. Whereas Ang II was found to have no effect on transcription, PE inhibits Kv4.3 promoter activity. Pharmacological experiments also indicate that PE and Ang II act independently to downregulate Kv4.3 gene expression. Thus, regulation of Kv4.3 gene expression is not a simple secondary response to hypertrophy. Rather, Ang II and PE use different mechanisms to decrease Kv4.3 channel expression in neonatal rat cardiac myocytes.
Key Words: hypertrophy • gene regulation • ion channels/membrane transport • angiotensin-converting enzyme/angiotensin receptor • physiological and pathological control of gene expression
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Introduction |
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Cardiac hypertrophy is a pathological enlargement of the heart. It is initially developed as an adaptive response to heart pressure and volume overload. However, sustained hypertrophy leads to severe consequences, with increased risk of morbidity and mortality. Many studies have shown that cardiac excitability is altered in hypertrophied myocardium from experimental animals and patients with heart failure.1 The most consistent change seen in hypertrophied myocytes is a prolongation of action potential duration.2 3 4 5 6 Intensive studies on mechanisms underlying this abnormal action potential revealed that the voltage-dependent, Ca2+-independent transient outward potassium current (Ito) significantly decreases with hypertrophy produced by different conditions in various species.6 7 8 9 Because Ito is important in the early phase of membrane repolarization, changes in its density will alter the time course of the action potential. Thus, it is important to elucidate the mechanism by which pathological conditions reduce the Ito in cardiac myocytes.
Recent studies have demonstrated that Kv4-channel family genes encode a large fraction of Ito in cardiac myocytes.10 In particular, the Kv4.3 gene is abundantly expressed in the rat, canine, and human hearts.11 The Kv4.3 gene, when expressed in Xenopus oocytes, generates a channel with properties similar to the native Ito.10 12 13 Furthermore, application of Kv4.3 antisense oligonucleotide to myocytes significantly reduces Ito.14 Likewise, expression of dominant-negative Kv4 constructs suppresses Ito and prolongs action potential duration.15 16 17 Finally, recent studies showed that ventricular Kv4.3 mRNA levels decrease in hypertensive rats, as well as in failing human heart.18 19 20 Thus, the decreased expression of Kv4.3 gene is, at least in part, responsible for the reduced Ito found in hypertrophied and diseased hearts.
Although decreases in Kv4.3 mRNA have been observed in
hypertrophied myocardium, no study has examined the mechanisms
underlying this gene regulation. Therefore, we studied the hypertrophic
responses of cultured neonatal rat cardiac myocytes to angiotensin II
(Ang II) and 
1-adrenergic receptor agonist
phenylephrine (PE). These agents have been shown to increase cell size,
RNA and protein synthesis, and the expression of immediate early genes
(eg, c-fos,
c-jun, and
c-myc) and fetal genes (eg,
-skeletal actin and ß-myosin heavy chain
[ß-MHC]).21 22 23 24 25 26 27 28 29 30
In this study, we show that PE and Ang II independently downregulate
Kv4.3 mRNA and protein in cardiac myocytes. Furthermore, our results
indicate that PE inhibits transcription of the Kv4.3 gene, whereas the
effect of Ang II likely involves destabilization of channel mRNA. Thus,
2 hypertrophic stimuli use distinct mechanisms to inhibit Kv4.3
expression in neonatal rat cardiac myocytes.
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Materials and Methods |
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Culture and Treatment of Rat Neonatal Myocytes
Neonatal rat cardiac myocytes were isolated and prepared from 1-day-old Sprague-Dawley rats, as described previously.31 Cells were fed with fresh medium every other day, except for transfections (see below). Four days after plating, myocytes were subjected to the treatment with 100 µmol/L PE (Sigma, in 100 mmol/L stock solution with 100 mmol/L vitamin C), 100 nmol/L human Ang II (Calbiochem-Novabiochem, in 100 mmol/L stock solution with 50 mmol/L acetic acid), or vehicles.
RNase Protection Assays
RNase protection assays were performed as previously
described.18 Kv4.3 cDNA
template was made by inserting Kv4.3
SmaI-KpnI
fragment (58 to 777 bp from the translation start site) into
pBluescript KS (+) (Stratagene). DNA templates for GAPDH and ß-actin
were obtained from Ambion Inc. ß-MHC cDNA fragment was prepared by
reverse transcriptase–polymerase chain reaction (PCR) using primers
5'-CACCAACCTGTCCAAGTTCCG-3' (nucleotides 5680–5701) and
5'-GTGTTTCTGCCTAAGGTGCTG-3' (complementary to nucleotides 5878–5899).
The amplified fragment was subcloned into pBluescript KS (+).
-Adrenergic receptor 1B (1B) template was
generated by digesting 1B cDNA plasmid (in
pGEM 7Z, kindly provided by Drs Kunos and Chin, Virginia Commonwealth
University, Richmond, Va) with
BssHII (nucleotides
1308–2080). Protection assays for ribosomal RNA were performed with an
5-fold molar excess of 28S RNA probe. Briefly, cold and
[32P]-labeled RNA probes were prepared
with a rat 28S cDNA template (Ambion). Concentration of the prepared
RNA probes was determined spectrophotometrically using 1
A260=33 µg. Approximately 0.5 µg total 28S
RNA probe (100 bases in length) was included in the hybridization.
Under these conditions, 28S RNA signals were linear up to at least 10
µg of total RNA. Quantitation was performed with a PhosphorImager
(Molecular Dynamics). Unless specified differently, each Kv4.3 result
was normalized to ß-actin mRNA and expressed as the percentage
compared with a matched vehicle control.
Immunoblot Analysis
Cell extracts were prepared from myocytes grown on
60-mm culture dishes, as described
previously.32 Immunoblot
analysis was performed after SDS-PAGE with anti-Kv4.3 antibody (1:300,
Alomone Labs). Bound antibody was detected with secondary goat
anti-rabbit IgG-HRP conjugate (1:3000, Bio-Rad) using enhanced
chemiluminescence method (NEN Life Science). The epitope (residues
451–467 of rat or human Kv4.3) used to raise the commercial anti-Kv4.3
antibody is unique and thus should not interact with other channel
proteins. To verify specificity, epitope-tagged or native Kv4.2
channels were expressed by transient transfection in HEK 293 cells.
This led to the production of Kv4.2 protein, as measured by immunoblot
with anti-epitope or anti-Kv4.2 antibodies. Yet Kv4.2 protein from
these same samples, unlike Kv4.3 protein, was not detectable with the
anti-Kv4.3 antibody (see the online data supplement, available at
http://www.circresaha.org). Thus, the anti-Kv4.3 antibody is specific
and does not cross-react with Kv4.2.
RACE Analysis
Rapid amplification of cDNA 5' ends (5' RACE) was
performed with 5 µg total RNAs from rat brain and neonatal myocytes
using GeneRacer kit from Invitrogen. The first-strand cDNA was obtained
by reverse transcription with Kv4.3-specific primer
5'-GGTAGAAGTTGAGCACACAACGG-3' (complementary to 272 to 294 bp from the
translation start site). 5' cDNA ends of Kv4.3 were amplified using
nested PCR with primers 5'-CTTCTC-TGTGCTACCCAGCAGGG-3' and
5'-TTAGCTCATCTTGC-CGCTTGTTCTTG-3' (complementary to
190 to 212 bp and 97 to 123 bp relative to the translation start site,
respectively). PCR products were separated on an 1.2% agarose gel and
cloned into pCR4-TOPO vector. Six clones from each sample were picked
and checked with restriction enzymes. The inserts were then
sequenced.
Luciferase Assay
Primers 5'-CTGTTTCACTCAGCAATGATC-3' (146 to 166 bp 5'
to the Kv4.3 translation start site) and
5'-GGTAGAAG-TTGAGCACACAACGG-3' (complementary to 272 to 294 bp
from the translation start site) were used to screen a P1 rat genomic
library (Genome Systems). The positive Kv4.3 clones were then mapped
with various restriction digestion. Approximately 3.2 kb of
BamHI fragment was subcloned
into pBluescript KS (+) and sequenced. Various lengths of Kv4.3 DNA
fragment upstream of the coding region were subcloned into the
pGL3-basic vector (Promega). On the third day after neonatal myocytes
were prepared, cells were transfected with 5 µg of one of these
luciferase constructs and 0.5 µg control vector pRL-TK at total DNA
amount of 25 µg with salmon sperm DNA by the calcium phosphate
method, as described
previously.31 Two hours
after transfection, myocytes were rinsed and incubated in
serum-containing medium overnight and then serum-free medium.
Twenty-four hours after transfection, luciferase activities were
measured using dual-luciferase reporter assay system
(Promega).
Statistical Analysis
Unpaired 2-tail
t test was used for statistical
analysis, with P<0.05 being
considered significant. Data are presented as mean±SEM (n
3, except
where specifically mentioned).
An expanded Materials and Methods section can be found in an online data supplement available at http://www.circresaha.org.
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Results |
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We first examined hypertrophic responses produced by Ang II and PE in neonatal rat cardiac myocytes. Treatment for 48 hours with Ang II or PE caused myocyte hypertrophy. In our cultures, PE was more effective than Ang II at increasing the size of myocytes (data not shown). Similarly, Ang II and PE increased the amount of fetal gene ß-MHC mRNA (Figure 1
). Again, PE produced a faster and larger increase
in ß-MHC mRNA than Ang II. Thus, PE and, to a lesser extent, Ang II
induce typical hypertrophic responses in the neonatal cardiac myocyte
cultures used for all subsequent studies.
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Ang II and PE Decrease Kv4.3 mRNA With Distinct
Time Courses
RNase protection assays showed that Ang II and PE
decrease Kv4.3 mRNA expression
(Figures 2A and 2B). The maximum reductions produced by Ang II
and PE were 48.7±2.1% and 51.4±3.3%, respectively, when normalized
to ß-actin mRNA. These responses were not simply a result of the
normalization, because significant decreases with 8-hour Ang II or PE
treatments were also detected when signals were normalized to the
number of cells plated or to total RNA
(P<0.01). Furthermore, the
bottom panel of
Figure 2A shows that downregulation was evident when Kv4.3
mRNA was normalized to 28S ribosomal RNA (n=2). Although the 2 agonists
produced similar maximum decreases in Kv4.3 mRNA levels, the time
courses for mRNA downregulation were different. Ang II caused a rapidly
induced and then slowly recovering decrease in Kv4.3 mRNA. In contrast,
the effect of PE developed slowly and was more sustained
(Figure 2B). Thus, unlike the induction of hypertrophy, Ang
II acts more quickly than PE to regulate Kv4.3 mRNA
expression.
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Consistent with the reductions in Kv4.3 mRNA levels,
immunoblot analysis revealed that Kv4.3 channel protein was
downregulated by treatment with Ang II or PE for 48 to 72 hours (n=4,
Figure 2C
). Because previous studies on regulation of Kv
channel gene expression have found that changes in total protein are
accompanied by proportional changes in cell-surface channel
expression,33 the
downregulation of Kv4.3 channel protein in cardiac myocytes is likely
to be functionally relevant.
Ang II and PE Independently Decrease Kv4.3 Gene
Expression
Mechanical stretch induces the secretion of Ang II from
cytosolic granules of neonatal
cardiomyocytes.34 Therefore,
PE might regulate Kv4.3 gene expression by inducing autocrine release
of Ang II. To test this possibility, we used the specific
AT1 receptor blocker L158,809. Treatment with
this drug completely prevented the Ang II–induced decrease in Kv4.3
mRNA
(Figure 3A). However, the effect of PE was not altered by
cotreatment with L158,809 for 8 or 24 hours
(Figure 3B). Furthermore, cotreatment with PE and Ang II
induced a decrease in Kv4.3 mRNA that was larger than those obtained
with either agent alone
(Figure 4). Indeed, downregulation of Kv4.3 mRNA induced by
one agent was not affected by the presence of the other agent for
either 8 or 24 hours. These results, along with the kinetic differences
shown in
Figure 2, suggest that Ang II and PE independently affect
Kv4.3 gene expression.
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PE Decreases Transcription of the Kv4.3
Gene
Next we tested whether Ang II and PE affect Kv4.3 gene
transcription or mRNA stability. To determine the stability of Kv4.3
mRNA, the disappearance of Kv4.3 mRNA was measured after the inhibition
of transcription by actinomycin D. We used a known unstable
1B-adrenergic receptor mRNA as a positive
control.35 36 The
disappearance of Kv4.3 and 1B-adrenergic
receptor mRNAs at various times after the drug addition was measured
(Figure 5A). Unlike the rapid decline in
1B-adrenergic receptor mRNA, we found that
Kv4.3 mRNA is very stable (t1/2>20 hours)
(Figure 5B). This implies that the rapid decrease in Kv4.3
mRNA produced by Ang II (ie, 50% in 8 hours) must involve mRNA
destabilization. In contrast, the delayed effect of PE is consistent
with transcriptional control. To test whether PE affects Kv4.3 mRNA
degradation, myocytes were pretreated with PE for 24 hours and then
incubated with actinomycin D in the continued presence of the agonist.
Kv4.3 mRNA levels decreased at the same rate in the presence or absence
of PE
(Figure 5C). Therefore, PE does not alter Kv4.3 mRNA
stability.
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To additionally test if PE affects Kv4.3 transcription, we
examined the effect of the drug on channel promoter activity. First we
obtained genomic clones for rat Kv4.3 gene and identified the
transcriptional start sites using RNase protection assays and 5' RACE
analysis. RNase protection assays with a 688-base RNA probe
encompassing the Kv4.3 translation initiation site detected single
protected fragments (380 bp) with adult rat brain, heart, and
neonatal myocyte RNAs
(Figure 6A). Moreover, RACE analysis obtained single
amplified products with brain and neonatal myocyte RNAs
(Figure 6B). The amplified fragments were 186 and 206
bp with brain and myocyte RNAs, respectively. The sequences of these
RACE products indicate that rat Kv4.3 transcription start sites in
myocytes and brain are located at 54 and 34 bp upstream of the
translation initiation site, respectively
(Figure 6C). Because the RNA probe of the RNase protection
assay contained 326 bases of the coding region, the size of protected
fragment (380 bp) is in agreement with the transcription start site
obtained from RACE analysis. Additionally, 5' primer extension analysis
with brain RNA provided a result consistent with the transcription
start point obtained from 5' RACE and RNase protection assays.
Unfortunately, we could not obtain a significant extension product with
neonatal myocyte RNA because of the relatively low expression of Kv4.3
mRNA in these cells (data not shown). Analysis of the genomic sequence
revealed that there is no TATA or CAAT box near the Kv4.3 transcription
start site. However, potential transcription-factor binding motifs,
including GATA, AP1, and nuclear factor-
B, exist in this region
(Figure 6C).
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To study Kv4.3 gene promoter activity, various lengths of
Kv4.3 DNA fragments upstream from the coding region were inserted into
a luciferase reporter vector. These constructs were transfected into
neonatal myocytes, and luciferase activities were compared
(Figure 7A). The 2 longest fragments (2.3 and 1.1 kb)
exhibited luciferase activities lower than the basic vector itself.
Experiments with other similar-sized inserts did not reveal such
inhibition. Therefore, these fragments contain negative regulatory
elements. The 661-bp fragment induced a 3.37±0.58-fold increase in
transcriptional activity compared with the basic vector. The shortest
fragment (293 bp) had the highest (6.75±0.96-fold) stimulation of
luciferase expression. Therefore, this 293-bp region contains the basal
or minimum Kv4.3 promoter.
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To test for the effects of Ang II and PE on Kv4.3
transcriptional activity, cells transfected with a luciferase construct
containing the 293-bp fragment were treated with Ang II or PE for 7
hours
(Figure 7B). Luciferase activities of Ang II–treated and
PE-treated cells were 96.6±10.7% and 69.8±3.8% of vehicle-treated
cells, respectively. Treatment with Ang II for 3 hours or PE for 11
hours produced similar results. Thus, PE, but not Ang II, significantly
decreases luciferase activity driven by the Kv4.3 promoter region
(P<0.01). Taken together, it
seems that PE mainly affects transcription of the Kv4.3 gene, whereas
Ang II likely changes stability of channel
mRNA.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One of the most common findings in hypertrophied hearts is action potential prolongation attributable to reduced transient outward K+ current (Ito). This abnormal cellular electrical property is potentially arrhythmogenic and may accelerate the progression toward heart failure. Directly studying the mechanisms underlying action potential prolongation with hypertrophy in human heart is not experimentally feasible. Therefore, we took advantage of the facts that Kv4.3 is a known Ito subunit10 11 12 13 14 15 16 17 18 19 20 and that disease-associated changes in gene expression produced in human heart can also be produced by Ang II and PE in neonatal rat cardiac myocytes.37 38 AT1 and
1-adrenergic
receptors activated by Ang II and PE are coupled to similar downstream
signaling pathways and produce similar hypertrophic responses in
neonatal
myocytes.39 40 41 42 43 44
Therefore, we expected that Ang II and PE would have similar effects on
the expression of Kv4.3 expression. Consistent with this prediction, PE
and Ang II each act directly to downregulate Kv4.3 mRNA and protein.
Yet, surprisingly, we demonstrated that Ang II and PE use different
mechanisms to decrease Kv4.3 channel gene expression. First, although
PE is a more effective inducer of hypertrophy, Ang II downregulated
Kv4.3 mRNA more quickly. Second, an Ang II receptor antagonist blocked
the Ang II effect but did not suppress PE action. Third, the effects of
the two agents summed. Finally, PE inhibited Kv4.3 promoter activity,
whereas Ang II did not. Hence, hypertrophic stimuli activate multiple
independent mechanisms to decrease expression of Kv4.3
Ito
channels in neonatal rat cardiac myocytes. We explicitly showed that PE inhibits Kv4.3 gene transcription. Although less direct, the simplest conclusion from our data is that Ang II destabilizes Kv4.3 mRNA. No effect of Ang II on promoter activity was observed. Furthermore, it acted too quickly to be explained by transcriptional regulation. However, it should be noted that the transient kinetics of Ang II action precluded direct steady-state measurements of a change in mRNA half-life. Furthermore, the promoter activity driven by a small 5' flanking region of the Kv4.3 gene may not fully reflect its transcription in native cells. Also, directly testing for an effect of Ang II on channel gene transcription using nuclear run-on assays is extremely difficult because of the low expression of Kv4.3 gene in myocytes. Therefore, our data do not eliminate the possibility that a reduction in channel gene transcription contributes to a later phase of Ang II action. Furthermore, elucidating the mechanism of rapid Kv4.3 mRNA destabilization will require cloning of sequences required for the Ang II effect. Nevertheless, we can conclude that the action of Ang II, in contrast to PE, cannot be solely explained by a change in Kv4.3 transcription.
Although it is known that cellular excitability and ion channel expression are altered in the hypertrophied heart, the causal relationship between hypertrophy and electrical changes has been unclear. For example, it is unknown whether cardiac hypertrophy is secondary to membrane action potential prolongation. Alternatively, abnormal cellular excitability may accelerate development of hypertrophy. Previous studies showed that Kv4.2 protein level is lowered in neonatal myocytes after incubation with PE, endothelin-1, or insulin-like growth factor for 3 days.45 This could be interpreted to imply that the decrease in Kv4.2 protein is secondary to hypertrophy. However, abnormal action potential duration and decreased Kv4.3 mRNA can been seen with heart failure in the absence of cardiac hypertrophy.19 Furthermore, our results with neonatal myocytes revealed reductions in Kv4.3 mRNA within several hours, a period before the appearance of hypertrophy. In addition, we found that PE induces hypertrophic responses with a faster onset and to a larger degree than Ang II. Yet Ang II downregulated Kv4.3 mRNA much earlier than PE. Finally, the 2 hypertrophic stimuli use different mechanisms to control Kv4.3 expression. All these findings suggest that downregulation of Kv4.3 gene expression is not secondary to hypertrophy in vitro. Rather, Kv4.3 gene regulation is a part of an early response produced by conditions that can later induce neonatal rat cardiac myocyte hypertrophy.
Our studies with cultured rat neonatal myocytes pose the question of whether distinct mechanisms involved in regulation of cardiac Kv4.3 channel gene expression could differentially participate in controlling excitability under physiological and pathological conditions in adult animals and humans. On the one hand, although the baseline levels of some individual channel mRNAs change during development, mechanisms that regulate gene expression may be conserved. This seems especially likely for Kv4.3, because the mRNA level of this channel is similar in the cultures studied here and in adult rat left ventricle (K. Takimoto, unpublished data, May 2000). Furthermore, it is well established that changes in gene expression found with neonatal myocyte hypertrophy in vitro occur with cardiac hypertrophy in adult human heart.37 38 Thus, it is possible that the 2 mechanisms described here are relevant to disease states in the fully mature heart. On the other hand, it is also possible that the molecular mechanisms identified in cultured neonatal rat cardiac myocytes do not operate in nonrodent species that have a less-prominent transient outward current or at later stages of development, after channel expression and the action potential waveform have changed. At the very least, additional studies on adaptive and maladaptive changes of cell excitability with cardiac hypertrophy in humans can be guided by and compared with the hypertrophic changes in Kv4.3 gene transcription and message stability demonstrated in an experimentally accessible model system.
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL 55312 (to E.S.L.), HL 63123 (to K.T.), and R29 HL 57211 (to A.F.R.S.). This research was also supported by a grant-in-aid from American Heart Association (to A.F.R.S.) and a predoctoral fellowship from American Heart Association, Pennsylvania-Delaware Affiliate (to T.-T.Z.). E.S.L. was also supported by an Established Investigator Award from the American Heart Association.
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Footnotes |
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Original received August 16, 2000; revision received January 12, 2001; accepted January 19, 2001.
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